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[ "Gameplay alternates among three characters: Mario and Luigi, who are controlled together on the bottom screen using A and B, and Bowser, who is controlled on the top screen with X and Y. There are two main worlds: the main overworld, which is played in an overhead view, and the world inside Bowser's body, which is a 2D side-scrolling world.", "Although most of the game is played with Mario and Luigi inside Bowser and Bowser himself in the overworld, Mario and Luigi also have opportunities to visit the overworld via warp pipes as the game progresses.", "Bowser can travel between different areas of the overworld using portals known as \"Chakroads\", which are hidden under objects that only Bowser can destroy, such as trees and boulders.", "Gameplay typically alternates between controlling the brothers and controlling Bowser.", "Some sections involve direct interaction between the brothers and Bowser.", "The battle system from the previous two games is re-used with Bowser as a playable character.", "Bowser's battles are similar to Mario and Luigi's, although Bowser specializes in punching and breathing fire.", "During Bowser's battles, he can inhale defenses and enemies from the top screen.", "Any inhaled enemies enter his body, where Mario and Luigi fight them.", "Mario, Luigi, and Bowser have their own sets of special attacks that use the touchscreen.", "Mario and Luigi can unlock abilities by finding attack pieces, while Bowser can earn new abilities by rescuing his caged minions or by finding living, kitten-like blocks called Blitties.\nCharacters have \"ranks\" that increase with their level.", "Upon reaching these milestones, that character receives a special bonus, such as an additional equipment slot, additional equipment, or being able to visit new shops.", "Mario and Luigi each have six ranks, while Bowser has four.", "The badge system from previous games has also changed; now Mario and Luigi can use certain effects by filling a meter and then touching it to activate its effect.", "The badge's effect, such as health recovery or raising stats, varies depending on the combination of badges equipped.", "There are various minigames in which the Mario Bros. have to help out Bowser's body from the inside in order to help him progress.", "Examples include the \"Arm Center\", where the brothers hit sparklike items into a muscle to strengthen Bowser's arms; the \"Leg Outpost\", where they stomp on leg muscles to strengthen Bowser's legs; and the \"Gut Check\", where they help digest food that Bowser eats.", "One location, the \"Rump Command\", has the player accumulate adrenaline in order to supersize Bowser if he is crushed, leading to a new battle system in which the DS is held vertically and all attacks require the stylus and microphone.", "The 3DS version substitutes button presses for the microphone but still incorporates the stylus for certain moves.", "The game opens with a disease called \"The Blorbs\" spreading across the Mushroom Kingdom.", "Toads that become infected with the disease inflate like a balloon and roll around uncontrollably.", "A council meeting is immediately called at Princess Peach's Castle to discuss what can be done about the epidemic.", "Starlow, a representative of the Star Sprites that watch over the Mushroom Kingdom, also attends, as do Mario and Luigi.", "At the meeting, it is discovered that all those affected had previously eaten a \"Blorb Mushroom\" given to them by a salesman, who is secretly the mad scientist Fawful.", "Bowser invades the castle, intending to kidnap Princess Peach, but is defeated by Mario and expelled from the castle, sending him flying outward.", "Bowser finds himself in Dimble Wood, where he is tricked by Fawful into eating a \"Vacuum Shroom\" that gives him the power to inhale things.", "Immediately after eating it, Bowser begins mindlessly inhaling everything in sight and goes back to the castle, where he inhales Mario, Luigi, Princess Peach, Starlow, and several Toads into his body, the process shrinking all of them to microscopic size.", "After this, Bowser passes out, and with Peach now gone and the Blorbs incapacitating the majority of the Mushroom Kingdom, Fawful proceeds to take over Peach's castle, while his assistant, the boar-like Midbus, takes over Bowser's castle.", "Navigating Bowser's body, Mario and Luigi manage to revive him, and he is revealed to have no memory of his mindless rampage; consequently, he does not know that the Mario brothers are inside his body.", "Bowser only communicates with Starlow, who nicknames herself \"Chippy\" to conceal her true identity.", "Bowser begins tracking down Fawful in an attempt to reclaim his castle with the assistance of the Mario brothers and Starlow.", "After leading Bowser into a trap, Fawful removes Peach from Bowser's body and kidnaps her, allowing him to take possession of the Dark Star, an evil and powerful entity with a seal that can only be broken by Peach.", "The Dark Star subsequently creates a barricade preventing anyone from entering Peach's Castle.", "Mario and Luigi are able to sneak out of Bowser's body together via warp pipe into Toad Town, where physician Dr. Toadley tells them they must gather the three Star Cures in order to create the Miracle Cure, a magical medicinal object that will cure the Blorbs and destroy the barricade.", "Bowser overhears this and races for the cures himself, only to be trapped in a safe by some of his minions who betrayed him to serve Fawful.", "Ultimately, the brothers collect all three star cures, and the Miracle Cure destroys the barricade, curing all victims of the Blorbs in the process.", "Bowser is freed from the safe and tracks down Fawful in Peach's transformed castle.", "After Bowser defeats Midbus, the Dark Star's seal is broken.", "Fawful starts absorbing its power until Bowser punches him away, and it enters Bowser's body, where it leeches on his cells and absorbs his DNA, allowing it to copy his abilities.", "Mario and Luigi, who have re-entered Bowser's body, engage in battle with the Dark Star, and emerge victorious, but it escapes, and uses Bowser's DNA to start to become a shadowy, powerful doppelgänger of Bowser named Dark Bowser, who seeks the power", "Fawful stole to complete the transformation.", "Fawful, meanwhile, has begun trying to locate the Dark Star to finish taking its power, but Bowser finds and defeats him.", "Soon after, however, Dark Bowser finds Fawful and inhales him, allowing it to finally complete its transformation, and it unleashes a dark storm over the Mushroom Kingdom.", "Bowser fights Dark Bowser, and inhales the Dark Star's core when it tries to get away, allowing Mario and Luigi to fight and destroy the Dark Star's core, thus destroying Dark Bowser and the Dark Star, restoring the Mushroom Kingdom to normal.", "Fawful, having been inhaled into Bowser as part of the Dark Star's core during the battle, initially feigns remorse, before suddenly self-destructing in a final effort to destroy Mario and Luigi.", "The explosion causes Bowser to regurgitate everyone that he had inhaled.", "Bowser is enraged by the discovery, and attacks Mario and Luigi.", "During the credits, the Mario Bros. battle Bowser.", "He is defeated, suffering many injuries in the process, and retreats back to his castle.", "The two castles are also rebuilt.", "In a post-credits scene, Bowser's minions return their loyalty to him and Peach sends Bowser a cake as gratitude for his unintentionally heroic efforts.", "The game was revealed at Nintendo's Tokyo Press Event, held in Japan on October 2, 2008 with the Japanese title of \"Mario & Luigi RPG 3!!!", "\".", "The conference revealed details of the then-upcoming game, relating to the plot and gameplay mechanics, as well as the fact that it would involve extensive use of the touchscreen.", "AlphaDream, developers of \"Superstar Saga\" and \"Partners in Time\", developed this game along with experienced contributors to the \"Mario\" series such as Yoko Shimomura and Charles Martinet working on music and voice acting respectively.", "At E3 2009, it was revealed that the official English name of the game would be \"Mario & Luigi: Bowser's Inside Story\" and that it would be released in fall 2009 for North America and Europe.", "\"Bowser's Inside Story\" received critical acclaim and is the second-highest rated game in the \"Mario\" role-playing games subseries (second only to \"Paper Mario\" for the Nintendo 64), with many of the praises going to the improved gameplay, storyline, humor, and Bowser's role as the focal character.", "The first North American critic to review it was the magazine \"Nintendo Power\", who scored the game a 9.5/10 saying it is \"the best RPG-style Mario adventure ever made,\" and that \"Anyone who loves the Mario characters, role-playing games, or even action games should absolutely give \"Bowser's Inside Story\" a look.\"", "IGN awarded it a 9.5 as well as an Editors Choice Award.", "GameInformer awarded the game an 8.75 out of 10 and gave it an award for \"Handheld Game of the Month\".", "GameDaily gave the game 10/10.", "\"Official Nintendo Magazine\" gave the game 92%, saying \"\"Bowser's Inside Story\" is the freshest, most vital RPG on the DS for ages\".", "GameSpot gave the game a 9.0, and awarded it with an Editors' Choice award, praising the overall plot and story.", "\"X-Play\"'s Blair Herter gave the game a 5 out of 5, highly praising the plot.", "Giant Bomb's Brad Shoemaker gave the game a 5 out of 5, and the website later named it the Best DS Game of 2009.", "\"Bowser's Inside Story\" is the top-selling game of its first week of release in Japan at 193,000 copies.", "It sold 650,000 copies during the first half of 2009 and finished out the year as the 11th best-selling game at 717,940 copies sold in the country.", "According to NPD Group, \"Bowser's Inside Story\" was the fourth best-selling game for its release month at 258,100 copies sold in the United States.", "It continued to sell well in the following months and had sold 656,700 copies in the region by the end of December 2009.", "On March 8, 2018, Nintendo revealed a Nintendo 3DS remake of the game, entitled Mario & Luigi: Bowser's Inside Story + Bowser Jr.'s Journey.", "The remake, following on from the success of the 3DS remake of \"Mario & Luigi: Superstar Saga\", features updated graphics, remastered music, quality-of-life improvements, and significant changes in gameplay, such as the reworking of special moves in combat.", "While the majority of the game was handled in-house at AlphaDream, the \"Giant Bowser\" boss fights were assisted by developer Arzest and are now presented as full 3D models.", "In addition, the game also involves a new side story entitled \"Bowser Jr.'s Journey\", which focuses on the story of Bowser Jr. during the events of \"Bowser's Inside Story\", playing similar to the \"Minion Quest\" side story found in the \"Superstar Saga\" remake.", "It was released in Japan in December 2018, with a worldwide release following in January 2019.", "Additionally, it is the final \"Mario\" game published for the Nintendo 3DS family of systems.", "In an interview with \"Game Informer\" shortly after the game's launch, AlphaDream producer Yoshihiko Maekawa and Nintendo producer Akira Otani stated that the main reason to remake \"Bowser's Inside Story\" for the 3DS instead of the Nintendo Switch was due to timing; they could easily build the game based on existing assets and, more critically, they wanted to retain the dual-screen elements of the original title such as the minigames and Giant Battles.", "The reason they skipped over a remake of \"Partners in Time\" was because they wanted to remake the best received title in the series.", "Additionally, they wanted to take the opportunity to explore the parent-child dynamics between Bowser and Bowser Jr., which manifested in \"Bowser Jr.'s Journey\".", "While critical reception was generally positive, \"Mario & Luigi: Bowser's Inside Story + Bowser Jr.'s Journey\" has had a poor launch sales record, being not only the worst-selling \"Mario & Luigi\" title in the series, but also one of the worst-selling \"Mario\" games of all time since the Virtual Boy, a stark contrast to the original release which remains the best-selling entry in the subseries.", "In Japan, it sold under 9,500 units in the first week and dropped off the top 20 charts by the second week.", "In comparison, of the time period released and another re-release of an older \"Mario\" game, \"New Super Mario Bros. U Deluxe\" has sold 381,469 units in a shorter period of time.", "Compared to other Nintendo 3DS ports of the \"Mario\" series released at a similar time frame on their first week, \"Luigi's Mansion\" and \"Captain Toad: Treasure Tracker\" sold 27,000 and 20,547 units respectively.", "\"Famitsu\"s sales tracker reported a lifetime total of 34,523 copies, making it one of the worst-selling games in the entire \"Mario\" franchise.", "The remake was nominated for the Freedom Tower Award for Best Remake at the New York Game Awards, and for \"Writing in a Comedy\" at the NAVGTR Awards." ]

[ 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 ]

[ "It is the third game in the \"Mario & Luigi\" role-playing series." ]

[ "Gameplay alternates among three characters: Mario and Luigi, who are controlled together on the bottom screen using A and B, and Bowser, who is controlled on the top screen with X and Y. There are two main worlds: the main overworld, which is played in an overhead view, and the world inside Bowser's body, which is a 2D side-scrolling world.", "Although most of the game is played with Mario and Luigi inside Bowser and Bowser himself in the overworld, Mario and Luigi also have opportunities to visit the overworld via warp pipes as the game progresses.", "Bowser can travel between different areas of the overworld using portals known as \"Chakroads\", which are hidden under objects that only Bowser can destroy, such as trees and boulders.", "Gameplay typically alternates between controlling the brothers and controlling Bowser.", "Some sections involve direct interaction between the brothers and Bowser.", "The battle system from the previous two games is re-used with Bowser as a playable character.", "Bowser's battles are similar to Mario and Luigi's, although Bowser specializes in punching and breathing fire.", "During Bowser's battles, he can inhale defenses and enemies from the top screen.", "Any inhaled enemies enter his body, where Mario and Luigi fight them.", "Mario, Luigi, and Bowser have their own sets of special attacks that use the touchscreen.", "Mario and Luigi can unlock abilities by finding attack pieces, while Bowser can earn new abilities by rescuing his caged minions or by finding living, kitten-like blocks called Blitties.\nCharacters have \"ranks\" that increase with their level.", "Upon reaching these milestones, that character receives a special bonus, such as an additional equipment slot, additional equipment, or being able to visit new shops.", "Mario and Luigi each have six ranks, while Bowser has four.", "The badge system from previous games has also changed; now Mario and Luigi can use certain effects by filling a meter and then touching it to activate its effect.", "The badge's effect, such as health recovery or raising stats, varies depending on the combination of badges equipped.", "There are various minigames in which the Mario Bros. have to help out Bowser's body from the inside in order to help him progress.", "Examples include the \"Arm Center\", where the brothers hit sparklike items into a muscle to strengthen Bowser's arms; the \"Leg Outpost\", where they stomp on leg muscles to strengthen Bowser's legs; and the \"Gut Check\", where they help digest food that Bowser eats.", "One location, the \"Rump Command\", has the player accumulate adrenaline in order to supersize Bowser if he is crushed, leading to a new battle system in which the DS is held vertically and all attacks require the stylus and microphone.", "The 3DS version substitutes button presses for the microphone but still incorporates the stylus for certain moves.", "The game opens with a disease called \"The Blorbs\" spreading across the Mushroom Kingdom.", "Toads that become infected with the disease inflate like a balloon and roll around uncontrollably.", "A council meeting is immediately called at Princess Peach's Castle to discuss what can be done about the epidemic.", "Starlow, a representative of the Star Sprites that watch over the Mushroom Kingdom, also attends, as do Mario and Luigi.", "At the meeting, it is discovered that all those affected had previously eaten a \"Blorb Mushroom\" given to them by a salesman, who is secretly the mad scientist Fawful.", "Bowser invades the castle, intending to kidnap Princess Peach, but is defeated by Mario and expelled from the castle, sending him flying outward.", "Bowser finds himself in Dimble Wood, where he is tricked by Fawful into eating a \"Vacuum Shroom\" that gives him the power to inhale things.", "Immediately after eating it, Bowser begins mindlessly inhaling everything in sight and goes back to the castle, where he inhales Mario, Luigi, Princess Peach, Starlow, and several Toads into his body, the process shrinking all of them to microscopic size.", "After this, Bowser passes out, and with Peach now gone and the Blorbs incapacitating the majority of the Mushroom Kingdom, Fawful proceeds to take over Peach's castle, while his assistant, the boar-like Midbus, takes over Bowser's castle.", "Navigating Bowser's body, Mario and Luigi manage to revive him, and he is revealed to have no memory of his mindless rampage; consequently, he does not know that the Mario brothers are inside his body.", "Bowser only communicates with Starlow, who nicknames herself \"Chippy\" to conceal her true identity.", "Bowser begins tracking down Fawful in an attempt to reclaim his castle with the assistance of the Mario brothers and Starlow.", "After leading Bowser into a trap, Fawful removes Peach from Bowser's body and kidnaps her, allowing him to take possession of the Dark Star, an evil and powerful entity with a seal that can only be broken by Peach.", "The Dark Star subsequently creates a barricade preventing anyone from entering Peach's Castle.", "Mario and Luigi are able to sneak out of Bowser's body together via warp pipe into Toad Town, where physician Dr. Toadley tells them they must gather the three Star Cures in order to create the Miracle Cure, a magical medicinal object that will cure the Blorbs and destroy the barricade.", "Bowser overhears this and races for the cures himself, only to be trapped in a safe by some of his minions who betrayed him to serve Fawful.", "Ultimately, the brothers collect all three star cures, and the Miracle Cure destroys the barricade, curing all victims of the Blorbs in the process.", "Bowser is freed from the safe and tracks down Fawful in Peach's transformed castle.", "After Bowser defeats Midbus, the Dark Star's seal is broken.", "Fawful starts absorbing its power until Bowser punches him away, and it enters Bowser's body, where it leeches on his cells and absorbs his DNA, allowing it to copy his abilities.", "Mario and Luigi, who have re-entered Bowser's body, engage in battle with the Dark Star, and emerge victorious, but it escapes, and uses Bowser's DNA to start to become a shadowy, powerful doppelgänger of Bowser named Dark Bowser, who seeks the power", "Fawful stole to complete the transformation.", "Fawful, meanwhile, has begun trying to locate the Dark Star to finish taking its power, but Bowser finds and defeats him.", "Soon after, however, Dark Bowser finds Fawful and inhales him, allowing it to finally complete its transformation, and it unleashes a dark storm over the Mushroom Kingdom.", "Bowser fights Dark Bowser, and inhales the Dark Star's core when it tries to get away, allowing Mario and Luigi to fight and destroy the Dark Star's core, thus destroying Dark Bowser and the Dark Star, restoring the Mushroom Kingdom to normal.", "Fawful, having been inhaled into Bowser as part of the Dark Star's core during the battle, initially feigns remorse, before suddenly self-destructing in a final effort to destroy Mario and Luigi.", "The explosion causes Bowser to regurgitate everyone that he had inhaled.", "Bowser is enraged by the discovery, and attacks Mario and Luigi.", "During the credits, the Mario Bros. battle Bowser.", "He is defeated, suffering many injuries in the process, and retreats back to his castle.", "The two castles are also rebuilt.", "In a post-credits scene, Bowser's minions return their loyalty to him and Peach sends Bowser a cake as gratitude for his unintentionally heroic efforts.", "The game was revealed at Nintendo's Tokyo Press Event, held in Japan on October 2, 2008 with the Japanese title of \"Mario & Luigi RPG 3!!!", "\".", "The conference revealed details of the then-upcoming game, relating to the plot and gameplay mechanics, as well as the fact that it would involve extensive use of the touchscreen.", "AlphaDream, developers of \"Superstar Saga\" and \"Partners in Time\", developed this game along with experienced contributors to the \"Mario\" series such as Yoko Shimomura and Charles Martinet working on music and voice acting respectively.", "At E3 2009, it was revealed that the official English name of the game would be \"Mario & Luigi: Bowser's Inside Story\" and that it would be released in fall 2009 for North America and Europe.", "\"Bowser's Inside Story\" received critical acclaim and is the second-highest rated game in the \"Mario\" role-playing games subseries (second only to \"Paper Mario\" for the Nintendo 64), with many of the praises going to the improved gameplay, storyline, humor, and Bowser's role as the focal character.", "The first North American critic to review it was the magazine \"Nintendo Power\", who scored the game a 9.5/10 saying it is \"the best RPG-style Mario adventure ever made,\" and that \"Anyone who loves the Mario characters, role-playing games, or even action games should absolutely give \"Bowser's Inside Story\" a look.\"", "IGN awarded it a 9.5 as well as an Editors Choice Award.", "GameInformer awarded the game an 8.75 out of 10 and gave it an award for \"Handheld Game of the Month\".", "GameDaily gave the game 10/10.", "\"Official Nintendo Magazine\" gave the game 92%, saying \"\"Bowser's Inside Story\" is the freshest, most vital RPG on the DS for ages\".", "GameSpot gave the game a 9.0, and awarded it with an Editors' Choice award, praising the overall plot and story.", "\"X-Play\"'s Blair Herter gave the game a 5 out of 5, highly praising the plot.", "Giant Bomb's Brad Shoemaker gave the game a 5 out of 5, and the website later named it the Best DS Game of 2009.", "\"Bowser's Inside Story\" is the top-selling game of its first week of release in Japan at 193,000 copies.", "It sold 650,000 copies during the first half of 2009 and finished out the year as the 11th best-selling game at 717,940 copies sold in the country.", "According to NPD Group, \"Bowser's Inside Story\" was the fourth best-selling game for its release month at 258,100 copies sold in the United States.", "It continued to sell well in the following months and had sold 656,700 copies in the region by the end of December 2009.", "On March 8, 2018, Nintendo revealed a Nintendo 3DS remake of the game, entitled Mario & Luigi: Bowser's Inside Story + Bowser Jr.'s Journey.", "The remake, following on from the success of the 3DS remake of \"Mario & Luigi: Superstar Saga\", features updated graphics, remastered music, quality-of-life improvements, and significant changes in gameplay, such as the reworking of special moves in combat.", "While the majority of the game was handled in-house at AlphaDream, the \"Giant Bowser\" boss fights were assisted by developer Arzest and are now presented as full 3D models.", "In addition, the game also involves a new side story entitled \"Bowser Jr.'s Journey\", which focuses on the story of Bowser Jr. during the events of \"Bowser's Inside Story\", playing similar to the \"Minion Quest\" side story found in the \"Superstar Saga\" remake.", "It was released in Japan in December 2018, with a worldwide release following in January 2019.", "Additionally, it is the final \"Mario\" game published for the Nintendo 3DS family of systems.", "In an interview with \"Game Informer\" shortly after the game's launch, AlphaDream producer Yoshihiko Maekawa and Nintendo producer Akira Otani stated that the main reason to remake \"Bowser's Inside Story\" for the 3DS instead of the Nintendo Switch was due to timing; they could easily build the game based on existing assets and, more critically, they wanted to retain the dual-screen elements of the original title such as the minigames and Giant Battles.", "The reason they skipped over a remake of \"Partners in Time\" was because they wanted to remake the best received title in the series.", "Additionally, they wanted to take the opportunity to explore the parent-child dynamics between Bowser and Bowser Jr., which manifested in \"Bowser Jr.'s Journey\".", "While critical reception was generally positive, \"Mario & Luigi: Bowser's Inside Story + Bowser Jr.'s Journey\" has had a poor launch sales record, being not only the worst-selling \"Mario & Luigi\" title in the series, but also one of the worst-selling \"Mario\" games of all time since the Virtual Boy, a stark contrast to the original release which remains the best-selling entry in the subseries.", "In Japan, it sold under 9,500 units in the first week and dropped off the top 20 charts by the second week.", "In comparison, of the time period released and another re-release of an older \"Mario\" game, \"New Super Mario Bros. U Deluxe\" has sold 381,469 units in a shorter period of time.", "Compared to other Nintendo 3DS ports of the \"Mario\" series released at a similar time frame on their first week, \"Luigi's Mansion\" and \"Captain Toad: Treasure Tracker\" sold 27,000 and 20,547 units respectively.", "\"Famitsu\"s sales tracker reported a lifetime total of 34,523 copies, making it one of the worst-selling games in the entire \"Mario\" franchise.", "The remake was nominated for the Freedom Tower Award for Best Remake at the New York Game Awards, and for \"Writing in a Comedy\" at the NAVGTR Awards." ]

[ 51, 52, 53, 54, 55 ]

[ "Mario & Luigi: Bowser's Inside Story is a role-playing video game, developed by AlphaDream and published by Nintendo for the Nintendo DS handheld game console in 2009.", "It is the third game in the \"Mario & Luigi\" role-playing series." ]

[ "Gameplay alternates among three characters: Mario and Luigi, who are controlled together on the bottom screen using A and B, and Bowser, who is controlled on the top screen with X and Y. There are two main worlds: the main overworld, which is played in an overhead view, and the world inside Bowser's body, which is a 2D side-scrolling world.", "Although most of the game is played with Mario and Luigi inside Bowser and Bowser himself in the overworld, Mario and Luigi also have opportunities to visit the overworld via warp pipes as the game progresses.", "Bowser can travel between different areas of the overworld using portals known as \"Chakroads\", which are hidden under objects that only Bowser can destroy, such as trees and boulders.", "Gameplay typically alternates between controlling the brothers and controlling Bowser.", "Some sections involve direct interaction between the brothers and Bowser.", "The battle system from the previous two games is re-used with Bowser as a playable character.", "Bowser's battles are similar to Mario and Luigi's, although Bowser specializes in punching and breathing fire.", "During Bowser's battles, he can inhale defenses and enemies from the top screen.", "Any inhaled enemies enter his body, where Mario and Luigi fight them.", "Mario, Luigi, and Bowser have their own sets of special attacks that use the touchscreen.", "Mario and Luigi can unlock abilities by finding attack pieces, while Bowser can earn new abilities by rescuing his caged minions or by finding living, kitten-like blocks called Blitties.\nCharacters have \"ranks\" that increase with their level.", "Upon reaching these milestones, that character receives a special bonus, such as an additional equipment slot, additional equipment, or being able to visit new shops.", "Mario and Luigi each have six ranks, while Bowser has four.", "The badge system from previous games has also changed; now Mario and Luigi can use certain effects by filling a meter and then touching it to activate its effect.", "The badge's effect, such as health recovery or raising stats, varies depending on the combination of badges equipped.", "There are various minigames in which the Mario Bros. have to help out Bowser's body from the inside in order to help him progress.", "Examples include the \"Arm Center\", where the brothers hit sparklike items into a muscle to strengthen Bowser's arms; the \"Leg Outpost\", where they stomp on leg muscles to strengthen Bowser's legs; and the \"Gut Check\", where they help digest food that Bowser eats.", "One location, the \"Rump Command\", has the player accumulate adrenaline in order to supersize Bowser if he is crushed, leading to a new battle system in which the DS is held vertically and all attacks require the stylus and microphone.", "The 3DS version substitutes button presses for the microphone but still incorporates the stylus for certain moves.", "The game opens with a disease called \"The Blorbs\" spreading across the Mushroom Kingdom.", "Toads that become infected with the disease inflate like a balloon and roll around uncontrollably.", "A council meeting is immediately called at Princess Peach's Castle to discuss what can be done about the epidemic.", "Starlow, a representative of the Star Sprites that watch over the Mushroom Kingdom, also attends, as do Mario and Luigi.", "At the meeting, it is discovered that all those affected had previously eaten a \"Blorb Mushroom\" given to them by a salesman, who is secretly the mad scientist Fawful.", "Bowser invades the castle, intending to kidnap Princess Peach, but is defeated by Mario and expelled from the castle, sending him flying outward.", "Bowser finds himself in Dimble Wood, where he is tricked by Fawful into eating a \"Vacuum Shroom\" that gives him the power to inhale things.", "Immediately after eating it, Bowser begins mindlessly inhaling everything in sight and goes back to the castle, where he inhales Mario, Luigi, Princess Peach, Starlow, and several Toads into his body, the process shrinking all of them to microscopic size.", "After this, Bowser passes out, and with Peach now gone and the Blorbs incapacitating the majority of the Mushroom Kingdom, Fawful proceeds to take over Peach's castle, while his assistant, the boar-like Midbus, takes over Bowser's castle.", "Navigating Bowser's body, Mario and Luigi manage to revive him, and he is revealed to have no memory of his mindless rampage; consequently, he does not know that the Mario brothers are inside his body.", "Bowser only communicates with Starlow, who nicknames herself \"Chippy\" to conceal her true identity.", "Bowser begins tracking down Fawful in an attempt to reclaim his castle with the assistance of the Mario brothers and Starlow.", "After leading Bowser into a trap, Fawful removes Peach from Bowser's body and kidnaps her, allowing him to take possession of the Dark Star, an evil and powerful entity with a seal that can only be broken by Peach.", "The Dark Star subsequently creates a barricade preventing anyone from entering Peach's Castle.", "Mario and Luigi are able to sneak out of Bowser's body together via warp pipe into Toad Town, where physician Dr. Toadley tells them they must gather the three Star Cures in order to create the Miracle Cure, a magical medicinal object that will cure the Blorbs and destroy the barricade.", "Bowser overhears this and races for the cures himself, only to be trapped in a safe by some of his minions who betrayed him to serve Fawful.", "Ultimately, the brothers collect all three star cures, and the Miracle Cure destroys the barricade, curing all victims of the Blorbs in the process.", "Bowser is freed from the safe and tracks down Fawful in Peach's transformed castle.", "After Bowser defeats Midbus, the Dark Star's seal is broken.", "Fawful starts absorbing its power until Bowser punches him away, and it enters Bowser's body, where it leeches on his cells and absorbs his DNA, allowing it to copy his abilities.", "Mario and Luigi, who have re-entered Bowser's body, engage in battle with the Dark Star, and emerge victorious, but it escapes, and uses Bowser's DNA to start to become a shadowy, powerful doppelgänger of Bowser named Dark Bowser, who seeks the power", "Fawful stole to complete the transformation.", "Fawful, meanwhile, has begun trying to locate the Dark Star to finish taking its power, but Bowser finds and defeats him.", "Soon after, however, Dark Bowser finds Fawful and inhales him, allowing it to finally complete its transformation, and it unleashes a dark storm over the Mushroom Kingdom.", "Bowser fights Dark Bowser, and inhales the Dark Star's core when it tries to get away, allowing Mario and Luigi to fight and destroy the Dark Star's core, thus destroying Dark Bowser and the Dark Star, restoring the Mushroom Kingdom to normal.", "Fawful, having been inhaled into Bowser as part of the Dark Star's core during the battle, initially feigns remorse, before suddenly self-destructing in a final effort to destroy Mario and Luigi.", "The explosion causes Bowser to regurgitate everyone that he had inhaled.", "Bowser is enraged by the discovery, and attacks Mario and Luigi.", "During the credits, the Mario Bros. battle Bowser.", "He is defeated, suffering many injuries in the process, and retreats back to his castle.", "The two castles are also rebuilt.", "In a post-credits scene, Bowser's minions return their loyalty to him and Peach sends Bowser a cake as gratitude for his unintentionally heroic efforts.", "The game was revealed at Nintendo's Tokyo Press Event, held in Japan on October 2, 2008 with the Japanese title of \"Mario & Luigi RPG 3!!!", "\".", "The conference revealed details of the then-upcoming game, relating to the plot and gameplay mechanics, as well as the fact that it would involve extensive use of the touchscreen.", "AlphaDream, developers of \"Superstar Saga\" and \"Partners in Time\", developed this game along with experienced contributors to the \"Mario\" series such as Yoko Shimomura and Charles Martinet working on music and voice acting respectively.", "At E3 2009, it was revealed that the official English name of the game would be \"Mario & Luigi: Bowser's Inside Story\" and that it would be released in fall 2009 for North America and Europe.", "\"Bowser's Inside Story\" received critical acclaim and is the second-highest rated game in the \"Mario\" role-playing games subseries (second only to \"Paper Mario\" for the Nintendo 64), with many of the praises going to the improved gameplay, storyline, humor, and Bowser's role as the focal character.", "The first North American critic to review it was the magazine \"Nintendo Power\", who scored the game a 9.5/10 saying it is \"the best RPG-style Mario adventure ever made,\" and that \"Anyone who loves the Mario characters, role-playing games, or even action games should absolutely give \"Bowser's Inside Story\" a look.\"", "IGN awarded it a 9.5 as well as an Editors Choice Award.", "GameInformer awarded the game an 8.75 out of 10 and gave it an award for \"Handheld Game of the Month\".", "GameDaily gave the game 10/10.", "\"Official Nintendo Magazine\" gave the game 92%, saying \"\"Bowser's Inside Story\" is the freshest, most vital RPG on the DS for ages\".", "GameSpot gave the game a 9.0, and awarded it with an Editors' Choice award, praising the overall plot and story.", "\"X-Play\"'s Blair Herter gave the game a 5 out of 5, highly praising the plot.", "Giant Bomb's Brad Shoemaker gave the game a 5 out of 5, and the website later named it the Best DS Game of 2009.", "\"Bowser's Inside Story\" is the top-selling game of its first week of release in Japan at 193,000 copies.", "It sold 650,000 copies during the first half of 2009 and finished out the year as the 11th best-selling game at 717,940 copies sold in the country.", "According to NPD Group, \"Bowser's Inside Story\" was the fourth best-selling game for its release month at 258,100 copies sold in the United States.", "It continued to sell well in the following months and had sold 656,700 copies in the region by the end of December 2009.", "On March 8, 2018, Nintendo revealed a Nintendo 3DS remake of the game, entitled Mario & Luigi: Bowser's Inside Story + Bowser Jr.'s Journey.", "The remake, following on from the success of the 3DS remake of \"Mario & Luigi: Superstar Saga\", features updated graphics, remastered music, quality-of-life improvements, and significant changes in gameplay, such as the reworking of special moves in combat.", "While the majority of the game was handled in-house at AlphaDream, the \"Giant Bowser\" boss fights were assisted by developer Arzest and are now presented as full 3D models.", "In addition, the game also involves a new side story entitled \"Bowser Jr.'s Journey\", which focuses on the story of Bowser Jr. during the events of \"Bowser's Inside Story\", playing similar to the \"Minion Quest\" side story found in the \"Superstar Saga\" remake.", "It was released in Japan in December 2018, with a worldwide release following in January 2019.", "Additionally, it is the final \"Mario\" game published for the Nintendo 3DS family of systems.", "In an interview with \"Game Informer\" shortly after the game's launch, AlphaDream producer Yoshihiko Maekawa and Nintendo producer Akira Otani stated that the main reason to remake \"Bowser's Inside Story\" for the 3DS instead of the Nintendo Switch was due to timing; they could easily build the game based on existing assets and, more critically, they wanted to retain the dual-screen elements of the original title such as the minigames and Giant Battles.", "The reason they skipped over a remake of \"Partners in Time\" was because they wanted to remake the best received title in the series.", "Additionally, they wanted to take the opportunity to explore the parent-child dynamics between Bowser and Bowser Jr., which manifested in \"Bowser Jr.'s Journey\".", "While critical reception was generally positive, \"Mario & Luigi: Bowser's Inside Story + Bowser Jr.'s Journey\" has had a poor launch sales record, being not only the worst-selling \"Mario & Luigi\" title in the series, but also one of the worst-selling \"Mario\" games of all time since the Virtual Boy, a stark contrast to the original release which remains the best-selling entry in the subseries.", "In Japan, it sold under 9,500 units in the first week and dropped off the top 20 charts by the second week.", "In comparison, of the time period released and another re-release of an older \"Mario\" game, \"New Super Mario Bros. U Deluxe\" has sold 381,469 units in a shorter period of time.", "Compared to other Nintendo 3DS ports of the \"Mario\" series released at a similar time frame on their first week, \"Luigi's Mansion\" and \"Captain Toad: Treasure Tracker\" sold 27,000 and 20,547 units respectively.", "\"Famitsu\"s sales tracker reported a lifetime total of 34,523 copies, making it one of the worst-selling games in the entire \"Mario\" franchise.", "The remake was nominated for the Freedom Tower Award for Best Remake at the New York Game Awards, and for \"Writing in a Comedy\" at the NAVGTR Awards." ]

[ 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68 ]

[ "Mario & Luigi: Bowser's Inside Story is a role-playing video game, developed by AlphaDream and published by Nintendo for the Nintendo DS handheld game console in 2009.", "It is the third game in the \"Mario & Luigi\" role-playing series.", "It is the second best-selling \"Mario\" role-playing game, with more than four million copies sold worldwide by April 2011." ]

[ "Gameplay alternates among three characters: Mario and Luigi, who are controlled together on the bottom screen using A and B, and Bowser, who is controlled on the top screen with X and Y. There are two main worlds: the main overworld, which is played in an overhead view, and the world inside Bowser's body, which is a 2D side-scrolling world.", "Although most of the game is played with Mario and Luigi inside Bowser and Bowser himself in the overworld, Mario and Luigi also have opportunities to visit the overworld via warp pipes as the game progresses.", "Bowser can travel between different areas of the overworld using portals known as \"Chakroads\", which are hidden under objects that only Bowser can destroy, such as trees and boulders.", "Gameplay typically alternates between controlling the brothers and controlling Bowser.", "Some sections involve direct interaction between the brothers and Bowser.", "The battle system from the previous two games is re-used with Bowser as a playable character.", "Bowser's battles are similar to Mario and Luigi's, although Bowser specializes in punching and breathing fire.", "During Bowser's battles, he can inhale defenses and enemies from the top screen.", "Any inhaled enemies enter his body, where Mario and Luigi fight them.", "Mario, Luigi, and Bowser have their own sets of special attacks that use the touchscreen.", "Mario and Luigi can unlock abilities by finding attack pieces, while Bowser can earn new abilities by rescuing his caged minions or by finding living, kitten-like blocks called Blitties.\nCharacters have \"ranks\" that increase with their level.", "Upon reaching these milestones, that character receives a special bonus, such as an additional equipment slot, additional equipment, or being able to visit new shops.", "Mario and Luigi each have six ranks, while Bowser has four.", "The badge system from previous games has also changed; now Mario and Luigi can use certain effects by filling a meter and then touching it to activate its effect.", "The badge's effect, such as health recovery or raising stats, varies depending on the combination of badges equipped.", "There are various minigames in which the Mario Bros. have to help out Bowser's body from the inside in order to help him progress.", "Examples include the \"Arm Center\", where the brothers hit sparklike items into a muscle to strengthen Bowser's arms; the \"Leg Outpost\", where they stomp on leg muscles to strengthen Bowser's legs; and the \"Gut Check\", where they help digest food that Bowser eats.", "One location, the \"Rump Command\", has the player accumulate adrenaline in order to supersize Bowser if he is crushed, leading to a new battle system in which the DS is held vertically and all attacks require the stylus and microphone.", "The 3DS version substitutes button presses for the microphone but still incorporates the stylus for certain moves.", "The game opens with a disease called \"The Blorbs\" spreading across the Mushroom Kingdom.", "Toads that become infected with the disease inflate like a balloon and roll around uncontrollably.", "A council meeting is immediately called at Princess Peach's Castle to discuss what can be done about the epidemic.", "Starlow, a representative of the Star Sprites that watch over the Mushroom Kingdom, also attends, as do Mario and Luigi.", "At the meeting, it is discovered that all those affected had previously eaten a \"Blorb Mushroom\" given to them by a salesman, who is secretly the mad scientist Fawful.", "Bowser invades the castle, intending to kidnap Princess Peach, but is defeated by Mario and expelled from the castle, sending him flying outward.", "Bowser finds himself in Dimble Wood, where he is tricked by Fawful into eating a \"Vacuum Shroom\" that gives him the power to inhale things.", "Immediately after eating it, Bowser begins mindlessly inhaling everything in sight and goes back to the castle, where he inhales Mario, Luigi, Princess Peach, Starlow, and several Toads into his body, the process shrinking all of them to microscopic size.", "After this, Bowser passes out, and with Peach now gone and the Blorbs incapacitating the majority of the Mushroom Kingdom, Fawful proceeds to take over Peach's castle, while his assistant, the boar-like Midbus, takes over Bowser's castle.", "Navigating Bowser's body, Mario and Luigi manage to revive him, and he is revealed to have no memory of his mindless rampage; consequently, he does not know that the Mario brothers are inside his body.", "Bowser only communicates with Starlow, who nicknames herself \"Chippy\" to conceal her true identity.", "Bowser begins tracking down Fawful in an attempt to reclaim his castle with the assistance of the Mario brothers and Starlow.", "After leading Bowser into a trap, Fawful removes Peach from Bowser's body and kidnaps her, allowing him to take possession of the Dark Star, an evil and powerful entity with a seal that can only be broken by Peach.", "The Dark Star subsequently creates a barricade preventing anyone from entering Peach's Castle.", "Mario and Luigi are able to sneak out of Bowser's body together via warp pipe into Toad Town, where physician Dr. Toadley tells them they must gather the three Star Cures in order to create the Miracle Cure, a magical medicinal object that will cure the Blorbs and destroy the barricade.", "Bowser overhears this and races for the cures himself, only to be trapped in a safe by some of his minions who betrayed him to serve Fawful.", "Ultimately, the brothers collect all three star cures, and the Miracle Cure destroys the barricade, curing all victims of the Blorbs in the process.", "Bowser is freed from the safe and tracks down Fawful in Peach's transformed castle.", "After Bowser defeats Midbus, the Dark Star's seal is broken.", "Fawful starts absorbing its power until Bowser punches him away, and it enters Bowser's body, where it leeches on his cells and absorbs his DNA, allowing it to copy his abilities.", "Mario and Luigi, who have re-entered Bowser's body, engage in battle with the Dark Star, and emerge victorious, but it escapes, and uses Bowser's DNA to start to become a shadowy, powerful doppelgänger of Bowser named Dark Bowser, who seeks the power", "Fawful stole to complete the transformation.", "Fawful, meanwhile, has begun trying to locate the Dark Star to finish taking its power, but Bowser finds and defeats him.", "Soon after, however, Dark Bowser finds Fawful and inhales him, allowing it to finally complete its transformation, and it unleashes a dark storm over the Mushroom Kingdom.", "Bowser fights Dark Bowser, and inhales the Dark Star's core when it tries to get away, allowing Mario and Luigi to fight and destroy the Dark Star's core, thus destroying Dark Bowser and the Dark Star, restoring the Mushroom Kingdom to normal.", "Fawful, having been inhaled into Bowser as part of the Dark Star's core during the battle, initially feigns remorse, before suddenly self-destructing in a final effort to destroy Mario and Luigi.", "The explosion causes Bowser to regurgitate everyone that he had inhaled.", "Bowser is enraged by the discovery, and attacks Mario and Luigi.", "During the credits, the Mario Bros. battle Bowser.", "He is defeated, suffering many injuries in the process, and retreats back to his castle.", "The two castles are also rebuilt.", "In a post-credits scene, Bowser's minions return their loyalty to him and Peach sends Bowser a cake as gratitude for his unintentionally heroic efforts.", "The game was revealed at Nintendo's Tokyo Press Event, held in Japan on October 2, 2008 with the Japanese title of \"Mario & Luigi RPG 3!!!", "\".", "The conference revealed details of the then-upcoming game, relating to the plot and gameplay mechanics, as well as the fact that it would involve extensive use of the touchscreen.", "AlphaDream, developers of \"Superstar Saga\" and \"Partners in Time\", developed this game along with experienced contributors to the \"Mario\" series such as Yoko Shimomura and Charles Martinet working on music and voice acting respectively.", "At E3 2009, it was revealed that the official English name of the game would be \"Mario & Luigi: Bowser's Inside Story\" and that it would be released in fall 2009 for North America and Europe.", "\"Bowser's Inside Story\" received critical acclaim and is the second-highest rated game in the \"Mario\" role-playing games subseries (second only to \"Paper Mario\" for the Nintendo 64), with many of the praises going to the improved gameplay, storyline, humor, and Bowser's role as the focal character.", "The first North American critic to review it was the magazine \"Nintendo Power\", who scored the game a 9.5/10 saying it is \"the best RPG-style Mario adventure ever made,\" and that \"Anyone who loves the Mario characters, role-playing games, or even action games should absolutely give \"Bowser's Inside Story\" a look.\"", "IGN awarded it a 9.5 as well as an Editors Choice Award.", "GameInformer awarded the game an 8.75 out of 10 and gave it an award for \"Handheld Game of the Month\".", "GameDaily gave the game 10/10.", "\"Official Nintendo Magazine\" gave the game 92%, saying \"\"Bowser's Inside Story\" is the freshest, most vital RPG on the DS for ages\".", "GameSpot gave the game a 9.0, and awarded it with an Editors' Choice award, praising the overall plot and story.", "\"X-Play\"'s Blair Herter gave the game a 5 out of 5, highly praising the plot.", "Giant Bomb's Brad Shoemaker gave the game a 5 out of 5, and the website later named it the Best DS Game of 2009.", "\"Bowser's Inside Story\" is the top-selling game of its first week of release in Japan at 193,000 copies.", "It sold 650,000 copies during the first half of 2009 and finished out the year as the 11th best-selling game at 717,940 copies sold in the country.", "According to NPD Group, \"Bowser's Inside Story\" was the fourth best-selling game for its release month at 258,100 copies sold in the United States.", "It continued to sell well in the following months and had sold 656,700 copies in the region by the end of December 2009.", "On March 8, 2018, Nintendo revealed a Nintendo 3DS remake of the game, entitled Mario & Luigi: Bowser's Inside Story + Bowser Jr.'s Journey.", "The remake, following on from the success of the 3DS remake of \"Mario & Luigi: Superstar Saga\", features updated graphics, remastered music, quality-of-life improvements, and significant changes in gameplay, such as the reworking of special moves in combat.", "While the majority of the game was handled in-house at AlphaDream, the \"Giant Bowser\" boss fights were assisted by developer Arzest and are now presented as full 3D models.", "In addition, the game also involves a new side story entitled \"Bowser Jr.'s Journey\", which focuses on the story of Bowser Jr. during the events of \"Bowser's Inside Story\", playing similar to the \"Minion Quest\" side story found in the \"Superstar Saga\" remake.", "It was released in Japan in December 2018, with a worldwide release following in January 2019.", "Additionally, it is the final \"Mario\" game published for the Nintendo 3DS family of systems.", "In an interview with \"Game Informer\" shortly after the game's launch, AlphaDream producer Yoshihiko Maekawa and Nintendo producer Akira Otani stated that the main reason to remake \"Bowser's Inside Story\" for the 3DS instead of the Nintendo Switch was due to timing; they could easily build the game based on existing assets and, more critically, they wanted to retain the dual-screen elements of the original title such as the minigames and Giant Battles.", "The reason they skipped over a remake of \"Partners in Time\" was because they wanted to remake the best received title in the series.", "Additionally, they wanted to take the opportunity to explore the parent-child dynamics between Bowser and Bowser Jr., which manifested in \"Bowser Jr.'s Journey\".", "While critical reception was generally positive, \"Mario & Luigi: Bowser's Inside Story + Bowser Jr.'s Journey\" has had a poor launch sales record, being not only the worst-selling \"Mario & Luigi\" title in the series, but also one of the worst-selling \"Mario\" games of all time since the Virtual Boy, a stark contrast to the original release which remains the best-selling entry in the subseries.", "In Japan, it sold under 9,500 units in the first week and dropped off the top 20 charts by the second week.", "In comparison, of the time period released and another re-release of an older \"Mario\" game, \"New Super Mario Bros. U Deluxe\" has sold 381,469 units in a shorter period of time.", "Compared to other Nintendo 3DS ports of the \"Mario\" series released at a similar time frame on their first week, \"Luigi's Mansion\" and \"Captain Toad: Treasure Tracker\" sold 27,000 and 20,547 units respectively.", "\"Famitsu\"s sales tracker reported a lifetime total of 34,523 copies, making it one of the worst-selling games in the entire \"Mario\" franchise.", "The remake was nominated for the Freedom Tower Award for Best Remake at the New York Game Awards, and for \"Writing in a Comedy\" at the NAVGTR Awards." ]

[ 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83 ]

[ "The game's plot involves Mario and Luigi being inhaled into the body of their long-time nemesis, Bowser.", "A remake for the Nintendo 3DS, titled Mario & Luigi: Bowser's Inside Story + Bowser Jr.'s Journey, was released in Japan on December 27, 2018, in North America on January 11, 2019, in Europe on January 25, 2019, and in Australia on January 26, 2019." ]

[ "At this stage, 41 clubs from the Football League Third Division North and South joined the 25 non-league clubs having come through the qualifying rounds.", "Barnsley, York City and Notts County were given a bye to the Third Round.", "To make the number of matches up, non-league Scarborough and Bromley were given byes to this round.", "34 matches were scheduled to be played on Saturday, 26 November 1938.", "Eight were drawn and went to replays in the following midweek fixture.", "The matches were played on Saturday, 10 December 1938.", "Four matches were drawn, with replays taking place in the following midweek fixture.", "One of these, Halifax Town vs. Mansfield Town, then went to two more replays before being settled.", "The 44 First and Second Division clubs entered the competition at this stage, along with Barnsley, York City and Notts County.", "The matches were scheduled for Saturday, 7 January 1939, although seven matches began at later dates.", "Eight matches were drawn and went to replays, with one of these requiring a second replay to settle the fixture.", "The matches were scheduled for Saturday, 21 January 1939.", "Five games were drawn and went to replays, of which two went to a second replay.", "The matches were scheduled for Saturday, 11 February 1939.", "There were four replays, of which two went to second replays.", "The four Sixth Round ties were scheduled to be played on Saturday, 4 March 1939.", "There was one replay, in the Huddersfield Town–Blackburn Rovers match.", "The semi-final matches were played on Saturday, 25 March 1939.", "Wolverhampton Wanderers and Portsmouth won their matches to meet in the final at Wembley.", "The 1939 FA Cup Final was contested by Portsmouth and Wolverhampton Wanderers at Wembley.", "Portsmouth won 4–1, with goals from Bert Barlow, John Anderson and two by Cliff Parker.", "Dicky Dorsett scored Wolves' effort.", "As a result of the suspension of the FA Cup for the duration of the Second World War, the next FA Cup final was not until seven years later in 1946, thereby enabling Portsmouth fans to claim that their team has held the Cup for the longest time." ]

[ 0, 1, 2, 3, 4 ]

[ "Matches were scheduled to be played at the stadium of the team named first on the date specified for each round, which was always a Saturday." ]

[ "At this stage, 41 clubs from the Football League Third Division North and South joined the 25 non-league clubs having come through the qualifying rounds.", "Barnsley, York City and Notts County were given a bye to the Third Round.", "To make the number of matches up, non-league Scarborough and Bromley were given byes to this round.", "34 matches were scheduled to be played on Saturday, 26 November 1938.", "Eight were drawn and went to replays in the following midweek fixture.", "The matches were played on Saturday, 10 December 1938.", "Four matches were drawn, with replays taking place in the following midweek fixture.", "One of these, Halifax Town vs. Mansfield Town, then went to two more replays before being settled.", "The 44 First and Second Division clubs entered the competition at this stage, along with Barnsley, York City and Notts County.", "The matches were scheduled for Saturday, 7 January 1939, although seven matches began at later dates.", "Eight matches were drawn and went to replays, with one of these requiring a second replay to settle the fixture.", "The matches were scheduled for Saturday, 21 January 1939.", "Five games were drawn and went to replays, of which two went to a second replay.", "The matches were scheduled for Saturday, 11 February 1939.", "There were four replays, of which two went to second replays.", "The four Sixth Round ties were scheduled to be played on Saturday, 4 March 1939.", "There was one replay, in the Huddersfield Town–Blackburn Rovers match.", "The semi-final matches were played on Saturday, 25 March 1939.", "Wolverhampton Wanderers and Portsmouth won their matches to meet in the final at Wembley.", "The 1939 FA Cup Final was contested by Portsmouth and Wolverhampton Wanderers at Wembley.", "Portsmouth won 4–1, with goals from Bert Barlow, John Anderson and two by Cliff Parker.", "Dicky Dorsett scored Wolves' effort.", "As a result of the suspension of the FA Cup for the duration of the Second World War, the next FA Cup final was not until seven years later in 1946, thereby enabling Portsmouth fans to claim that their team has held the Cup for the longest time." ]

[ 8, 9, 10 ]

[ "If the replayed match was drawn further replays would be held until a winner was determined." ]

[ "At this stage, 41 clubs from the Football League Third Division North and South joined the 25 non-league clubs having come through the qualifying rounds.", "Barnsley, York City and Notts County were given a bye to the Third Round.", "To make the number of matches up, non-league Scarborough and Bromley were given byes to this round.", "34 matches were scheduled to be played on Saturday, 26 November 1938.", "Eight were drawn and went to replays in the following midweek fixture.", "The matches were played on Saturday, 10 December 1938.", "Four matches were drawn, with replays taking place in the following midweek fixture.", "One of these, Halifax Town vs. Mansfield Town, then went to two more replays before being settled.", "The 44 First and Second Division clubs entered the competition at this stage, along with Barnsley, York City and Notts County.", "The matches were scheduled for Saturday, 7 January 1939, although seven matches began at later dates.", "Eight matches were drawn and went to replays, with one of these requiring a second replay to settle the fixture.", "The matches were scheduled for Saturday, 21 January 1939.", "Five games were drawn and went to replays, of which two went to a second replay.", "The matches were scheduled for Saturday, 11 February 1939.", "There were four replays, of which two went to second replays.", "The four Sixth Round ties were scheduled to be played on Saturday, 4 March 1939.", "There was one replay, in the Huddersfield Town–Blackburn Rovers match.", "The semi-final matches were played on Saturday, 25 March 1939.", "Wolverhampton Wanderers and Portsmouth won their matches to meet in the final at Wembley.", "The 1939 FA Cup Final was contested by Portsmouth and Wolverhampton Wanderers at Wembley.", "Portsmouth won 4–1, with goals from Bert Barlow, John Anderson and two by Cliff Parker.", "Dicky Dorsett scored Wolves' effort.", "As a result of the suspension of the FA Cup for the duration of the Second World War, the next FA Cup final was not until seven years later in 1946, thereby enabling Portsmouth fans to claim that their team has held the Cup for the longest time." ]

[ 17, 18 ]

[ "Portsmouth won the competition for the first time, beating Wolverhampton Wanderers 4–1 in the final at Wembley." ]

[ "At this stage, 41 clubs from the Football League Third Division North and South joined the 25 non-league clubs having come through the qualifying rounds.", "Barnsley, York City and Notts County were given a bye to the Third Round.", "To make the number of matches up, non-league Scarborough and Bromley were given byes to this round.", "34 matches were scheduled to be played on Saturday, 26 November 1938.", "Eight were drawn and went to replays in the following midweek fixture.", "The matches were played on Saturday, 10 December 1938.", "Four matches were drawn, with replays taking place in the following midweek fixture.", "One of these, Halifax Town vs. Mansfield Town, then went to two more replays before being settled.", "The 44 First and Second Division clubs entered the competition at this stage, along with Barnsley, York City and Notts County.", "The matches were scheduled for Saturday, 7 January 1939, although seven matches began at later dates.", "Eight matches were drawn and went to replays, with one of these requiring a second replay to settle the fixture.", "The matches were scheduled for Saturday, 21 January 1939.", "Five games were drawn and went to replays, of which two went to a second replay.", "The matches were scheduled for Saturday, 11 February 1939.", "There were four replays, of which two went to second replays.", "The four Sixth Round ties were scheduled to be played on Saturday, 4 March 1939.", "There was one replay, in the Huddersfield Town–Blackburn Rovers match.", "The semi-final matches were played on Saturday, 25 March 1939.", "Wolverhampton Wanderers and Portsmouth won their matches to meet in the final at Wembley.", "The 1939 FA Cup Final was contested by Portsmouth and Wolverhampton Wanderers at Wembley.", "Portsmouth won 4–1, with goals from Bert Barlow, John Anderson and two by Cliff Parker.", "Dicky Dorsett scored Wolves' effort.", "As a result of the suspension of the FA Cup for the duration of the Second World War, the next FA Cup final was not until seven years later in 1946, thereby enabling Portsmouth fans to claim that their team has held the Cup for the longest time." ]

[ 19, 20, 21, 22 ]

[ "Portsmouth won the competition for the first time, beating Wolverhampton Wanderers 4–1 in the final at Wembley.", "As this was the last full FA Cup competition before the Second World War, Portsmouth held the trophy until the end of the 1945–46 season." ]

[ "The mass collectivization drive of the late 1920s and early 1930s pushed the peasantry from individual household production into an archipelago of collective farms.", "The question of internal organization was important in the new kolkhozes.", "The most basic measure was to divide the workforce into a number of groups, generally known as brigades, for working purposes.", "`By July 1929 it was already normal practice for the large kolkhoz of 200-400 households to be divided into temporary or permanent work units of 15-30 households.'\nThe authorities gradually came down in favour of the fixed, combined brigade, that is the brigade with its personnel, land, equipment and draught horses fixed to it for the whole period of agricultural operations, and taking responsibility for all relevant tasks during that period.", "The brigade was headed by a brigade leader (\"brigadir\").", "He was usually a local man (few were women).", "The authorities resolved that each brigade was to have a fixed plot in every field of the crop rotation.", "A Communist Party resolution of 4 February 1932 said the brigade's land should be fixed for the agricultural year, but some kolkhozes found that it helped forward planning to fix it for the whole period of the crop-rotation, and this practice was formally adopted in the kolkhoz Model Statute of 1935.", "In the central Asian cotton-growing kolkhozes, each brigade might hold its land as an integral unit, its members living within this unit.", "Almost two-thirds of kolkhozes (65.1%) had two or more field brigades in 1937.", "(Presumably it was the smaller kolkhozes, in northern Russia and elsewhere, that were not divided into brigades.)", "Brigades varied in size from 200 workers in the north, north-west and parts of the non-black-earth centre, to about 100 in the Lower and Middle Volga.", "The average, in 1937, was 62 people.", "A brigade in the black-earth had about 10 hectares of land per member; thus a brigade of 50, for example, had 500 hectares.", "After the kolkhoz amalgamations of 1950 the territorial successor of the old village kolkhoz was the \"complex brigade\" (brigade of brigades), a sub-unit of the new enlarged kolkhoz." ]

[ 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 ]

[ "The brigade () was a labor force division within the Soviet collective farm (\"kolkhoz\")." ]

[ "K.S. Rama Rao saw the film and bought the remake rights for Telugu.", "Rama Rao brought Madhavi in to reprise her role from \"Akshadhoodu\" since she was also a familiar face to the Telugu audience.", "Major portions of the Telugu remake were shot in the same locations as the original film.", "In 2008, the movie was remade in Hindi as \"Tulsi\" by the same producer-director duo, but with Manisha Koirala and Irrfan Khan.", "Satyam (Nassar) is a driver and his wife Sarada (Madhavi) is a music teacher.", "They were both orphans brought up in the Seva Ashram (run by Charuhasan).", "Sarada and Satyam have four kids.", "Satyam, though good at heart, is addicted to liquor.", "Apparao (Tanikella Bharani), a toddy milk vendor, has an eye on Sarada.", "When Satyam discovers Apparao making advances on Sarada, he assaults him in front of everyone.", "Avenging the assault, Apparao kills Satyam.", "Sarada, who is diagnosed with cancer, wants her children to be brought up in a family atmosphere rather than in the Ashram and the children are adopted by different families.", "The music for this film was composed by M. M. Keeravani.", "This album featured four tracks, which were highly successful.", "The track \"Venuvai Vachanu\", sung by K. S. Chithra was a huge chart buster and won a Nandi Award for best playback singer female.", "All the lyrics are written by Veturi and he won his first National Award for best lyrics category for the track \"Raalipoyye Poova\".", "Nandi Awards - 1993" ]

[ 12, 13, 14, 15, 16 ]

[ "The film won two Nandi Awards." ]

[ "After a scoreless first half during which Antonio Cabrini fired a penalty low and wide to the right of goal, Paolo Rossi scored first, heading home a bouncing Claudio Gentile cross from the right from close range.", "Marco Tardelli then scored from the edge of the area with a low left footed shot before Alessandro Altobelli, at the end of a counterattack by winger Bruno Conti, made it 3–0 with another low left footed shot.", "Italy's lead appeared secure, encouraging Italian president Sandro Pertini to wag his finger at the cameras in a playful 'not going to catch us now' gesture from the stands.", "Paul Breitner scored for Germany in the 83rd minute, firing low past the goalkeeper from the right, but Italy held on to claim their first World Cup title in 44 years, and their third in total with a 3–1 victory.", "<section begin=Final /><section end=Final />\n<section begin=Lineups />\n</includeonly><section end=Lineups />\nMatch rules:" ]

[ 0, 1, 2, 3, 4 ]

[ "The 1982 FIFA World Cup Final was a football match contested between Italy and West Germany." ]

[ "Sean Penkywicz was born in Wigan, Greater Manchester, England.", "Beginning his career with Halifax, Penkywicz made his Super League début in 2000.", "He left Halifax and joined the Huddersfield Giants in 2004 following Halifax's relegation from the Super League.", "In 2007 he rejoined Halifax in the Championship.", "After 5 seasons with Halifax, Penkywicz joined the Leigh Centurions in 2013.", "Penkywicz joined the Toronto Wolfpack on a short-term contract, making 13 appearances for the club during their inaugural 2017 season in League 1, and helping the team to promotion, after which he joined Workington Town.", "Penkywicz joined the Rochdale Hornets for the 2020 season and was appointed captain by coach Matt Calland.", "In 2008, he was named in the Wales squad to face England at the Keepmoat Stadium prior to England's departure for the 2008 Rugby League World Cup." ]

[ 0, 1, 2, 3, 4, 5, 6 ]

[ "He has played at club level in the Super League for Halifax (Heritage No. 1147) (two spells, including the second in the Championship), and the Huddersfield Giants, in the Championship for the Leigh Centurions (Heritage No. 1370), he appeared in the inaugural 2017 season for the Toronto Wolfpack, as of 2018 he plays for Workington Town in Betfred League 1, as a or ." ]

[ "\"WarioWare D.I.Y.\" allows players to design their own microgames, creating their own graphics and music, and designing a 'cartridge' for them.", "The game features five sections in its main menu: D.I.Y. Studio, where the player designs microgames; WarioWare Inc., the tutorial; D.I.Y Shop, where the player makes microgame cartridges; Options Garage, where players edit preferences and names; and Distribution Center, in which players send games to the Wii or vice versa.", "Players can also receive games from the NinSoft store while at the Distribution Center.", "Due to its cross-compatibility with the Wii, the gameplay is restricted to tapping mechanics.", "When creating the music, the player can hum into the DS's microphone, which the DS then converts into notes, or create their own music.", "These notes can then be performed by various instruments such as pig noises, similar to music creation in \"Mario Paint\".", "Prior to the discontinuation of Nintendo Wi-Fi Connection on May 20, 2014, players could send their creations to other \"D.I.Y.\" owners or receive other people's works.", "They could also be uploaded online for contest purposes.", "Additional microgames pre-built by Nintendo could be downloaded from the service, along with \"Big Name Games\", microgames created by well-known individuals such as other game developers or television personalities.", "Additionally, the WiiWare game \"WarioWare: D.I.Y. Showcase\" allows users to play the microgames on the Wii using the Wii Remote.\nAside from the user-generated microgames, \"WarioWare D.I.Y.\" includes 167 pre-made microgames featuring the characters Mona, Jimmy T., Ashley, Orbulon, 9-Volt, 18-Volt, Dribble & Spitz, Kat & Ana, and Wario-Man.", "Each character has microgames set to certain themes, similar to the original \"WarioWare, Inc.: Mega Microgames!\".", "Dr. Crygor dreams that he is playing on a game console (which resembles a Wii with a Classic Controller).", "Suddenly, the characters in the game emerge from the screen, causing a stampede.", "Waking up from the nightmare, Dr. Crygor comes up with a brainstorm and invents the Super MakerMatic 21.", "While the machines are being assembled in Dr. Crygor's lab, Wario enters with a broken television set for repair and notices the Super MakerMatic 21 is being assembled.", "He wants to trade his broken television for one of the Super MakerMatics (thinking that it is a television set as well), at which point Dr. Crygor explains what it actually is and its ability to make microgames easily.", "Wario is amazed and realizes that Dr. Crygor's invention is the key to making huge fortunes and revamps WarioWare, Inc. once again.", "Unfortunately, many of his employees had quit, so he hires the player to make microgames for him.", "Development of \"WarioWare D.I.Y.\" began in September 2003 when series director Goro Abe decided that due to how entertaining it was for the team to create microgames, they should make a game that allowed players to do the same.", "In an interview, Abe referenced other video games that allow players to create their own role-playing or shooting games, but despite finding it fun he would quit making them before finishing them.", "Because of this, he decided that the short nature of the \"WarioWare\" series' microgames were perfect for this kind of game, allowing for those with a shorter attention span to make use of the game.", "Development took a long time as a result of the launch of the successor to the Game Boy Advance, the touch-controlled Nintendo DS, which Abe felt was a more ideal way to create microgames.", "However, due to a combination of the difficulty in creating microgames and other projects Abe had to develop at the time, the title was put on hold and development ceased for a time.", "The project gained new life during the development of the Wii title \"WarioWare: Smooth Moves\" when the developers learned of the WiiConnect24 feature that allows players to exchange or send data to other players.", "He decided that with \"D.I.Y.\", players would be able to make microgames on the Nintendo DS and then send them to the Wii to play.", "Development restarted after the completion of \"Smooth Moves\".", "Another designer, Masahito Hatakeyama, got involved after discussing the project with Abe.", "Hatakeyama was also interested in video games that allow players to make their own content, but he suffered from the same problem and would quit creating his content a third of the way through.", "He also cited \"Mario Paint\" as another influence for allowing him to make his own content.", "He eventually asked Abe if he could participate in the game's development, which Abe agreed to.", "Taku Sugioka, an employee of Intelligent Systems who had also worked on the DSiWare video game \"WarioWare: Snapped!\", had heard that after \"Smooth Moves\" was completed, Abe was going to try something new.", "Soon after, Abe asked him if he would be interested in participating in its development.", "He found it to be an interesting project, but was not sure if Abe's ideas could translate well into a video game.", "The drawing and music-making portions were made to be based on the drawing and music-making tools of \"Mario Paint\".", "However, they found difficulty in designing the portion of the game where players designate the objectives of the microgames.", "Originally, they intended to make characters and items, which they designated as \"objects\", able to move depending on the players wishes, but they needed to make the game interactive and approachable for players.", "After \"Smooth Moves\", development of \"D.I.Y.\" took two more years to complete; one of those years was spent attempting to figure out how to make such interaction and approachability doable.", "Eventually, they decided on splitting the microgame design process into three phases – the object phase, the background phase, and the sound phase.", "They created a framework on which they viewed as successful after a designer created a microgame in a few hours.", "The first version of the editor was far less complex than that of the final version, the approach being to start with a small number of necessary functions and only add others if necessary, rather than having an overly complex editor and removing unnecessary functions.", "To test its capabilities, the development team set to recreate Wario's stage in \"WarioWare: Touched!\"", "They were able to replicate \"almost 100%\", with some adjustments made to games that could not be fully recreated.", "During development, Abe emphasized to the other staff members that it was unnecessary to create highly complex and technical games, as they would only last a few seconds.", "At this point, the development had picked up, Sugioka commenting that the team was amazed by this since he was just a designer and not a programmer, meaning he did not have access to special techniques to do this.", "As the development continued, the game design mechanics grew from the simple test model, as if they were adding to a puzzle, in Sugioka's words.", "The developers intended on keeping it simple, however, only implementing six buttons.", "For example, for a microgame that features a jumping character, players may dictate where the character may jump by selecting the \"Boing!\"", "button.", "While Hatakeyama wanted to add more functionality, Abe retorted by commenting either that the player could combine two functions to do what Hatakeyama wanted or that the microgames only lasted a few seconds and did not need to be too complex.", "The development team attempted to recreate microgames from \"WarioWare: Touched!\" to test how easy it would be for players to do so.", "For some they could recreate, while others they could not.", "In response, they adjusted the game to make the ones they could not recreate workable.", "The debugging process was a difficult part of the development due to how many possibilities there were in creating microgames.", "While the game originally was going to use a normal Nintendo DS game cartridge, it uses a NAND flash memory card in order to save and load microgames faster and allow players to store more microgames.", "While this was initially rejected due to a tight schedule, it was eventually implemented.", "However, during the mass production phase of the development, the game would stop when they tried to utilize the memory.", "Sugioka was placed in charge of debugging the NAND card, and eventually found the cause.", "While Abe considered that there would be people who would not want to make microgames, he implemented a feature that would allow players to edit the microgames the developers included to make their own.", "Initially, they considered having players download microgames from people who have given their friend codes to them, Abe commenting that microgames made by friends and family are more entertaining than those downloaded from anonymous people.", "However, both methods of exchanging microgames were eventually implemented in the final game.", "\"WarioWare D.I.Y.\" also uses connectivity with a WiiWare title called \"WarioWare: D.I.Y. Showcase\", unofficially called \"WarioWare: Do It Yourself Showcase\" in PAL regions, allowing users to upload their creations to play on a big screen, and even upload them for contests.", "The game allows players to play up to 72 pre-made games, listen to pre-made music, or read pre-made comics.", "Players can also play, listen, or read the things they have already made.", "Along with that, users can fill out surveys for games that their friends have made.", "They can also download new content as it becomes available and upload their games for other players to download.", "\"WarioWare: D.I.Y. Showcase\" also includes an unlockable versus mode, but options are limited to shuffling every game, user-created and pre-made, alike.", "\"WarioWare D.I.Y.\" holds a score of 82/100 on Metacritic, indicating generally favorable reviews.", "\"IGN\" gave the game an 'Outstanding' score of 9/10.", "Wiiloveit.com awarded the WiiWare download a similar grade, with a 27/30 (or 90%), claiming it's a \"great complement to the DS release\".", "Additionally, British publication \"Official Nintendo Magazine\" gave the game a 92%.", "\"Famitsu\" reported that by May 31, 2009, \"WarioWare D.I.Y.\" sold 156,692 units in Japan." ]

[ 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59 ]

[ "It is the seventh title in the \"WarioWare\" series and the last to be developed for the Nintendo DS family of systems." ]

[ "Ohashi was born in Yokohama on June 23, 1981.", "He joined J1 League club Yokohama F. Marinos from youth team in 1999.", "He played several matches as offensive midfielder until 2000.", "In 2001, he moved to J2 League club Mito HollyHock on loan.", "He played many matches as regular player.", "In 2002, he returned to Yokohama F. Marinos.", "However he could hardly play in the match.", "In August 2002, he moved to J2 club Albirex Niigata on loan.", "In 2003, he returned to Yokohama F. Marinos.", "Although he could not play many matches until 2004, he became a regular player as offensive midfielder in 2005.", "In 2006, he moved to J2 club Tokyo Verdy and played many matches.", "In 2007, he moved to Kawasaki Frontale.", "He played many matches as substitute midfielder in 2 seasons.", "In 2009, he moved to South Korean club Gangwon FC.", "He is the third Japanese footballer who played in the K-League.", "Ohashi scored his first goal in the K-League in Gangwon FC, against Suwon Samsung Bluewings on May 2, 2009.", "In 2010, he returned to Japan and joined J2 club Mito HollyHock for the first time in 9 years.", "He played many matches as regular player.", "In 2011, he moved to Gangwon FC again.", "However he could not play at all in the match for injury and left the club in June.", "In August 2011, he returned to Japan and joined Japan Football League club Matsumoto Yamaga FC.", "The club was promoted to J2 from 2012.", "He retired end of 2012 season.", "Yokohama F. Marinos\n\nKawasaki Frontale" ]

[ 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22 ]

[ "is a former Japanese football player." ]

[ "Betancourt (Trinidad pronunciation: Betancou) was born and raised in Laventille, near Port of Spain, in Trinidad.", "His father, Edwin, was a musician and a man of all trades, his mother Stella Bowen was a seamstress and a cleaner.", "At a very early age, Betancourt was involved with music with the Tambo Bambo family band and grew up experimenting with the steelpan, becoming a member of the Tripoli Steel band and Cross Fire.", "He began his career in the 1930s and became a steelpan tuner and eventually the leader of Crossfire, a steelband from the St James area.", "He also played a large part in the development of steelpan in Trinidad and Europe.", "Betancourt was chosen with 11 steelpan players to form the Trinidad All-Steel Percussion Orchestra (TASPO) and play in London at the 1951 Festival of Britain, in the same year he toured England and Europe with the band and was the only member of TASPO to remain in England when the others returned to Trinidad on 12 November 1951.", "Betancourt's calypso \"Taspo's Story\" features on the \"RASPO Rhythms\" CD by the Reading All Steel Percussion Orchestra (RASPO), relates the tribulations encountered by the arrival of the first Steel Band in London: The Trinidad All Steel Percussion Orchestra (TASPO).", "Betancourt, Russell Henderson and Mervyn Constantine, who later on was replaced by Max Cherrie, followed by his brother Ralph Cherrie, formed the first steelband in the UK and performed all over London as well as in radio shows, jazz clubs and the BBC.", "In 1955 Betancourt was taught by Tony Kinsey to play the traps drums to form The Henderson combo.", "Henderson, Betancourt and Ralph Cherrie, initiated the multicultural Notting Hill children street festival organised by Rhaune Laslett in 1964.", "A festival that grew to become the biggest street event in Europe, the Notting Hill Carnival.", "Betancourt has also taken steelpan to many other countries throughout Europe and Asia, including Switzerland, Hong Kong, Bahrain, Dubai, Abu Dhabi, Qatar, Morocco, Indonesia, Germany, Spain, France, Oman, Italy, Sicily, Sweden and Norway.", "A 1976 performance he gave in a hotel in Zurich, Switzerland, inspired some locals to form their own Swiss group, which they called Tropefieber (\"Tropical Fever\"), the first steel band in Zurich, followed then by many others.", "In 1985 Betancourt's steel band, \"Nostalgia\", was born and continued with him as the leader, player, and arranger until 2005.", "Honours and awards that Betancourt has received include: in 1993 Trinidad and Tobago’s Scarlet Ibis award.", "A University of East London Honorary Fellowship in 1996, a membership of the FRSA for his commitment in promoting steelpan culture throughout the United Kingdom, and pioneering steelpan projects in English schools and in the same year, the New York Sunshine Award.", "He was appointed as a Member of the Most Excellent Order of the British Empire in the New Year Honours 2002 \"for services to the steel band movement\".", "In 2004 he received a Fellowship of the Royal Society, in 2006 a Pantrinbago Pioneer award, in 2010 Pan Jazz Life Time Achievement, 2011 Pan Trinbago Commemorative Plaque for Life Time Achievement.", "In 2012, on the occasion of the Trinidad and Tobago Independence Jubilee celebrations, he was a recipient of one of the Arts awards recognising citizens who made a positive contribution to the promotion and development of Trinidad and Tobago in the United Kingdom during the past 50 years, given at a gala dinner in London hosted by High Commissioner Garvin Nicholas.", "In February 2018, Sterling Betancourt recorded his latest calypso, \"Brexit Bacchanal Story\", with Dik Cadbury singer/guitar/bass guitar/violin, Tamla Batra on steelpan and piano and Betancourt on steel drum and percussion." ]

[ 5, 6, 7, 8, 9, 10, 11, 12, 13 ]

[ "Betancourt lives in London, England." ]

[ "Houben studied at the University of Bonn and changed his subjects from mathematics and astronomy to chemistry under the influence of August Kekulé.", "He received his Ph.D. for work with Julius Bredt in 1898, and they collaborated on the initial 1902 publication of what became known as Bredt's Rule.", "After some time at the University of Aachen and University of Bonn Houben joined the laboratory of Emil Fischer at the University of Berlin.", "After his habilitation in 1908 he stayed in Berlin until the beginning of World War I. Houben served in the army and after being wounded several times he became head of the war laboratory.", "After the war Houben became professor at the Biologische Reichsanstalt in Berlin Dahlem in 1921, a position he held until his forced retirement in 1933.", "Houben died in Tübingen in 1940.", "During his time with Emil Fisher his research was focused on the Organomagnesium compounds, while in his time at the Biologischen Reichsanstalt Houben was improving the already known Hoesch reaction." ]

[ 0, 1, 2, 3, 4, 5 ]

[ "After being wounded several times on the front lines in World War I, Houben was made head of the war laboratory." ]

[ "Houben studied at the University of Bonn and changed his subjects from mathematics and astronomy to chemistry under the influence of August Kekulé.", "He received his Ph.D. for work with Julius Bredt in 1898, and they collaborated on the initial 1902 publication of what became known as Bredt's Rule.", "After some time at the University of Aachen and University of Bonn Houben joined the laboratory of Emil Fischer at the University of Berlin.", "After his habilitation in 1908 he stayed in Berlin until the beginning of World War I. Houben served in the army and after being wounded several times he became head of the war laboratory.", "After the war Houben became professor at the Biologische Reichsanstalt in Berlin Dahlem in 1921, a position he held until his forced retirement in 1933.", "Houben died in Tübingen in 1940.", "During his time with Emil Fisher his research was focused on the Organomagnesium compounds, while in his time at the Biologischen Reichsanstalt Houben was improving the already known Hoesch reaction." ]

[ 6 ]

[ "He improved the Hoesch reaction which is now normally called Houben-Hoesch reaction." ]

[ "Robert Whipple's father, George Mathews Whipple, was superintendent of the Royal Observatory at Kew, where his mother Elizabeth Beckley also worked.", "After attending King's College School, Whipple began his career at the Kew Observatory as an assistant, before leaving to become assistant manager at instrument making firm L. P. Casella.", "Whipple moved to Cambridge in 1898 to take up the post of personal assistant to Horace Darwin, the founder of the Cambridge Scientific Instrument Company.", "He spent the rest of his career there, rising to become Managing Director of the firm and later its Chairman.", "Whipple was a Founder-Fellow of the Institute of Physics, a Fellow of the Physical Society, where he served as Vice-President and Honorary Treasurer, and President of the British Optical Instrument Manufacturers' Association.", "He began collecting antique scientific instruments in 1913, eventually donating about a thousand instruments and a thousand antiquarian science books to the University of Cambridge in 1944.", "The collection formed the basis for the University's Whipple Museum of the History of Science, and has been displayed publicly on the same site since 1959.", "Whipple was keen that both the Museum and the Whipple Library play an active role in the teaching of history and philosophy of science, and both have remained at the centre of the Department of History and Philosophy of Science, University of Cambridge.", "Robert Whipple had a younger brother, Francis, a meteorologist who, like his father, served as Superintendent of Kew Observatory." ]

[ 0, 1, 2, 3, 4, 5, 6, 7, 8 ]

[ "He amassed a unique collection of antique scientific instruments that he later donated to found the Whipple Museum of the History of Science in Cambridge in 1944." ]

[ "Hom may be:", "In the Netherlands, there were 166 people with the surname Hom as of 2007, up from 124 in 1947.", "As of 2018, 29 people in Denmark bore the surname Høm, and two the surname Hom.", "According to statistics cited by Patrick Hanks, 17 people on the island of Great Britain and none on the island of Ireland bore the surname Hom in 2011.", "In 1881 there were four people with the surname in Great Britain.", "The 2010 United States Census found 4,863 people with the surname Hom, making it the 6,906th-most-common name in the country.", "This represented an decrease from 5,015 (6,262nd-most-common) in the 2000 Census.", "In both censuses, about four-fifths of the bearers of the surname identified as Asian, and one-tenth as White.", "It was the 269th-most-common surname among respondents to the 2000 Census who identified as Asian.", "People with the surname Hom or Høm include:" ]

[ 1, 2, 3, 4, 5, 6, 7, 8 ]

[ "Hom is a surname in various cultures." ]

[ "Mar may be a variant spelling of:", "According to statistics cited by Patrick Hanks, as of 2011 there were 81 people on the island of Great Britain and one on the island of Ireland with the surname Mar.", "In 1881 there had been 54 people with the surname in Great Britain.", "The 2010 United States Census found 5,375 people with the surname Mar, making it the 6,342nd-most-common name in the country.", "This represented an increase from 4,327 (7,120th-most-common) in the 2000 Census.", "In the 2010 census, about 13% of bearers of the surname identified as White, 49% as Asian, and 30% as Hispanic." ]

[ 1, 2, 3, 4, 5 ]

[ "Mar is a Chinese and Scottish surname." ]

[ "As a Chinese surname, Chin could originate from numerous Chinese characters including the following, listed by their spelling in Mandarin Pinyin:\n\n\nAs a Korean surname, Chin is the McCune–Reischauer romanisation of the four surnames more commonly spelled Jin in the Revised Romanization of Korean (; IPA: ).", "There is no modern Korean surname which Revised Romanization would spell as Chin ().", "As an English surname, Chin is a variant spelling of Chinn (from Middle English or ), which originated as a nickname for people with prominent or distinctive chins.", "The 2000 South Korean census found 170,980 people with the four Korean surnames spelled Chin in McCune–Reischauer.", "However, relatively few South Koreans with these surnames choose to spell them as Chin.", "In a study based on year 2007 application data for South Korean passports, 94.3% of the applicants with one of these surnames chose the spelling Jin for their passport, while only 4.7% chose the spelling Chin.", "According to statistics cited by Patrick Hanks, 1,504 people on the island of Great Britain and 17 on the island of Ireland bore the surname Chin in 2011.", "In 1881 there were 53 people with the surname in Great Britain, primarily at Cornwall.", "The 2010 United States Census found 27,487 people with the surname Chin, making it the 1,279th-most-common name overall.", "This represented an increase in absolute numbers, but a decrease in relative frequency, from 25,673 (1,255th-most-common) in the 2000 Census.", "In both censuses, slightly more than three quarters of the bearers of the surname identified as Asian, about 6% as White, and about 6% as Black.", "It was the 50th-most-common surname among respondents to the 2000 Census who identified as Asian." ]

[ 0, 1, 2 ]

[ "Chin is a surname.", "As a Chinese surname or Korean surname, it could originate from various Chinese characters (including , , and ), and it is also a surname in other cultures as well." ]

[ "Ančić was born in Split, at the time in SR Croatia, SFR Yugoslavia.", "During his career, from 1996 until 2001, Ančić played Challenger and Futures tournaments.", "He played doubles in two main draw matches at the ATP Tour-level.", "Ančić captured one Futures title, Croatia F1 in 2000 in doubles partnering his brother Mario.", "Ančić's career highest singles ranking was world no. 378, which he reached October 27, 1997.", "In September 2011, he became the coach of Dutch tennis player Thiemo de Bakker.", "He began coaching fellow Croatian Borna Ćorić in September 2016." ]

[ 0, 1, 2, 3, 4, 5, 6 ]

[ "Ivica Ančić (; born October 29, 1979) is a former professional tennis player from Croatia." ]

[ "In open air, when a vehicle travels along, air pushed aside can move in any direction except into the ground.", "Inside a tunnel, air is confined by the tunnel walls to move along the tunnel.", "Behind the moving vehicle, as air has been pushed away, suction is created, and air is pulled to flow into the tunnel.", "In addition, because of fluid viscosity, the surface of the vehicle drags the air to flow with vehicle, a force experienced as skin drag by the vehicle.", "This movement of air by the vehicle is analogous to the operation of a mechanical piston as inside a reciprocating compressor gas pump, hence the name 'piston effect.'", "The effect is also similar to the pressure fluctuations inside drainage pipes as waste water pushes air in front of it.", "The piston effect is very pronounced in railway tunnels, because the cross sectional area of trains is large and in many cases almost completely fills the tunnel cross section.", "The wind felt by the passengers on underground railway platforms (that do not have platform screen doors installed) when a train is approaching is air flow from the piston effect.", "The effect is less pronounced in road vehicle tunnels, as the cross-sectional area of vehicle is small compared to the total cross-sectional area of the tunnel.", "Single track tunnels experience the maximum effect but clearance between rolling stock and the tunnel as well as the shape of the front of the train affect its strength.", "Air flow caused by the piston effect can exert large forces on the installations inside the tunnel and so these installations have to be carefully designed and installed properly.", "Non-return dampers are sometimes needed to prevent stalling of ventilation fans caused by this air flow.", "The piston effect has to be considered by building designers in relation to smoke movement within an elevator shaft.", "A moving elevator car forces the air in front of it out of the shaft and pulls air into the shaft behind it with the effect most apparent in elevator systems with a fast moving car in a single shaft.", "This means that in a fire a moving elevator may push smoke into lower floors.", "The piston effect is used in tunnel ventilation.", "In railway tunnels, the train pushes out the air in front of it toward the closest ventilation shaft in front, and sucks air into the tunnel from the closest ventilation shaft behind it.", "The piston effect can also assist ventilation in road vehicle tunnels.", "In underground rapid transit systems, the piston effect contributes to ventilation and in some cases provides enough air movement to make mechanical ventilation unnecessary.", "At wider stations with multiple tracks, air quality remains the same and can even improve when mechanical ventilation is disabled.", "At narrow platforms with a single tunnel, however, air quality worsens when relying on the piston effect alone for ventilation.", "This still allows for potential energy savings by taking advantage of the piston effect rather than mechanical ventilation where possible.", "Tunnel boom is a loud boom sometimes generated by high-speed trains when they enter tunnels.", "These shock waves can disturb nearby residents and damage trains and nearby structures.", "People perceive this sound similarly to that of a sonic boom from supersonic aircraft.", "However, unlike a sonic boom, tunnel boom is not caused by trains exceeding the speed of sound.", "Instead, tunnel boom results from the structure of the tunnel preventing the air around the train from escaping in all directions.", "As a train passes through a tunnel, it creates compression waves in front of it.", "These waves coalesce into a shock wave that generates a loud boom when it reaches the tunnel exit.", "The strength of this wave is proportional to the cube of the train's speed, so the effect is much more pronounced with faster trains.", "Tunnel boom can disturb residents near the mouths of tunnels, and it is exacerbated in mountain valleys where the sound echoes.", "Reducing these disturbances is a significant challenge for high-speed lines such as Japan's Shinkansen, French TGV and Spain's AVE.", "Tunnel boom has become a principal limitation to increased train speeds in Japan where the mountainous terrain requires frequent tunnels.", "Japan has enacted a law limiting noise to 70 dB in residential areas, which include many tunnel exit zones.", "Methods of reducing tunnel boom include making the train's profile highly aerodynamic, adding hoods to tunnel entrances, installing perforated walls at tunnel exits, and drilling vent holes in the tunnel (similar to fitting a silencer on a firearm, but on a far bigger scale).", "Passengers and crew may experience ear discomfort as a train enters a tunnel because of rapid pressure changes." ]

[ 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 ]

[ "Piston effect refers to the forced-air flow inside a tunnel or shaft caused by moving vehicles." ]

[ "Château Franc Mayne was bought by Axa-Millésimes in 1984 from the nephew of a Libourne négociant by the name of Theillasoubre, who had owned it for some years, and died with no descendants.", "In June 1996, the château was sold to a Belgian entrepreneur named Georgy Fourcroy.\nSince 2005 Château Franc Mayne has been owned by Griet & Hervé Laviale.", "There have been major renovations both in the main house and the wine making facilities, with a new vat house containing wooden and stainless steel vats.", "The property also comprises 2 hectares of underground quarries.", "As with most Saint-Émilion wines Franc Mayne is produced mostly from Merlot grapes.", "Yields are limited to 38 hl/ha, and the grapes are hand-picked, with successive sorting in the vineyard and in the winery (by Triebaie sorting machine).", "Malolactic fermentation takes place in new oak barrels.", "Apart from its first wine Château Franc Mayne Grand Cru Classé, the estate also produces a second wine, Les Cèdres de Franc Mayne.", "It is produced from the same terroir as the Grand Vin but from younger vines, and is accessible at an earlier stage than Château Franc Mayne." ]

[ 4, 5, 6, 7, 8 ]

[ "Château Franc Mayne is a Bordeaux wine from the Appellation d'origine contrôlée of Saint-Émilion, ranked \"Grand cru classé\" in the Classification of Saint-Émilion wine." ]

[ "Note: Professional firsts are on the national level unless otherwise indicated.", "Started racing: MacPherson started racing in 1976 at the age of four, where crashed on his first lap around the track in practice.", "He didn't attempt to race again until 1981, and this time he did not qualify.", "In his third race he got fourth place.", "He had a successful child amateur career after that, and then left the sport in late 1986 at 15 years of age.", "He resumed racing in 1994 with the ABA Fall Nationals in Burbank, California on October 21–23, 1994.", "Sanctioning body district(s): American Bicycle Association (ABA) California 9 (CA-9) (1983), CA-22 (1985)\nFirst race result: Did not qualify in 1981.", "Turned professional: November 1995, moments after his victory in becoming National No.1 Amateur at the ABA grand nationals.", "He was 23 years old.", "First professional race result: Eighth place (last) in Superclass at the National Bicycle League (NBL) Christmas Classic in Columbus, Ohio on December 28, 1995 (Day 1).", "Retired: MacPherson first retired after the 1986 ABA grand nationals to pursue football.", "He resumed racing in 1994 after an eight-year layoff at 23 years old.", "He missed the travel and camaraderie.", "He retired again in December 2002 to spend more time with his daughter.", "Note: This listing only denotes the racer's primary sponsors.", "At any given time a racer could have numerous ever-changing co-sponsors.", "Primary sponsorships can be verified by BMX press coverage and sponsor's advertisements at the time in question.", "When possible exact dates are used.", "Note: Listed are District, State/Provincial/Department, Regional, National, and International titles in \"italics\".", "Depending on point totals of individual racers, winners of Grand Nationals do not necessarily win National titles.", "Only sanctioning bodies active during the racer's career are listed.", "National Bicycle Association (NBA)\nNational Bicycle League (NBL)\n\nAmerican Bicycle Association (ABA)\n\n\n\n\n\nUnited States Bicycle Motocross Association (USBA)\n\nInternational Bicycle Motocross Federation (IBMXF)\n\nUnited States Cycling Federation (USCF)\nIndependent Events, Race Series and Invitationals", "American Bicycle Association (ABA)", "Pro Series Championships", "Product evaluation\n\"BMX Plus!\"", "February 1998 Vol.21 No.2 pg.", "71 Note: this bicycle was jointly evaluated with the GT Speed Series Team bicycle.", "Product evaluation\n\"Snap BMX Magazine\" December 2000 Vol. 7", "Iss.", "12 No. 50 pg.", "118", "Note: Only magazines that were in publication at the time of the racer's career(s) are listed unless specifically noted.", "BMX Plus!:\nABA Action, American BMXer, BMXer (the official membership publication of the ABA under three different names):" ]

[ 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 ]

[ "Robert D. MacPherson (born February 9, 1971 in Norwalk, California) is a retired professional American \"Old/Mid School\" Bicycle Motocross (BMX) racer who competed mainly from 1995 to 2001." ]

[ "The Flier was introduced, under the leadership of Chief Commissioner Harold Clapp, to replace the railway-operated bus service from Melbourne to Geelong, and to allow the Victorian Railways to compete with a private bus service operating along the same route.", "The train ran daily except Sundays.", "Patronage on the new service was high enough that further expenditure was justified.", "Within a few months the schedule was accelerated by ten minutes southbound and nine minutes northbound, due to the provision of Automatic Staff Exchange equipment at crossing loops on the single track between Newport South and North Geelong.", "That allowed the train to maintain a higher average speed, because it only needed to slow from to , rather than , when exchanging its section authority.", "By mid-1927 the train was regularly operating with more and larger carriages, using the newly built Long W fleet to provide more seats for less train weight.", "However, those cars had a different roof style, so their introduction changed the appearance of the train.", "From October 17, 1927, the train was extended to Port Fairy; the former run was now .", "The train's title was simplified to The Flyer, and it saved 90 minutes for the whole journey, compared with the schedule of its predecessors.", "The W-class cars, supplemented with PL-class carriages, were utilised for passengers between Melbourne and Geelong, and detached there.", "The longer-distance passengers rode in E-class carriages.", "The train was altered to depart from Spencer Street at 8:20 am, arriving at Geelong at 9:23 am, and waiting ten minutes to allow passengers to buy refreshments and to swap the engine for a lighter unit.", "It then proceeded to Birregurra at 10:35 am, Colac from 10:55 to 11:00 am, and arrived at Camperdown at 11:39 am.", "The train departed Camperdown at 11:59 pm and stopped all stations to Port Fairy, arriving at 2:59 pm.", "The train from Geelong to Melbourne was formed by a passenger service leaving Camperdown at 2:20pm, running express to Colac and Birregurra, then stopping at Armytage, Winchelsea, Buckley (on request), Moriac, Pettavel (on request), Grovedale (on request), Marshall (on request) and South Geelong, arriving at Geelong at 4:40 pm.", "The return train left Geelong station at 5:00 pm.", "Passengers could not travel on cheaper Excursion or Special Football tickets, and arrival was at Spencer Street Station at 6:05 pm.\nTo allow for the new timetable, 33 suburban services in the Melbourne area had to be adjusted, and to allow for the longer, heavier train, the schedule from Melbourne to Geelong was increased from 60 to 63 minutes.", "As better locomotives became available, the schedule was cut to 57 minutes outbound and 55 minutes inbound, and those times applied after 1938.", "World War II reduced the priority given to passenger trains, and any engine might be used on The Flier, with resulting schedule penalties.", "Locomotives from the C, D3, K and N classes were all employed.", "By the end of the war, the portion of the A2 fleet fitted with Walschaerts valve gear had been converted to oil firing, which meant the performance of the locomotives was not restricted by the fireman's capacity to shovel coal, but that benefit did not outweigh problems caused by the deteriorated state of the rolling stock and track.", "In 1951 the new R-class locomotives took over the run, and a few years later B-class diesel engines were introduced.", "The 1954 timetable had the train leaving Spencer Street at 8:25 am and arriving at Geelong at 9:20 am, continuing at 9:35 am and stopping at most stations (depending on the day) to Port Fairy, arriving at 2 pm.", "The train did not stop at Marshall, Buckley, Armytage or Crossley, and Pomborneit and Allansford were only serviced on Tuesdays through Thursdays.", "Warncoort, Larpent, Stoneyford, Garvoc and Cudgee were only served on Tuesdays, Thursdays and Saturdays, and Irrewarra, Pirron Yallock, Weerite, Boorcan and Panmure only on Mondays, Wednesdays and Fridays.", "South Geelong, Moriac, Winchelsea, Birregurra, Colac, Camperdown, Terang, Warrnambool, Koroit and Port Fairy were all served from Monday to Saturday.", "On the return, the train identified as The Flier departed Geelong at 5:08 pm and ran express to Spencer Street Station, arriving 6:05 pm.", "There was no train from Port Fairy scheduled to form it, but the 3:05 pm Melbourne-bound train from Port Fairy (2:50 pm on Saturdays) had a similar stopping pattern from Port Fairy to Geelong to that of The Flier, and arrived at Spencer Street Station at 8:33 pm, or 8:10 pm on Saturdays.", "The stations served on particular days of the week were identical, except that all Melbourne-bound trains stopped at Pomborneit, even though only half the Port Fairy-bound trains stopped there.", "Occasionally, The Flier was used to transfer random locomotives to or from Melbourne's South Dynon Locomotive Depot, and if those engines were of the T class, the train speed would be restricted to .", "Post-war, additional S type carriages were built which allowed some of the older air-conditioned carriages to be cascaded over to The Flier, and by 1960 the train was assembled with whatever stock was available, giving a mixture of classes, styles and colours.", "The 1967 timetable shows The Flier as a Geelong service, leaving Spencer Street at 8:25 am for Geelong, arriving at 9:20 am (where it formed a Port Fairy train), and as a 5:12 pm train from Geelong, arriving at Spencer Street at 6:10 pm, extending to Flinders Street at 6:17 pm.", "There is no reference to The Flier on the Port Fairy timetable.", "In late 2019, Port Phillip Ferries began running an Incat-built, 403-seat ferry, named \"Geelong Flyer\" after the Geelong Football Club player Bob Davis who in turn was named after the former train service.", "The ferry initially operated a twice-daily service to and from Melbourne Docklands, using a mooring at the bottom of Moorabool Street.", "The service complemented the company's Portarlington to Docklands service, and was advertised as providing a more relaxed journey than the increasingly crowded trains on the Geelong-Melbourne line." ]

[ 0, 1 ]

[ "The Geelong Flier was an Australian named passenger train operated by the Victorian Railways, running from Melbourne to Geelong." ]

[ "The Flier was introduced, under the leadership of Chief Commissioner Harold Clapp, to replace the railway-operated bus service from Melbourne to Geelong, and to allow the Victorian Railways to compete with a private bus service operating along the same route.", "The train ran daily except Sundays.", "Patronage on the new service was high enough that further expenditure was justified.", "Within a few months the schedule was accelerated by ten minutes southbound and nine minutes northbound, due to the provision of Automatic Staff Exchange equipment at crossing loops on the single track between Newport South and North Geelong.", "That allowed the train to maintain a higher average speed, because it only needed to slow from to , rather than , when exchanging its section authority.", "By mid-1927 the train was regularly operating with more and larger carriages, using the newly built Long W fleet to provide more seats for less train weight.", "However, those cars had a different roof style, so their introduction changed the appearance of the train.", "From October 17, 1927, the train was extended to Port Fairy; the former run was now .", "The train's title was simplified to The Flyer, and it saved 90 minutes for the whole journey, compared with the schedule of its predecessors.", "The W-class cars, supplemented with PL-class carriages, were utilised for passengers between Melbourne and Geelong, and detached there.", "The longer-distance passengers rode in E-class carriages.", "The train was altered to depart from Spencer Street at 8:20 am, arriving at Geelong at 9:23 am, and waiting ten minutes to allow passengers to buy refreshments and to swap the engine for a lighter unit.", "It then proceeded to Birregurra at 10:35 am, Colac from 10:55 to 11:00 am, and arrived at Camperdown at 11:39 am.", "The train departed Camperdown at 11:59 pm and stopped all stations to Port Fairy, arriving at 2:59 pm.", "The train from Geelong to Melbourne was formed by a passenger service leaving Camperdown at 2:20pm, running express to Colac and Birregurra, then stopping at Armytage, Winchelsea, Buckley (on request), Moriac, Pettavel (on request), Grovedale (on request), Marshall (on request) and South Geelong, arriving at Geelong at 4:40 pm.", "The return train left Geelong station at 5:00 pm.", "Passengers could not travel on cheaper Excursion or Special Football tickets, and arrival was at Spencer Street Station at 6:05 pm.\nTo allow for the new timetable, 33 suburban services in the Melbourne area had to be adjusted, and to allow for the longer, heavier train, the schedule from Melbourne to Geelong was increased from 60 to 63 minutes.", "As better locomotives became available, the schedule was cut to 57 minutes outbound and 55 minutes inbound, and those times applied after 1938.", "World War II reduced the priority given to passenger trains, and any engine might be used on The Flier, with resulting schedule penalties.", "Locomotives from the C, D3, K and N classes were all employed.", "By the end of the war, the portion of the A2 fleet fitted with Walschaerts valve gear had been converted to oil firing, which meant the performance of the locomotives was not restricted by the fireman's capacity to shovel coal, but that benefit did not outweigh problems caused by the deteriorated state of the rolling stock and track.", "In 1951 the new R-class locomotives took over the run, and a few years later B-class diesel engines were introduced.", "The 1954 timetable had the train leaving Spencer Street at 8:25 am and arriving at Geelong at 9:20 am, continuing at 9:35 am and stopping at most stations (depending on the day) to Port Fairy, arriving at 2 pm.", "The train did not stop at Marshall, Buckley, Armytage or Crossley, and Pomborneit and Allansford were only serviced on Tuesdays through Thursdays.", "Warncoort, Larpent, Stoneyford, Garvoc and Cudgee were only served on Tuesdays, Thursdays and Saturdays, and Irrewarra, Pirron Yallock, Weerite, Boorcan and Panmure only on Mondays, Wednesdays and Fridays.", "South Geelong, Moriac, Winchelsea, Birregurra, Colac, Camperdown, Terang, Warrnambool, Koroit and Port Fairy were all served from Monday to Saturday.", "On the return, the train identified as The Flier departed Geelong at 5:08 pm and ran express to Spencer Street Station, arriving 6:05 pm.", "There was no train from Port Fairy scheduled to form it, but the 3:05 pm Melbourne-bound train from Port Fairy (2:50 pm on Saturdays) had a similar stopping pattern from Port Fairy to Geelong to that of The Flier, and arrived at Spencer Street Station at 8:33 pm, or 8:10 pm on Saturdays.", "The stations served on particular days of the week were identical, except that all Melbourne-bound trains stopped at Pomborneit, even though only half the Port Fairy-bound trains stopped there.", "Occasionally, The Flier was used to transfer random locomotives to or from Melbourne's South Dynon Locomotive Depot, and if those engines were of the T class, the train speed would be restricted to .", "Post-war, additional S type carriages were built which allowed some of the older air-conditioned carriages to be cascaded over to The Flier, and by 1960 the train was assembled with whatever stock was available, giving a mixture of classes, styles and colours.", "The 1967 timetable shows The Flier as a Geelong service, leaving Spencer Street at 8:25 am for Geelong, arriving at 9:20 am (where it formed a Port Fairy train), and as a 5:12 pm train from Geelong, arriving at Spencer Street at 6:10 pm, extending to Flinders Street at 6:17 pm.", "There is no reference to The Flier on the Port Fairy timetable.", "In late 2019, Port Phillip Ferries began running an Incat-built, 403-seat ferry, named \"Geelong Flyer\" after the Geelong Football Club player Bob Davis who in turn was named after the former train service.", "The ferry initially operated a twice-daily service to and from Melbourne Docklands, using a mooring at the bottom of Moorabool Street.", "The service complemented the company's Portarlington to Docklands service, and was advertised as providing a more relaxed journey than the increasingly crowded trains on the Geelong-Melbourne line." ]

[ 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32 ]

[ "The Geelong Flier was an Australian named passenger train operated by the Victorian Railways, running from Melbourne to Geelong.", "The first run was on 3 May 1926, departing from Flinders Street station Platform No.1 at 9:00 am, stopping only at Spencer Street before running express to Geelong, arriving at 10:10 am.", "The train left Geelong on the return journey at 4:00 pm, arriving at Flinders Street at 5:11 pm." ]

[ "Takada started his goalkeeper career in Japan, then England, Ireland, Norway, Germany, Australia, Hong Kong, Indonesia.", "He then ended his professional career in Hong Kong.", "Takada signed for Hong Kong Rangers in 2007.", "In 2010, Takada played for Persitara in the Indonesia Super League before returning to Japan.", "Takada finished his three-month contract with Persitara and then became a free agent.", "He returned to Hong Kong to train with Citizen.", "He went to the 2010–11 Hong Kong Senior Challenge Shield final, then uploaded a match video to YouTube and telling people that he was looking for a club on facebook.", "In the end he joined Pegasus in the summer of 2011.", "Takada appeared in Hongkong Post's advertising campaign.", "He said it was a part-time job he found during the summer break." ]

[ 0, 1, 2, 3, 4, 5, 6, 7 ]

[ "was a Japanese professional footballer who played as a goalkeeper." ]

[ "The electoral coalition won 35 seats out of 60 in the Grand and General Council in the Sammarinese parliamentary election, 2008 gaining 54.22% of the national vote and an automatic governmental majority of 5 and became the new government of San Marino with Ernesto Benedettini of the Sammarinese Christian Democratic Party and Assunta Meloni of Popular Alliance becoming Captains Regent of San Marino, defeating the left-wing Reforms and Freedom coalition which gained 25 seats in the Grand and General council and failed to get a governing majority.", "Pact for San Marino replaced the previous left-wing governing coalition of Party of Socialists and Democrats, United Left and Popular Alliance.", "The alliance collapsed in 2011, with San Marino returning to the old governing alliance between Christian Democrats, Socialists and Liberals." ]

[ 0, 1, 2 ]

[ "Pact for San Marino () was a centrist coalition of parties for the 2008 general election in San Marino." ]

[ "The electoral coalition won 25 seats out of 60 in the Grand and General Council in the Sammarinese parliamentary election, 2008 gaining 45.78% of the national vote but failed to gain a governmental majority.", "As a result, the coalition became the opposition to the new government of the right-wing coalition of Pact for San Marino.", "After the political crisis of 2011, the alliance was disbanded, the Party of Socialists and Democrats joining their ancient opponents into a government of national unity." ]

[ 0, 1, 2 ]

[ "Reforms and Freedom () was a left-wing coalition of parties for the 2008 general election in San Marino." ]

[ "The USAF Warfare Center manages advanced pilot training and integrates many of the Air Force's test and evaluation requirements.", "It was established in 1966 as the USAF Tactical Fighter Weapons Center which concentrated on the development of forces and weapons systems that were specifically geared to tactical air operations in conventional (non-nuclear) war and contingencies.", "It continued to perform this mission for nearly thirty years, undergoing several name changes in the 1990s.", "In 1991, the center became the USAF Fighter Weapons Center, and then the USAF Weapons and Tactics Center in 1992.", "The USAF Warfare Center uses the lands and airspace of the Nevada Test and Training Range (NTTR) – which occupies about three million acres (12,000 km²) of land, the largest such range in the United States, and another five-million-acre (20,000 km²) military operating area which is shared with civilian aircraft.", "The center also uses Eglin AFB, FL, range, which adds even greater depth to the center's capabilities, providing over water and additional electronic expertise to the center.", "The USAF Warfare Center oversees operations of the 57th Wing, the NTTR, and the 99th Air Base Wings at Nellis AFB, Nevada; the 53rd Wing at Eglin AFB, Florida (with Geographically Separated Units at Tyndall AFB, Florida and Holloman AFB, New Mexico); and the 505th Command and Control Wing at Hurlburt Field, Florida.", "The 53d Wing serves as the focal point for the combat air forces in electronic combat, armament and avionics, chemical defense, reconnaissance, command and control, and aircrew training devices.", "The 57th Wing is responsible for a variety of activities, such as Red Flag, which provides realistic training in a combined air, ground and electronic threat environment for U.S. and allied forces.", "It is also the parent unit for both the USAF Weapons School (USAFWS) and the USAF Air Demonstration Squadron, the latter better known as the United States Air Force Thunderbirds.", "Previously known as the 98th Range Wing (98 RANW), the military organization known as NTTR provides command and control of the actual Nevada Test and Training Range facility located north and northwest of Nellis AFB.", "The 25th Space Range Squadron (SRS) operates and maintains the Space Test and Training Range and is a subordinate unit the NTTR.", "The 99th Air Base Wing is the host wing at Nellis AFB and manages the day-to-day operations of the base.", "The 505th CCW is dedicated to improving warfighter readiness through integrated training, tactics, and testing for operational-level command and control of air, space, and cyber power.", "It hosts the Air Force's only Air Operations Center Formal Training Unit (FTU).", "By the mid-1960s, USAF aircraft and aircrew losses in the Vietnam War had convinced Tactical Air Command (TAC) of the need to improve technical and operational skills for the widening conflict.", "TAC established the Tactical Fighter Weapons Center at Nellis Air Force Base, Nevada in 1966 for the expressed purpose of improving fighter operations and tactics.", "Nellis AFB had been referred to as the \"Home of the Fighter Pilot\" since the Korean War period of the early 1950s, and had a long history of conducting postgraduate fighter training and operational testing and evaluation of fighter weapons systems.", "Additionally, the Nellis Range, largest in the free world, readily complemented the new center's mission.", "Redesignated: USAF Fighter Weapons Center in 1991\n Redesignated: USAF Weapons and Tactics Center in 1992\n Redesignated: USAF Warfare Center in 2005.", "Operational units assigned to the USAFWC have been:\nWing\n\n Redesignated: 57th Tactical Training Wing, 1 April 1977 – 1 March 1980\n Redesignated: 57th Fighter Wing, 1 October 1991 – 15 June 1993\n Redesignated: 57th Wing, June 15, 1993 – present\nGroups\n\n Attached 1 October 1979 – 28 February 1980\n Assigned 1 March 1980 – 1 November 1991\nSquadrons", "F-4G Wild Weasel, 1992 – 1995\n QF-4 and QRF-4 Phantom II (Drone), 1993 – 2016 \n QF-100 Super Sabre (Drone), 1983 – 1993\n\n\n\n\n\n F-15E Strike Eagle, 1992 – present" ]

[ 0, 1, 2, 3, 4, 5, 6 ]

[ "The United States Air Force Warfare Center (USAFWC) at Nellis Air Force Base, Nevada, reports directly to Air Combat Command.", "The Center was founded September 1, 1966, as the U.S. Air Force Tactical Fighter Weapons Center.", "It was renamed the U.S. Air Force Warfare Center in 2005." ]

[ "The USAF Warfare Center manages advanced pilot training and integrates many of the Air Force's test and evaluation requirements.", "It was established in 1966 as the USAF Tactical Fighter Weapons Center which concentrated on the development of forces and weapons systems that were specifically geared to tactical air operations in conventional (non-nuclear) war and contingencies.", "It continued to perform this mission for nearly thirty years, undergoing several name changes in the 1990s.", "In 1991, the center became the USAF Fighter Weapons Center, and then the USAF Weapons and Tactics Center in 1992.", "The USAF Warfare Center uses the lands and airspace of the Nevada Test and Training Range (NTTR) – which occupies about three million acres (12,000 km²) of land, the largest such range in the United States, and another five-million-acre (20,000 km²) military operating area which is shared with civilian aircraft.", "The center also uses Eglin AFB, FL, range, which adds even greater depth to the center's capabilities, providing over water and additional electronic expertise to the center.", "The USAF Warfare Center oversees operations of the 57th Wing, the NTTR, and the 99th Air Base Wings at Nellis AFB, Nevada; the 53rd Wing at Eglin AFB, Florida (with Geographically Separated Units at Tyndall AFB, Florida and Holloman AFB, New Mexico); and the 505th Command and Control Wing at Hurlburt Field, Florida.", "The 53d Wing serves as the focal point for the combat air forces in electronic combat, armament and avionics, chemical defense, reconnaissance, command and control, and aircrew training devices.", "The 57th Wing is responsible for a variety of activities, such as Red Flag, which provides realistic training in a combined air, ground and electronic threat environment for U.S. and allied forces.", "It is also the parent unit for both the USAF Weapons School (USAFWS) and the USAF Air Demonstration Squadron, the latter better known as the United States Air Force Thunderbirds.", "Previously known as the 98th Range Wing (98 RANW), the military organization known as NTTR provides command and control of the actual Nevada Test and Training Range facility located north and northwest of Nellis AFB.", "The 25th Space Range Squadron (SRS) operates and maintains the Space Test and Training Range and is a subordinate unit the NTTR.", "The 99th Air Base Wing is the host wing at Nellis AFB and manages the day-to-day operations of the base.", "The 505th CCW is dedicated to improving warfighter readiness through integrated training, tactics, and testing for operational-level command and control of air, space, and cyber power.", "It hosts the Air Force's only Air Operations Center Formal Training Unit (FTU).", "By the mid-1960s, USAF aircraft and aircrew losses in the Vietnam War had convinced Tactical Air Command (TAC) of the need to improve technical and operational skills for the widening conflict.", "TAC established the Tactical Fighter Weapons Center at Nellis Air Force Base, Nevada in 1966 for the expressed purpose of improving fighter operations and tactics.", "Nellis AFB had been referred to as the \"Home of the Fighter Pilot\" since the Korean War period of the early 1950s, and had a long history of conducting postgraduate fighter training and operational testing and evaluation of fighter weapons systems.", "Additionally, the Nellis Range, largest in the free world, readily complemented the new center's mission.", "Redesignated: USAF Fighter Weapons Center in 1991\n Redesignated: USAF Weapons and Tactics Center in 1992\n Redesignated: USAF Warfare Center in 2005.", "Operational units assigned to the USAFWC have been:\nWing\n\n Redesignated: 57th Tactical Training Wing, 1 April 1977 – 1 March 1980\n Redesignated: 57th Fighter Wing, 1 October 1991 – 15 June 1993\n Redesignated: 57th Wing, June 15, 1993 – present\nGroups\n\n Attached 1 October 1979 – 28 February 1980\n Assigned 1 March 1980 – 1 November 1991\nSquadrons", "F-4G Wild Weasel, 1992 – 1995\n QF-4 and QRF-4 Phantom II (Drone), 1993 – 2016 \n QF-100 Super Sabre (Drone), 1983 – 1993\n\n\n\n\n\n F-15E Strike Eagle, 1992 – present" ]

[ 7, 8, 9, 10, 11, 12, 13, 14 ]

[ "It was renamed the U.S. Air Force Warfare Center in 2005." ]

[ "The hospital was started in 1991 by National Medical Enterprises (later renamed Tenet Healthcare).", "While Tenet had ownership of the hospital it was staffed by doctors from the Keck School Of Medicine.", "In 2006, USC sued Tenet to end the agreement.", "Three years later in 2009, Tenet Healthcare sold the hospital and USC Norris Cancer Hospital to USC for $275 million, which then allowed USC to fully integrate the hospitals under the Keck Medicine Of USC branding." ]

[ 0, 1, 2, 3 ]

[ "Under the Keck Medicine of USC banner there is a third hospital, USC Verdugo Hills Hospital located in the city of Glendale." ]

[ "While working as a consultant for larger high tech companies, Jan-Olof Granlund spent his free time working on a specification for a search engine technology.", "The goal was to (1) develop a number of new algorithms for ranking independent of the type of data and (2) efficient distribution and scaling of processing power and data over a large cluster of servers.", "The specification was ready in 2004 and the first beta search engine system was implemented in 2005 and a license was sold to a search engine company on Iceland.", "In 2007, the company Munax AB was founded and Granlund left his consultant business to work full-time in the new company.", "Munax had shareholders from Sweden, Iceland, the United States, and China.", "The major investor in Munax was :sv:Affärsstrategerna.", "The technology of the Munax company was later sold and the company was closed down.", "On the system level, Munax can be installed on a single computer or an arbitrary number of computers on a local area network, or over computers on the internet.", "The execution is logically distributed over subsystems, not machines.", "One machine can host several subsystems or one subsystem can span over several machines.", "This way, Munax can be scaled and distributed freely and each machine's execution power can be utilized to its maximum.", "On the indexing level, Munax full-indexes a range of document types, including: htm html shtm shtml jhtm asp php php3 pdf ps", "doc xls ppt rtf wp wp5 wp6 wpd txt c cpp h.", "When it comes to link-indexing in Munax, this is more complex than just indexing the anchor text and the URL.", "Amongst other things, Munax relates each link to the other links on the page and to the text of the page itself.", "Munax supports the link-indexing of gif, jpg, tga, bmp, iff, img, jif, mac, msp, pcx, pic, tif, ico, jpe, mp3, wav, ram, snd, mp4, aif, mid, vqf, la1, lav, mp2, avi, mpg, mpeg, rm, qt, asx, mov, fli, flc, eps, wri, asc, fmk, for, zip, gzip, tar, arc, lzh, sit, rar, arj, dd, tgz, lha, exe, hqx, dll, vbs, vxd, bat, cmd, class, jar, java, jav and email addresses.", "Munax knows what type of files these are and groups them accordingly.", "Munax also allows for structured indexing, i.e. the indexing of XML files and automatically creates each xml tag as an individual search item.", "On the search level, several independent ranking algorithms processes the inverted index together with hundreds of search parameters to produce the final ranking for each document.", "For the visitor, Munax provided a long range of search features, including the search for pages, documents, audio, video, images, compressed files, torrents, software and email addresses, or to get all type of results on the same page (composite search, supersearch).", "The visitor could also decide which ranking algorithms to be used, search across domains, search within sites, before/after/between dates, demand objects-on-page, pre-view & pre-listen to multimedia files and view objects-on-page and pages with the tags stripped away.", "Munax started the construction of the PlayAudioVideo multimedia search engine in July 2007 and opened it for beta testers in December the same year.", "PlayAudioVideo, beta 1, was opened for the public in February 2008 and beta 2 opened in June 2008.", "PlayAudioVideo was the first true search engine for multimedia, i.e., providing search on the web for images, video and audio/music in the same search engine.", "Through Munax composite search, the visitor gets the results for all multimedia types on the same result page, or he could decide to search for each individual type.", "Audio and Video could be pre-listened and pre-viewed before connecting to the original multimedia file.", "This saved time when deciding among versions of the same song or video.", "The visitor could start his own web application and make any search result accessible in any type of device.", "This includes audio for mp3 players and video and audio for mobile phones and/or VCD/DVD.", "Munax acknowledged the demand from the mobile operators to provide their customers with search beyond the traditional text search.", "Munax provided the users with the search and play of songs and videos regardless of the type of device being used.", "For metasearch engines, Munax provided any type of search, including traditional text search (pages/documents) and multimedia search, to be presented on their result pages.", "Munax provided a range of search products to be installed on a corporation's computers, to index their local area network, their website and/or sites on the web.", "Munax could be tailored individually to suit the needs for each corporation.", "Munax also provided outsourced search—i.e., any corporation could have their website indexed and searchable from the Munax search engine, but presented as if the search results came from the corporation itself.", "With or without authentication and encryption.", "The outsourced search functionality was used in the service All Site Search.", "MUNAX, from Munin and Corax.", "The scientific name for the raven is \"Corvus corax\", as named in 1758 by Carl Linnaeus, the Swedish biologist who invented the system of classifying organisms by Latin.", "Munin is one of the two ravens of Odin, the god of wisdom in the Nordic Viking mythology (Viking ages 700–1100 AD).", "The ravens fly over the earth and remember everything; when the ravens come back, they tell Odin what they have seen—similar to the Munax ravens, or crawlers, which inform the Munax database of what's on the web." ]

[ 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 ]

[ "Munax XE, is an all-content search engine and powered nationwide and worldwide public search engines with page, document, audio, video, images, software, and email search.", "For multimedia, Munax also developed functionality that let the visitors pre-listen to audio and preview videos, making it easier for the visitor to decide what song or video he is looking for before playing it, or visiting the site hosting it." ]

[ "While working as a consultant for larger high tech companies, Jan-Olof Granlund spent his free time working on a specification for a search engine technology.", "The goal was to (1) develop a number of new algorithms for ranking independent of the type of data and (2) efficient distribution and scaling of processing power and data over a large cluster of servers.", "The specification was ready in 2004 and the first beta search engine system was implemented in 2005 and a license was sold to a search engine company on Iceland.", "In 2007, the company Munax AB was founded and Granlund left his consultant business to work full-time in the new company.", "Munax had shareholders from Sweden, Iceland, the United States, and China.", "The major investor in Munax was :sv:Affärsstrategerna.", "The technology of the Munax company was later sold and the company was closed down.", "On the system level, Munax can be installed on a single computer or an arbitrary number of computers on a local area network, or over computers on the internet.", "The execution is logically distributed over subsystems, not machines.", "One machine can host several subsystems or one subsystem can span over several machines.", "This way, Munax can be scaled and distributed freely and each machine's execution power can be utilized to its maximum.", "On the indexing level, Munax full-indexes a range of document types, including: htm html shtm shtml jhtm asp php php3 pdf ps", "doc xls ppt rtf wp wp5 wp6 wpd txt c cpp h.", "When it comes to link-indexing in Munax, this is more complex than just indexing the anchor text and the URL.", "Amongst other things, Munax relates each link to the other links on the page and to the text of the page itself.", "Munax supports the link-indexing of gif, jpg, tga, bmp, iff, img, jif, mac, msp, pcx, pic, tif, ico, jpe, mp3, wav, ram, snd, mp4, aif, mid, vqf, la1, lav, mp2, avi, mpg, mpeg, rm, qt, asx, mov, fli, flc, eps, wri, asc, fmk, for, zip, gzip, tar, arc, lzh, sit, rar, arj, dd, tgz, lha, exe, hqx, dll, vbs, vxd, bat, cmd, class, jar, java, jav and email addresses.", "Munax knows what type of files these are and groups them accordingly.", "Munax also allows for structured indexing, i.e. the indexing of XML files and automatically creates each xml tag as an individual search item.", "On the search level, several independent ranking algorithms processes the inverted index together with hundreds of search parameters to produce the final ranking for each document.", "For the visitor, Munax provided a long range of search features, including the search for pages, documents, audio, video, images, compressed files, torrents, software and email addresses, or to get all type of results on the same page (composite search, supersearch).", "The visitor could also decide which ranking algorithms to be used, search across domains, search within sites, before/after/between dates, demand objects-on-page, pre-view & pre-listen to multimedia files and view objects-on-page and pages with the tags stripped away.", "Munax started the construction of the PlayAudioVideo multimedia search engine in July 2007 and opened it for beta testers in December the same year.", "PlayAudioVideo, beta 1, was opened for the public in February 2008 and beta 2 opened in June 2008.", "PlayAudioVideo was the first true search engine for multimedia, i.e., providing search on the web for images, video and audio/music in the same search engine.", "Through Munax composite search, the visitor gets the results for all multimedia types on the same result page, or he could decide to search for each individual type.", "Audio and Video could be pre-listened and pre-viewed before connecting to the original multimedia file.", "This saved time when deciding among versions of the same song or video.", "The visitor could start his own web application and make any search result accessible in any type of device.", "This includes audio for mp3 players and video and audio for mobile phones and/or VCD/DVD.", "Munax acknowledged the demand from the mobile operators to provide their customers with search beyond the traditional text search.", "Munax provided the users with the search and play of songs and videos regardless of the type of device being used.", "For metasearch engines, Munax provided any type of search, including traditional text search (pages/documents) and multimedia search, to be presented on their result pages.", "Munax provided a range of search products to be installed on a corporation's computers, to index their local area network, their website and/or sites on the web.", "Munax could be tailored individually to suit the needs for each corporation.", "Munax also provided outsourced search—i.e., any corporation could have their website indexed and searchable from the Munax search engine, but presented as if the search results came from the corporation itself.", "With or without authentication and encryption.", "The outsourced search functionality was used in the service All Site Search.", "MUNAX, from Munin and Corax.", "The scientific name for the raven is \"Corvus corax\", as named in 1758 by Carl Linnaeus, the Swedish biologist who invented the system of classifying organisms by Latin.", "Munin is one of the two ravens of Odin, the god of wisdom in the Nordic Viking mythology (Viking ages 700–1100 AD).", "The ravens fly over the earth and remember everything; when the ravens come back, they tell Odin what they have seen—similar to the Munax ravens, or crawlers, which inform the Munax database of what's on the web." ]

[ 29, 30, 31 ]

[ "Other customers included vertical search engines and mobile operators." ]

[ "Robert was born of lowly origin in Levington, near Ipswich, and educated at the Free School at Ipswich and later Pembroke College, Cambridge, studying law.", "He was admitted to Gray's Inn on 3 November 1589 from Barnard's Inn and was called to the Bar in 1595.", "He became a Member of Parliament for West Looe, Cornwall from 1597 to 1598; for King's Lynn, Norfolk from 1604 to 1611; for Cambridge in 1614 and for Orford, Suffolk from 1624 to 1626.", "He held a number of posts including: Attorney-General to Anne of Denmark, Queen Consort to James I (1603–?); Sergeant-at-law (1614–?); and King's Senior Sergeant-at-law (1616–?).", "He was knighted on 29 June 1604 by King James I.", "On 14 May 1635 he purchased Framlingham Castle, Suffolk from Theophilus Howard, 2nd Earl of Suffolk for the sum of £14,000.", "He died on 15 August 1636 and now lies in a tomb in the Church of St Michael the Archangel, Framlingham.", "His will stated that the castle, save for the outer walls, be demolished and the stone used to build a poor house.", "The inner buildings were duly demolished and a poor house, Sir Robert Hitcham's Almshouses, was built in its place.", "He also endowed a school for local children (originally boys only), which was the foundation of the current Framlingham Sir Robert Hitcham primary school.", "His also left money in his will to fund a school in both Debenham & Coggeshall.", "With the school in Debenham being named after him; Sir Robert Hitcham CEVA Primary School.", "He bequeathed the site of the castle to the Master, Fellows and Scholars of Pembroke College, Cambridge.", "Some of the land he left was later given by the College as the site for Framlingham College, a school built as a memorial to Prince Albert.\nHitcham's Cloister in Pembroke College (built 1666) was named after him as is the Hitcham House at Thomas Mills High School." ]

[ 2, 3, 4 ]

[ "Sir Robert Hitcham (1572? – 1636) was a Member of Parliament and Attorney General under King James I." ]

[ "In 2013 and 2014 the Brompton World Championship took place in the Goodwood Motor Circuit, as part of the wider Orbital Festival cycling exposition.", "It features three main events, with separate prizes for the category winners in each event and then the grand prize for the overall victor of the Treble.\n800 entrants were expected in 2014.", "The Championship consists of a \"Le Mans\" style sprint start to the folded bikes before completing 4 laps – over 15 km – of the circuit.", "Dress code requires a suit jacket, shirt and tie with trousers/skirts/shorts according to participant preference, with all Lycra and sportswear strictly forbidden.", "Prizes are awarded to the three fastest male and female competitors, as well as the male and female Junior (between 12 and 18 years of age) and Veteran (over 50 years of age) winners.", "Teams of between 3 and 5 members are permitted and are placed according to the aggregated time of the team's top three finishers.", "There is also a prize awarded to the ‘Best Dressed’ male and female competitors.", "\"Brompton Sprint\"\nOnly open to the 200 participants who have registered for the Brompton Treble, the Brompton Sprint consists of a 500m sprint organised in heats of 12 entrants before the final.", "There is no dress code and prizes are awarded to the fastest male, female, junior and veteran competitors.", "\"Brompton Marathon\"\nThe Marathon consists of a 26 km untimed ride through the Sussex countryside, open to 300 participants (compulsory for the Brompton Treble entrants), with food and drink and sightseeing options organised en route.", "There is no dress code.", "\"Brompton Treble\"\nThe 200 participants who compete in all three events are eligible for the Brompton Treble; the male and female competitors with the fastest times from the Sprint and the World Championship, together with successful completion of the Marathon, will be the Brompton Treble Champions.", "The Brompton World Championship was first held in 2006 in Barcelona, Spain, before relocating to England in 2008 where the event was then held at Blenheim Palace in Oxfordshire.", "In 2013 the BWC was merged with the Orbital Festival and moved to the Goodwood Motor Circuit in Chichester, West Sussex.", "Since 2010 many countries around the globe have held their own Brompton National Championships featuring comparative events, with the winners invited to participate in the World Championships every summer.", "The list of countries that have held National Championships::", "Fastest Male\n1st Alastair Kay\n2nd Roberto Heras\n3rd Pau Milla\nFastest Female\n1st Debbie Lister\n2nd Helen Lucas\n3rd Jane Bradbury\nFastest Veteran\n1st Rob Howells\nFastest Junior\n1st Piers Benton\nTeam Category\n1st Cap Problema\n2nd Transport for London Tornados\n3rd Eunomia 1\nBest Dressed\n1st David Presly", "Official results as published by Brompton.", "Fastest Male\n1st Roberto Heras\n2nd Michael Hutchinson\n3rd Alastair Kay\nFastest Female\n1st Julia Shaw\n2nd Rachael Elliott\n3rd Delia Beddis\nFastest Male Veteran\n1st Gary Higton\nFastest Female Veteran\n1st Sarah Wookey\nFastest Junior\n1st Brock Duncumb Rogers\nTeam Category\n1st Brompton 1\n2nd Bike Tech\n3rd Cap Problema\nVeteran Team Category\nNorfolk Enchants\nBest Dressed Male\n1st Gary Foulger\nBest Dressed Female\n1st Susie Smith", "Official results as published by Brompton.", "Fastest Male \n1st Philip Liam Curran\n2nd Pau Milla Canals\n3rd Marcel Batlle Giró\nFastest Female\n1st Rachael Elliott\n2nd Mercè Pacios\n3rd Charlotte Barnes\nFastest Junior \n1st Brock Duncomb\nFastest Male Veteran\n1st Richard Trim\nFastest Female Veteran\n1st Sarah Wookey\nBest Dressed Male\n1st Ian Harvey\nBest Dressed Female\n1st Mary Till\nTeam Event\n1st Cap Problema 1\n2nd Brompton Factory 1\n3rd BerLon\nVeterans \n1st Barnsley Hospice Bromptoneers: Team A", "Official results as published by Brompton.", "Fastest Male\n1st Michael Hutchinson\n2nd Gavin Morton\n3rd Aaron Ritz\nFastest Female\n1st Rachael Elliott\n2nd Julia Shaw\n3rd Julie Secor\nFastest Male Veteran\n1st Stewart Yates\nFastest Female Veteran\n1st Caroline Powell\nFastest Junior\n1st Jake Norman\nTeam Category\n1st Brompton Factory 1\n2nd Kingston Wheelers\n3rd Where's Nigel?\nVeteran Team Category\nAbromination\nBest Dressed Male\n1st Fokko Bakker\nBest Dressed Female\n1st Rachael Jackson", "Official results as published by Brompton.", "Fastest Male\n1st Michael Hutchinson\n2nd Paul Flynn\n3rd Gavin Morton\nFastest Female\n1st Julia Shaw\n2nd Lee Miseon\n3rd Isabel Hastie\nFastest Male Veteran\n1st Hubert Kivit\nFastest Female Veteran\n1st Pauline Warner\nFastest Junior\n1st Jake Norman\nTeam Category\n1st Brompton Factory 1\n2nd Kingston Wheelers CC\n3rd Small Wheels, Big Difference", "Official results as published by Brompton.", "Fastest Male\n1st Michael Hutchinson\nFastest Female\n1st Isabel Hastie\nFastest Male Veteran\n1st Anthony Rogers\nFastest Female Veteran\n1st Caroline Powell\nFastest Junior\n1st Jake Norman\nTeam Category\n1st BBike\n2nd Brompton Factory 1\n3rd True Wheels/Sleaze Club", "Official results as published by Brompton\nFastest Male\n1st Mark Emsley (GBR)\n2nd Yavor Mitev (GBR)\n3rd Eduardo Gomes (GBR)\nFastest Female\n1st Isabel Hastie(GBR)\n2nd Kim Myojin (KOR)\n3rd Nao Tanaka (JPN)", "Official results as published by Brompton.", "Fastest Male\n1st Mark Emsley\n2nd Richard Spencer\n3rd Vojtech Blazejovsky\n4th David Mackay\nFastest Female\n1st Isabel Hastie\n2nd Sarah Phelps\n3rd Nao Tanaka\n4th Caroline Powell\nFastest Male Veteran\n1st Andrea Scavezzon\n2nd Nigel Saffery\n3rd Peter Hutchinson\n4th Adrian Baergi\nFastest Female Veteran\n1st Caroline Powell\n2nd Giuliana Massarotto\n3rd Gina Vaughan\n4th Alison Wright\nMen's Team Category\n1st Brompton Brazing Heritage Team\n2nd Joseph Kousac\n3rd Team Cadence\n4th Brompton Design Racing\nWomen's Team Category\n1st JH Wonder Woman\n2nd Green Brompton\nVeterans Team Category\n1st Abromination" ]

[ 12, 13, 14, 15 ]

[ "The Brompton World Championship, sponsored by Brompton Bicycle Ltd, is a British cycling event held every summer in England and preceded by national competitions around the globe." ]

[ "Windon attended Randwick Public School before Sydney Grammar where he was a mediocre rugby player, and never progressed beyond the lower grades.", "He showed promise as a young cricketer and from Grammar was selected in a Combined Schoolboys representative cricket side.", "Colin's father Stan was a foundation member of the Coogee Surf Life Saving Club and played rugby with the Randwick club in Sydney.", "Both Colin and his brother Keith inherited their father's love of rugby; Keith played as a flanker for Australia between 1936 and 1946, with his career interrupted by the Second World War.", "According to author Max Howell, Keith was a \"football genius\", and was a star during the 1937 South African tour of Australia.", "It was after watching his brother play for Australia in 1937 that Colin decided he too wanted to play for Australia; at the time Colin was struggling in school rugby, and his father said to him \"Son, I don't think you will ever play for Australia\".", "Keith was on the ill-fated 1939 Wallaby tour to England; the team docked at Plymouth, but the next day war was declared and they returned to Australia without playing a game.", "Keith did manage to briefly resume his career after the war, touring to New Zealand with the 1946 Wallabies, but he was diagnosed with gout while on tour and was forced to retire.", "Col Windon joined Randwick in 1938 at the age of 17, and started playing in the fourth grade.", "He had progressed to first grade when aged 18, and went on to play 98 first grade matches with the club.", "Windon played at flanker or \"breakaway\", and earned the knick-name \"Breeze\" because, according to former Wallaby Max Howell \"he ran like the wind\".", "In an obituary of Windon, he was described as \"not only a rugged, hard-tackling breakaway, he was a speedy, elusive runner with a gift for scoring tries\".", "According to Max Howell Windon claimed his best coach was his brother Keith.", "In order to analyse opponents, he would look up from the scrum before the ball was fed.", "Enlisting in the Second Australian Imperial Force on 18 December 1941 after basic training in Dubbo, Windon was posted to the 2/3 Infantry Battalion, 6th Division, He saw service in the Owen Stanley Ranges in Papua New Guinea where he contracted malaria, and after convalescence in the Atherton Tablelands he returned to New Guinea.", "He recovered to see action Aitape-Wewak campaign in 1945.", "Windon was a runner, and would weave and \"zig-zag\" to avoid enemy fire.", "He was discharged from the Army on 13 August 1946.", "Col Windon made his debut for Australia on their 1946 tour of New Zealand.", "His brother Keith was in the side (the only player in the squad that had toured New Zealand previously) which was captained by Bill McLean.", "Col Windon played nine of Australia's twelve matches on tour, and played both test matches against New Zealand.", "The first test was played in Dunedin, where New Zealand won 31–8.", "Despite the loss, the \"New Zealand Rugby Almanack\" described Windon as \"the outstanding forward on either side\".", "The second test was a much tighter affair; played at Auckland, New Zealand scored only one try to win 14–10, but according to rugby writer Winston McCarthy, it was \"only [New Zealand fullback]", "Bob Scott's boot that prevented them [Australia] from winning\".", "The following year New Zealand reciprocated and toured Australia.", "Windon played twice for the New South Wales Waratahs against the touring All Blacks, and in one of the two test matches.", "The tour was treated as a trial for Australia's 1947–48 tour of Europe and North America that commenced later that year.", "Windon played 27 matches on the 36-match tour, and in all five test matches: against Scotland, Ireland, Wales, England and France.", "The Wallabies did not concede a try in any of their four Home Nations matches.", "Windon scored eight tries to be the fourth highest try scorer on tour behind three-quarters John MacBride, Charlie Eastes and Trevor Allan.", "He debuted as Australian captain in tour matches against Aberdeen and Leicester.", "In the Test against England at Twickenham he dominated the matchjournalist Phil Tressider said: \"I saw him [Windon] single-handedly destroy England\".", "Windon scored two tries in the first half, with the second coming after England fly-half Tommy Kemp spilled the ball which Windon collected before running to score.", "The try was converted to give Australia an unassailable lead., and they went on to win 11–0.", "In 1949 a New Zealand Māori side toured Australia where they played three Test matches.", "The tour was organised by the New Zealand Rugby Football Union (NZRFU) after Māori players were excluded from the All Blacks' 1949 tour to apartheid South Africa.", "Windon appeared in all three Tests, as well as playing for New South Wales against the tourists.", "He scored a try in all three Tests; the first was won by the Maori, the second a draw, and the third won by Australia.", "Later that year Windon he was selected as vice-captain to Trevor Allan for a tour of New Zealand.", "The 12-match tour included two Tests against the All Blacks.", "The series against New Zealand, for the Bledisloe Cup, was considered a consolation for the Maori players after the \"guilt\" of the NZRFU for not selecting them for the All Black tour of South Africa that was occurring at the same time.", "Windon played in ten tour matches, scored eight tries, and captained his side against Manawatu-Horowhenua.", "The Wallabies defeated the All Blacks in the two-Test series, winning the first 6–11 and the second 9–16.", "Windon scored in both matches, and despite the weakened opposition made history as part of the first Australian team to win the Bledisole Cup on New Zealand soil.", "Windon's next Test was against the All Blacks when they reciprocated with a tour of Australia in 1951.", "Keith Winning captained the Wallabies in the first Test of the series, but broke his jaw in an Australian XV match.", "He was replaced as captain by Windon for the second and third TestsWindon's only Tests as captain.", "All three Tests were lost, and New Zealand went undefeated on tour.", "It was during this series that Windon got engaged, and celebrated by inviting the entire New Zealand side to his house.", "In 1952 he was selected for the domestic series against Fiji and later that year again toured New Zealand with the Wallabies.", "He played in nine of Australia's ten tour matches in New Zealand.", "The Wallabies lost only two of their matches, a game against Southland, and their second Test against the All Blacks.", "In the first Test Windon harassed the New Zealand fly-half with his aggressive defence, and pounced on a loose ball to score a try after the ball was dropped following a mistimed All Blacks' back-line move.", "The New Zealanders adjusted to Australia's tactics to win the second Test 15–8, but Windon did get the consolation of another try.", "Windon's last tour was to South Africa in 1953, but he never fully recovered from an injury suffered prior to the tour, and only made six appearances.", "He announced his retirement immediately following the tour.", "Early in his retirement he coached his club Randwick from 1954 to 1957.", "Following a tour of New Zealand, in 1946 he was selected by the \"New Zealand Rugby Almanac\" as one of its five players of the year.", "The magazine \"Sporting Life\" picked him in its All Australian team in five years 1947, 1948, 1949, 1951 and 1952.", "After being named in Australian rugby's team of the century in 1999, he was given a plaque on the Sydney Cricket Ground's Walk of Honour.", "In 2005 he was honoured as one of the inaugural five inductees into the Australian Rugby Union Hall of Fame, and in 2013 was named as an inaugural inductee in \"Inside Rugby\"'s Invincibles.", "For over thirty years Windon was Australia's leading Test try-scorer with 11, until his record was overtaken by winger Brendan Moon in the 1980s.", "Upon his induction Australian Rugby Union President Paul McLean referred to Windon as \"an electrifying talent and a try scoring machine\".", "His 1947 Wallaby tour teammate Sir Nicholas Shehadie described him as follows: \"As back-row forwards go, he was the very best.", "A try-scoring machine, a superb attacker and with the speed of a three-quarter, the man they nicknamed 'Breeze' was simply peerless in supporting play\".", "Windon married Judy Macdonald in 1954, and the couple had three daughters Julie, Fiona and Kate.", "He lived nearly all his life near Randwick, and was eventually elected to the city council's Sporting Hall of Fame.", "He supported the sporting pursuits of his children and later his grandchildren.", "He died of cancer in 2003 just short of his 82nd birthday." ]

[ 0, 1, 2, 3, 4, 5, 6, 7 ]

[ "By age 18 Windon was playing at flanker for his club Randwick in Sydney's Shute Shield.", "After serving with the Second Australian Imperial Force in the Pacific Theatre during the Second World War, Windon resumed his rugby career in 1946." ]

[ "Windon attended Randwick Public School before Sydney Grammar where he was a mediocre rugby player, and never progressed beyond the lower grades.", "He showed promise as a young cricketer and from Grammar was selected in a Combined Schoolboys representative cricket side.", "Colin's father Stan was a foundation member of the Coogee Surf Life Saving Club and played rugby with the Randwick club in Sydney.", "Both Colin and his brother Keith inherited their father's love of rugby; Keith played as a flanker for Australia between 1936 and 1946, with his career interrupted by the Second World War.", "According to author Max Howell, Keith was a \"football genius\", and was a star during the 1937 South African tour of Australia.", "It was after watching his brother play for Australia in 1937 that Colin decided he too wanted to play for Australia; at the time Colin was struggling in school rugby, and his father said to him \"Son, I don't think you will ever play for Australia\".", "Keith was on the ill-fated 1939 Wallaby tour to England; the team docked at Plymouth, but the next day war was declared and they returned to Australia without playing a game.", "Keith did manage to briefly resume his career after the war, touring to New Zealand with the 1946 Wallabies, but he was diagnosed with gout while on tour and was forced to retire.", "Col Windon joined Randwick in 1938 at the age of 17, and started playing in the fourth grade.", "He had progressed to first grade when aged 18, and went on to play 98 first grade matches with the club.", "Windon played at flanker or \"breakaway\", and earned the knick-name \"Breeze\" because, according to former Wallaby Max Howell \"he ran like the wind\".", "In an obituary of Windon, he was described as \"not only a rugged, hard-tackling breakaway, he was a speedy, elusive runner with a gift for scoring tries\".", "According to Max Howell Windon claimed his best coach was his brother Keith.", "In order to analyse opponents, he would look up from the scrum before the ball was fed.", "Enlisting in the Second Australian Imperial Force on 18 December 1941 after basic training in Dubbo, Windon was posted to the 2/3 Infantry Battalion, 6th Division, He saw service in the Owen Stanley Ranges in Papua New Guinea where he contracted malaria, and after convalescence in the Atherton Tablelands he returned to New Guinea.", "He recovered to see action Aitape-Wewak campaign in 1945.", "Windon was a runner, and would weave and \"zig-zag\" to avoid enemy fire.", "He was discharged from the Army on 13 August 1946.", "Col Windon made his debut for Australia on their 1946 tour of New Zealand.", "His brother Keith was in the side (the only player in the squad that had toured New Zealand previously) which was captained by Bill McLean.", "Col Windon played nine of Australia's twelve matches on tour, and played both test matches against New Zealand.", "The first test was played in Dunedin, where New Zealand won 31–8.", "Despite the loss, the \"New Zealand Rugby Almanack\" described Windon as \"the outstanding forward on either side\".", "The second test was a much tighter affair; played at Auckland, New Zealand scored only one try to win 14–10, but according to rugby writer Winston McCarthy, it was \"only [New Zealand fullback]", "Bob Scott's boot that prevented them [Australia] from winning\".", "The following year New Zealand reciprocated and toured Australia.", "Windon played twice for the New South Wales Waratahs against the touring All Blacks, and in one of the two test matches.", "The tour was treated as a trial for Australia's 1947–48 tour of Europe and North America that commenced later that year.", "Windon played 27 matches on the 36-match tour, and in all five test matches: against Scotland, Ireland, Wales, England and France.", "The Wallabies did not concede a try in any of their four Home Nations matches.", "Windon scored eight tries to be the fourth highest try scorer on tour behind three-quarters John MacBride, Charlie Eastes and Trevor Allan.", "He debuted as Australian captain in tour matches against Aberdeen and Leicester.", "In the Test against England at Twickenham he dominated the matchjournalist Phil Tressider said: \"I saw him [Windon] single-handedly destroy England\".", "Windon scored two tries in the first half, with the second coming after England fly-half Tommy Kemp spilled the ball which Windon collected before running to score.", "The try was converted to give Australia an unassailable lead., and they went on to win 11–0.", "In 1949 a New Zealand Māori side toured Australia where they played three Test matches.", "The tour was organised by the New Zealand Rugby Football Union (NZRFU) after Māori players were excluded from the All Blacks' 1949 tour to apartheid South Africa.", "Windon appeared in all three Tests, as well as playing for New South Wales against the tourists.", "He scored a try in all three Tests; the first was won by the Maori, the second a draw, and the third won by Australia.", "Later that year Windon he was selected as vice-captain to Trevor Allan for a tour of New Zealand.", "The 12-match tour included two Tests against the All Blacks.", "The series against New Zealand, for the Bledisloe Cup, was considered a consolation for the Maori players after the \"guilt\" of the NZRFU for not selecting them for the All Black tour of South Africa that was occurring at the same time.", "Windon played in ten tour matches, scored eight tries, and captained his side against Manawatu-Horowhenua.", "The Wallabies defeated the All Blacks in the two-Test series, winning the first 6–11 and the second 9–16.", "Windon scored in both matches, and despite the weakened opposition made history as part of the first Australian team to win the Bledisole Cup on New Zealand soil.", "Windon's next Test was against the All Blacks when they reciprocated with a tour of Australia in 1951.", "Keith Winning captained the Wallabies in the first Test of the series, but broke his jaw in an Australian XV match.", "He was replaced as captain by Windon for the second and third TestsWindon's only Tests as captain.", "All three Tests were lost, and New Zealand went undefeated on tour.", "It was during this series that Windon got engaged, and celebrated by inviting the entire New Zealand side to his house.", "In 1952 he was selected for the domestic series against Fiji and later that year again toured New Zealand with the Wallabies.", "He played in nine of Australia's ten tour matches in New Zealand.", "The Wallabies lost only two of their matches, a game against Southland, and their second Test against the All Blacks.", "In the first Test Windon harassed the New Zealand fly-half with his aggressive defence, and pounced on a loose ball to score a try after the ball was dropped following a mistimed All Blacks' back-line move.", "The New Zealanders adjusted to Australia's tactics to win the second Test 15–8, but Windon did get the consolation of another try.", "Windon's last tour was to South Africa in 1953, but he never fully recovered from an injury suffered prior to the tour, and only made six appearances.", "He announced his retirement immediately following the tour.", "Early in his retirement he coached his club Randwick from 1954 to 1957.", "Following a tour of New Zealand, in 1946 he was selected by the \"New Zealand Rugby Almanac\" as one of its five players of the year.", "The magazine \"Sporting Life\" picked him in its All Australian team in five years 1947, 1948, 1949, 1951 and 1952.", "After being named in Australian rugby's team of the century in 1999, he was given a plaque on the Sydney Cricket Ground's Walk of Honour.", "In 2005 he was honoured as one of the inaugural five inductees into the Australian Rugby Union Hall of Fame, and in 2013 was named as an inaugural inductee in \"Inside Rugby\"'s Invincibles.", "For over thirty years Windon was Australia's leading Test try-scorer with 11, until his record was overtaken by winger Brendan Moon in the 1980s.", "Upon his induction Australian Rugby Union President Paul McLean referred to Windon as \"an electrifying talent and a try scoring machine\".", "His 1947 Wallaby tour teammate Sir Nicholas Shehadie described him as follows: \"As back-row forwards go, he was the very best.", "A try-scoring machine, a superb attacker and with the speed of a three-quarter, the man they nicknamed 'Breeze' was simply peerless in supporting play\".", "Windon married Judy Macdonald in 1954, and the couple had three daughters Julie, Fiona and Kate.", "He lived nearly all his life near Randwick, and was eventually elected to the city council's Sporting Hall of Fame.", "He supported the sporting pursuits of his children and later his grandchildren.", "He died of cancer in 2003 just short of his 82nd birthday." ]

[ 8, 9, 10, 11, 12, 13 ]

[ "By age 18 Windon was playing at flanker for his club Randwick in Sydney's Shute Shield." ]

[ "Windon attended Randwick Public School before Sydney Grammar where he was a mediocre rugby player, and never progressed beyond the lower grades.", "He showed promise as a young cricketer and from Grammar was selected in a Combined Schoolboys representative cricket side.", "Colin's father Stan was a foundation member of the Coogee Surf Life Saving Club and played rugby with the Randwick club in Sydney.", "Both Colin and his brother Keith inherited their father's love of rugby; Keith played as a flanker for Australia between 1936 and 1946, with his career interrupted by the Second World War.", "According to author Max Howell, Keith was a \"football genius\", and was a star during the 1937 South African tour of Australia.", "It was after watching his brother play for Australia in 1937 that Colin decided he too wanted to play for Australia; at the time Colin was struggling in school rugby, and his father said to him \"Son, I don't think you will ever play for Australia\".", "Keith was on the ill-fated 1939 Wallaby tour to England; the team docked at Plymouth, but the next day war was declared and they returned to Australia without playing a game.", "Keith did manage to briefly resume his career after the war, touring to New Zealand with the 1946 Wallabies, but he was diagnosed with gout while on tour and was forced to retire.", "Col Windon joined Randwick in 1938 at the age of 17, and started playing in the fourth grade.", "He had progressed to first grade when aged 18, and went on to play 98 first grade matches with the club.", "Windon played at flanker or \"breakaway\", and earned the knick-name \"Breeze\" because, according to former Wallaby Max Howell \"he ran like the wind\".", "In an obituary of Windon, he was described as \"not only a rugged, hard-tackling breakaway, he was a speedy, elusive runner with a gift for scoring tries\".", "According to Max Howell Windon claimed his best coach was his brother Keith.", "In order to analyse opponents, he would look up from the scrum before the ball was fed.", "Enlisting in the Second Australian Imperial Force on 18 December 1941 after basic training in Dubbo, Windon was posted to the 2/3 Infantry Battalion, 6th Division, He saw service in the Owen Stanley Ranges in Papua New Guinea where he contracted malaria, and after convalescence in the Atherton Tablelands he returned to New Guinea.", "He recovered to see action Aitape-Wewak campaign in 1945.", "Windon was a runner, and would weave and \"zig-zag\" to avoid enemy fire.", "He was discharged from the Army on 13 August 1946.", "Col Windon made his debut for Australia on their 1946 tour of New Zealand.", "His brother Keith was in the side (the only player in the squad that had toured New Zealand previously) which was captained by Bill McLean.", "Col Windon played nine of Australia's twelve matches on tour, and played both test matches against New Zealand.", "The first test was played in Dunedin, where New Zealand won 31–8.", "Despite the loss, the \"New Zealand Rugby Almanack\" described Windon as \"the outstanding forward on either side\".", "The second test was a much tighter affair; played at Auckland, New Zealand scored only one try to win 14–10, but according to rugby writer Winston McCarthy, it was \"only [New Zealand fullback]", "Bob Scott's boot that prevented them [Australia] from winning\".", "The following year New Zealand reciprocated and toured Australia.", "Windon played twice for the New South Wales Waratahs against the touring All Blacks, and in one of the two test matches.", "The tour was treated as a trial for Australia's 1947–48 tour of Europe and North America that commenced later that year.", "Windon played 27 matches on the 36-match tour, and in all five test matches: against Scotland, Ireland, Wales, England and France.", "The Wallabies did not concede a try in any of their four Home Nations matches.", "Windon scored eight tries to be the fourth highest try scorer on tour behind three-quarters John MacBride, Charlie Eastes and Trevor Allan.", "He debuted as Australian captain in tour matches against Aberdeen and Leicester.", "In the Test against England at Twickenham he dominated the matchjournalist Phil Tressider said: \"I saw him [Windon] single-handedly destroy England\".", "Windon scored two tries in the first half, with the second coming after England fly-half Tommy Kemp spilled the ball which Windon collected before running to score.", "The try was converted to give Australia an unassailable lead., and they went on to win 11–0.", "In 1949 a New Zealand Māori side toured Australia where they played three Test matches.", "The tour was organised by the New Zealand Rugby Football Union (NZRFU) after Māori players were excluded from the All Blacks' 1949 tour to apartheid South Africa.", "Windon appeared in all three Tests, as well as playing for New South Wales against the tourists.", "He scored a try in all three Tests; the first was won by the Maori, the second a draw, and the third won by Australia.", "Later that year Windon he was selected as vice-captain to Trevor Allan for a tour of New Zealand.", "The 12-match tour included two Tests against the All Blacks.", "The series against New Zealand, for the Bledisloe Cup, was considered a consolation for the Maori players after the \"guilt\" of the NZRFU for not selecting them for the All Black tour of South Africa that was occurring at the same time.", "Windon played in ten tour matches, scored eight tries, and captained his side against Manawatu-Horowhenua.", "The Wallabies defeated the All Blacks in the two-Test series, winning the first 6–11 and the second 9–16.", "Windon scored in both matches, and despite the weakened opposition made history as part of the first Australian team to win the Bledisole Cup on New Zealand soil.", "Windon's next Test was against the All Blacks when they reciprocated with a tour of Australia in 1951.", "Keith Winning captained the Wallabies in the first Test of the series, but broke his jaw in an Australian XV match.", "He was replaced as captain by Windon for the second and third TestsWindon's only Tests as captain.", "All three Tests were lost, and New Zealand went undefeated on tour.", "It was during this series that Windon got engaged, and celebrated by inviting the entire New Zealand side to his house.", "In 1952 he was selected for the domestic series against Fiji and later that year again toured New Zealand with the Wallabies.", "He played in nine of Australia's ten tour matches in New Zealand.", "The Wallabies lost only two of their matches, a game against Southland, and their second Test against the All Blacks.", "In the first Test Windon harassed the New Zealand fly-half with his aggressive defence, and pounced on a loose ball to score a try after the ball was dropped following a mistimed All Blacks' back-line move.", "The New Zealanders adjusted to Australia's tactics to win the second Test 15–8, but Windon did get the consolation of another try.", "Windon's last tour was to South Africa in 1953, but he never fully recovered from an injury suffered prior to the tour, and only made six appearances.", "He announced his retirement immediately following the tour.", "Early in his retirement he coached his club Randwick from 1954 to 1957.", "Following a tour of New Zealand, in 1946 he was selected by the \"New Zealand Rugby Almanac\" as one of its five players of the year.", "The magazine \"Sporting Life\" picked him in its All Australian team in five years 1947, 1948, 1949, 1951 and 1952.", "After being named in Australian rugby's team of the century in 1999, he was given a plaque on the Sydney Cricket Ground's Walk of Honour.", "In 2005 he was honoured as one of the inaugural five inductees into the Australian Rugby Union Hall of Fame, and in 2013 was named as an inaugural inductee in \"Inside Rugby\"'s Invincibles.", "For over thirty years Windon was Australia's leading Test try-scorer with 11, until his record was overtaken by winger Brendan Moon in the 1980s.", "Upon his induction Australian Rugby Union President Paul McLean referred to Windon as \"an electrifying talent and a try scoring machine\".", "His 1947 Wallaby tour teammate Sir Nicholas Shehadie described him as follows: \"As back-row forwards go, he was the very best.", "A try-scoring machine, a superb attacker and with the speed of a three-quarter, the man they nicknamed 'Breeze' was simply peerless in supporting play\".", "Windon married Judy Macdonald in 1954, and the couple had three daughters Julie, Fiona and Kate.", "He lived nearly all his life near Randwick, and was eventually elected to the city council's Sporting Hall of Fame.", "He supported the sporting pursuits of his children and later his grandchildren.", "He died of cancer in 2003 just short of his 82nd birthday." ]

[ 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57 ]

[ "Colin \"Col\" Windon, (8 November 1921 – 3 December 2003) was a rugby union player and soldier who captained Australiathe Wallabiesin two Test matches in 1951.", "He was first selected for Australia for their tour of New Zealand that year.", "Despite the Wallabies losing both their Tests on tour, Windon impressed with his play.", "In 1947 Windon was selected for Australia's tour of Europe and North America where he played 27 of his side's 36 matches.", "He played all five Tests on tour, against Scotland, Ireland, Wales, England and France.", "In the match against England, which Australia won 11–0 after a dominant display from Windon that included two tries.", "He was appointed vice-captain for the Wallabies 1949 tour of New Zealand, where Australia won both Test matches to win the Bledisloe Cup in New Zealand for the first time.", "He captained his country in two matches against the touring New Zealanders in 1951.", "Windon's career ended after an injury interrupted tour to South Africa in 1953." ]

[ "Windon attended Randwick Public School before Sydney Grammar where he was a mediocre rugby player, and never progressed beyond the lower grades.", "He showed promise as a young cricketer and from Grammar was selected in a Combined Schoolboys representative cricket side.", "Colin's father Stan was a foundation member of the Coogee Surf Life Saving Club and played rugby with the Randwick club in Sydney.", "Both Colin and his brother Keith inherited their father's love of rugby; Keith played as a flanker for Australia between 1936 and 1946, with his career interrupted by the Second World War.", "According to author Max Howell, Keith was a \"football genius\", and was a star during the 1937 South African tour of Australia.", "It was after watching his brother play for Australia in 1937 that Colin decided he too wanted to play for Australia; at the time Colin was struggling in school rugby, and his father said to him \"Son, I don't think you will ever play for Australia\".", "Keith was on the ill-fated 1939 Wallaby tour to England; the team docked at Plymouth, but the next day war was declared and they returned to Australia without playing a game.", "Keith did manage to briefly resume his career after the war, touring to New Zealand with the 1946 Wallabies, but he was diagnosed with gout while on tour and was forced to retire.", "Col Windon joined Randwick in 1938 at the age of 17, and started playing in the fourth grade.", "He had progressed to first grade when aged 18, and went on to play 98 first grade matches with the club.", "Windon played at flanker or \"breakaway\", and earned the knick-name \"Breeze\" because, according to former Wallaby Max Howell \"he ran like the wind\".", "In an obituary of Windon, he was described as \"not only a rugged, hard-tackling breakaway, he was a speedy, elusive runner with a gift for scoring tries\".", "According to Max Howell Windon claimed his best coach was his brother Keith.", "In order to analyse opponents, he would look up from the scrum before the ball was fed.", "Enlisting in the Second Australian Imperial Force on 18 December 1941 after basic training in Dubbo, Windon was posted to the 2/3 Infantry Battalion, 6th Division, He saw service in the Owen Stanley Ranges in Papua New Guinea where he contracted malaria, and after convalescence in the Atherton Tablelands he returned to New Guinea.", "He recovered to see action Aitape-Wewak campaign in 1945.", "Windon was a runner, and would weave and \"zig-zag\" to avoid enemy fire.", "He was discharged from the Army on 13 August 1946.", "Col Windon made his debut for Australia on their 1946 tour of New Zealand.", "His brother Keith was in the side (the only player in the squad that had toured New Zealand previously) which was captained by Bill McLean.", "Col Windon played nine of Australia's twelve matches on tour, and played both test matches against New Zealand.", "The first test was played in Dunedin, where New Zealand won 31–8.", "Despite the loss, the \"New Zealand Rugby Almanack\" described Windon as \"the outstanding forward on either side\".", "The second test was a much tighter affair; played at Auckland, New Zealand scored only one try to win 14–10, but according to rugby writer Winston McCarthy, it was \"only [New Zealand fullback]", "Bob Scott's boot that prevented them [Australia] from winning\".", "The following year New Zealand reciprocated and toured Australia.", "Windon played twice for the New South Wales Waratahs against the touring All Blacks, and in one of the two test matches.", "The tour was treated as a trial for Australia's 1947–48 tour of Europe and North America that commenced later that year.", "Windon played 27 matches on the 36-match tour, and in all five test matches: against Scotland, Ireland, Wales, England and France.", "The Wallabies did not concede a try in any of their four Home Nations matches.", "Windon scored eight tries to be the fourth highest try scorer on tour behind three-quarters John MacBride, Charlie Eastes and Trevor Allan.", "He debuted as Australian captain in tour matches against Aberdeen and Leicester.", "In the Test against England at Twickenham he dominated the matchjournalist Phil Tressider said: \"I saw him [Windon] single-handedly destroy England\".", "Windon scored two tries in the first half, with the second coming after England fly-half Tommy Kemp spilled the ball which Windon collected before running to score.", "The try was converted to give Australia an unassailable lead., and they went on to win 11–0.", "In 1949 a New Zealand Māori side toured Australia where they played three Test matches.", "The tour was organised by the New Zealand Rugby Football Union (NZRFU) after Māori players were excluded from the All Blacks' 1949 tour to apartheid South Africa.", "Windon appeared in all three Tests, as well as playing for New South Wales against the tourists.", "He scored a try in all three Tests; the first was won by the Maori, the second a draw, and the third won by Australia.", "Later that year Windon he was selected as vice-captain to Trevor Allan for a tour of New Zealand.", "The 12-match tour included two Tests against the All Blacks.", "The series against New Zealand, for the Bledisloe Cup, was considered a consolation for the Maori players after the \"guilt\" of the NZRFU for not selecting them for the All Black tour of South Africa that was occurring at the same time.", "Windon played in ten tour matches, scored eight tries, and captained his side against Manawatu-Horowhenua.", "The Wallabies defeated the All Blacks in the two-Test series, winning the first 6–11 and the second 9–16.", "Windon scored in both matches, and despite the weakened opposition made history as part of the first Australian team to win the Bledisole Cup on New Zealand soil.", "Windon's next Test was against the All Blacks when they reciprocated with a tour of Australia in 1951.", "Keith Winning captained the Wallabies in the first Test of the series, but broke his jaw in an Australian XV match.", "He was replaced as captain by Windon for the second and third TestsWindon's only Tests as captain.", "All three Tests were lost, and New Zealand went undefeated on tour.", "It was during this series that Windon got engaged, and celebrated by inviting the entire New Zealand side to his house.", "In 1952 he was selected for the domestic series against Fiji and later that year again toured New Zealand with the Wallabies.", "He played in nine of Australia's ten tour matches in New Zealand.", "The Wallabies lost only two of their matches, a game against Southland, and their second Test against the All Blacks.", "In the first Test Windon harassed the New Zealand fly-half with his aggressive defence, and pounced on a loose ball to score a try after the ball was dropped following a mistimed All Blacks' back-line move.", "The New Zealanders adjusted to Australia's tactics to win the second Test 15–8, but Windon did get the consolation of another try.", "Windon's last tour was to South Africa in 1953, but he never fully recovered from an injury suffered prior to the tour, and only made six appearances.", "He announced his retirement immediately following the tour.", "Early in his retirement he coached his club Randwick from 1954 to 1957.", "Following a tour of New Zealand, in 1946 he was selected by the \"New Zealand Rugby Almanac\" as one of its five players of the year.", "The magazine \"Sporting Life\" picked him in its All Australian team in five years 1947, 1948, 1949, 1951 and 1952.", "After being named in Australian rugby's team of the century in 1999, he was given a plaque on the Sydney Cricket Ground's Walk of Honour.", "In 2005 he was honoured as one of the inaugural five inductees into the Australian Rugby Union Hall of Fame, and in 2013 was named as an inaugural inductee in \"Inside Rugby\"'s Invincibles.", "For over thirty years Windon was Australia's leading Test try-scorer with 11, until his record was overtaken by winger Brendan Moon in the 1980s.", "Upon his induction Australian Rugby Union President Paul McLean referred to Windon as \"an electrifying talent and a try scoring machine\".", "His 1947 Wallaby tour teammate Sir Nicholas Shehadie described him as follows: \"As back-row forwards go, he was the very best.", "A try-scoring machine, a superb attacker and with the speed of a three-quarter, the man they nicknamed 'Breeze' was simply peerless in supporting play\".", "Windon married Judy Macdonald in 1954, and the couple had three daughters Julie, Fiona and Kate.", "He lived nearly all his life near Randwick, and was eventually elected to the city council's Sporting Hall of Fame.", "He supported the sporting pursuits of his children and later his grandchildren.", "He died of cancer in 2003 just short of his 82nd birthday." ]

[ 58, 59, 60, 61, 62, 63, 64, 65 ]

[ "His eleven Test tries was the most by an Australian until the 1980s, and he was named in Australian rugby's team of the century in 1999.", "In 2005 he was honoured as one of the inaugural five inductees into the Australian Rugby Union Hall of Fame, and in 2013 was named as an inaugural inductee in \"Inside Rugby\"'s Invincibles." ]

[ "The Lie algebra formula_5 is central to the study of special relativity, general relativity and supersymmetry: its fundamental representation is the so-called spinor representation, while its adjoint representation generates the Lorentz group SO(3,1) of special relativity.", "The algebra formula_6 plays an important role in the study of chaos and fractals, as it generates the Möbius group SL(2,R), which describes the automorphisms of the hyperbolic plane, the simplest Riemann surface of negative curvature; by contrast, SL(2,C) describes the automorphisms of the hyperbolic 3-dimensional ball.", "By definition, the Lie algebra formula_8 consists of two-by-two complex matrices with zero trace.", "There are three standard basis elements, formula_9,formula_10, and formula_11, with\nformula_12, formula_13, formula_14.\nThe commutators are\nformula_15, formula_16, and formula_17\nThe Lie algebra formula_8 can be viewed as a subspace of its universal enveloping algebra formula_19", "and, in formula_20, there are the following commutator relations shown by induction:\nformula_21,\nformula_22.\nNote that, here, the powers formula_23, etc. refer to powers as elements of the algebra \"U\" and not matrix powers.", "The first basic fact (that follows from the above commutator relations) is: \nFrom this lemma, one deduces the following fundamental result:\nThe first statement is true since either formula_24 is zero or has formula_11-eigenvalue distinct from the eigenvalues of the others that are nonzero.", "Saying formula_26 is a formula_27-weight vector is equivalent to saying that it is simultaneously an eigenvector of formula_28; a short calculation then shows that, in that case, the formula_9-eigenvalue of formula_26 is zero: formula_31.", "Thus, for some integer formula_32, formula_33 and in particular, by the early lemma,\nformula_34\nwhich implies that formula_35.", "It remains to show formula_36 is irreducible.", "If formula_37 is a subrepresentation, then it admits an eigenvector, which must have eigenvalue of the form formula_38; thus is proportional to formula_24.", "By the preceding lemma, we have formula_40 is in formula_41 and thus formula_42.", "formula_43\nAs a corollary, one deduces:\n\nThe beautiful special case of formula_54 shows a general way to find irreducible representations of Lie algebras.", "Namely, we divide the algebra to three subalgebras \"h\" (the Cartan Subalgebra), \"e\", and \"f\", which behave approximately like their namesakes in formula_54.", "Namely, in an irreducible representation, we have a \"highest\" eigenvector of \"h\", on which \"e\" acts by zero.", "The basis of the irreducible representation is generated by the action of \"f\" on the highest eigenvectors of \"h\".", "See the theorem of the highest weight.", "When formula_57 for a complex vector space formula_44, each finite-dimensional irreducible representation of formula_59 can be found as a subrepresentation of a tensor power of formula_44." ]

[ 0, 1 ]

[ "The Lie group that it generates is the special linear group." ]

[ "In Ostend, West Flanders, three physically disabled musicians are looking for a drummer for their punk rock band.", "They want to perform only one time at a music competition.", "They approach famous writer Dries to be their drummer, the idea being that he also has a \"handicap\" in that he cannot actually play the drums.", "They plan to master only one song, Devo's \"Mongoloid.\"", "For Dries, this is an opportunity to get some inspiration for a new novel, so he accepts the offer.", "The band members decide to call the band The Feminists, since, they think four \"handicapped\" musicians are just as worthless as a group of feminists.", "Their main opponents are the band Harry Mulisch (an allusion to Harry Mulisch), also led by a writer, nicknamed Dikke Lul (\"Fat Cock\").", "As the story goes on Dries becomes more and more obsessed by his new novel and he tries to manipulate the band members and tries to find their weak spot.", "The music of The Feminists was in fact performed by Belgian band Millionaire and the Harry Mulisch song was sung by Belgian singer Flip Kowlier.", "# Lightning Bolt – \"2 Morro Morro Land\"\n# Madensuyu – \"Papa Bear\"\n# An Pierlé & White Velvet – \"Need You Now\"\n# The Tritones – \"Chagrin De La Mer\"\n# Mogwai – \"Hunted by a Freak\"\n# The Experimental Tropic Blues Band – \"Mexico Dream Blues\"\n# Flip Kowlier – \"De Grotste Lul Van 't Stad\"\n# Millionaire – \"Mongoloid\"\n# Isis - \"In Fiction\"\n# Isis – \"Grinning Mouths\"\n# Arno Hintjens – \"Een Boeket Met Pissebloemen\"\n# Augusta National Golf Club – \"People in Pairs\"\n# Mel Dune – \"Time Hangs Heavy on Your Hands\"\n# Ghinzu – \"Blow\"\n# Funeral Dress – \"Hello from the Underground\"\n# Millionaire – \"Deep Fish\"\n# Blutch – \"Moving Ground\"", "The film received mixed reviews.", "On Rotten Tomatoes the film has an approval rating of 44% based on 18 reviews, with an average rating of 4.81/10.", "On Metacritic, the film has a rating of 36 out of 100 based on 4 reviews, indicating \"generally unfavorable reviews\".", "In Belgium it caused some controversy due to the violence and explicit sex in the film." ]

[ 10, 11, 12, 13 ]

[ "While receiving mixed reviews at the time, it went on to become a cult film." ]

[ "Reviews of \"& Then Boom\" upon release were mixed.", "As of March 2015, the album holds an aggregated score of a 42 out of 100, indicating \"mixed or average reviews\", based on six sources.", "Allmusic journalist Anthony Tognazzini described \"& Then Boom\" as \"fizzy, fun retro-glam-electro-pop from beginning to end\", also noting the variety of the sounds on the record.", "There were three-star reviews from the \"Hot Press\" and \"Q\", with the former's Edwin McFee calling it a \"guilty pleasure\" and latter calling it a \"kitchen-sink hybrid\" that \"works remarkably well\".", "Caroline Sullivan of \"The Guardian\" gave the album a similar score, praising it as \"crisp electro-rock with a big hook in every tune, and lyrics that present them as a bunch of civic-minded young fellows.", "\"\nHowever, in more varied reviews, \"The Guardian\"'s sister paper \"The Observer\", Craig McLean opined that \"On the one hand, it's riotously good fun; on the other, it's a bit naff.\"", "Shaun Newport, writing for musicOMH, called it a \"frustration and disappointment\" to listen to, saying that the group \"sound nice, look nice but you’d be pressed to find any substance.\"", "However, he did give them credit for \"absolutely signif[ying] the beginning of the end of our love affair with the ’80s.", "It was cool, then it was pop and now it has shamelessly gone too far.", "Thank goodness we always have time to learn from our mistakes.\"", "Entertainment.ie's Lauren Murphy called most of the rapping \"cringeworthy\", with her overall verdict of the album describing it as \"two different, disjointed and discordant bands - neither with any direction, and both offering only minimal splashes of fun.", "\"\nThere were extremely negative reviews that questioned if BBC Radio 1's promotion of Iglu & Hartly was a joke, as well as criticized the record's cheap and unprofessional-sounding production and songwriting.", "It got a zero-out-of-ten review from David Renshaw of \"Drowned in Sound\", calling it \"the worst album of [2008].\"", "Racheal Crowther, a critic for \"DIY\", rated it a one out of ten, writing that the tracks were \"so similar it feels like listening to one really long song rather than an album.\"", "In a two-out-of-ten review from \"NME\", Rick Martin called it \"an abomination of a debut album, informed by all the most disgusting musical faux pas of the past 20 years.\"", "Jarvis Anderson responded to this negative critical reception in an interview; \"Reviews are interesting, I'll take negative criticism if someone explains why.", "We laugh hard at some of them – we take it with a light heart.", "I certainly haven't really read a negative review that's changed my mind about anything.", "If anyone's got an opinion maybe I'll use it if it's good, I'm not that stubborn.\"", "All songs written and composed by Iglu & Hartly" ]

[ 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 ]

[ "& Then Boom is the debut studio album by American new wave band Iglu & Hartly.", "It was released on September 29, 2008." ]

[ "Suning Commerce Group Co., Ltd. principally operates franchised retail shops of electronics appliances in China.", "The Company mainly offers colour televisions (TVs), audio and video (AV) players, disc players, refrigerators, washing machines, digital and information technology (IT) products, small household electronics, air conditioners, telecommunications products and other products.", "The company also provides installation and repair services for electronic appliances.", "As of December 31, 2010, the company had 1,311 stores in 231 cities across China.", "As of June 30, 2020, after the acquisition of the Carrefour supermarket network in China, Suning.", "Com owned 2,756 stores of various types:\n\n\n\nThere were 5,660 Suning.", "Com franchise stores, for a total of 8682.", "In the first quarter of 2021, another 831 stores were opened in June bringing the total to over 9000 cloud retail stores.", "Suning.com is present in China (the mainland China and Hong Kong S.A.R.) and Japan, in the retail industry, with over 10,000 stores.", "The company has been on the Fortune Global 500 list since 2017.", "On 26 December 1990, the predecessor of Suning was founded in Nanjing as an air-conditioner retail store.", "On 15 May 1996, ( \"Suning Domestic Appliance Co., Ltd.\") was incorporated.", "In 2000 the company was renamed into ( \"Suning Domestic Appliance (Group) Co., Ltd.\") and then Suning Appliance Chain Store (Group) Co., Ltd. ().", "In July 2004, Suning Appliance Chain Store (Group) was listed on SZSE.", "As at 31 December 2004, founder and chairman Zhang Jindong owned 35.12% stake, followed by Jiangsu Suning Appliance Co., Ltd. (), which was the parent company of Suning Appliance Chain Store (Group) Co., Ltd., for 18.29% stake.", "Chen Jinfeng () owned 8.78% stake.", "Moreover, Liu Xiaomeng, Zhang Jindong, Sun Weimin (CEO of Suning) and Chen Jinfeng owned 42%, 28%, 18% and 12% stake respectively in Jiangsu Suning Appliance, as at 2002.", "Suning Appliance Chain Store (Group) was renamed into Suning Appliance Co., Ltd. () in 2005.", "In 2009 Suning Appliance purchased Hong Kong based retail chain Citicall (as Citicall Retail Management), which became Hongkong Suning Commerce Co., Ltd., for HK$35 million and not more than HK$180 million for fixed assets.", "2011-, Suning's been gradually exploring \"online and offline\" multi-channel integration.", "On 19 February 2013, Suning Appliance announced to change the company name to Suning Commerce Group Co., Ltd. ()\nOn November 19, 2013, the Suning US R&D Center and Silicon Valley Research Institute was inaugurated in the city Palo Alto in California.", "The president of Suning Holdings Group Zhang Jindong officially announced the launch of the world's first research institute.", "Suning has clearly released the One-Wing Internet Roadmap, facility search will advance Suning's online to offline (O2O) business model (business strategy that attracts potential customers from online channels to shop in physical stores ) and will strengthen its back office, which include big data, business intelligence, high performance computing, online banking to improve efficiency operating in the retail sector.", "In October 2015 PPTV was sold to chairman Zhang Jindong via a subsidiary of Suning Culture Investment Management for US$398.4102 million, making a profit of RMB 1.355 billion.", "In 2015 financial year the comprehensive income of Suning Commerce Group in consolidated basis was just 1.01168 billion RMB.", "In April 2016 Suning Commerce acquired 4.90% stake in Nubia Technology from chairman Zhang Jindong for 283.7 million RMB, proportional to Zhang's subscription in the capital increase of Nubia in December 2015.", "On 3 June 2016 Suning Commerce Group issued about 1.86 billion new shares to Taobao (China) Software Co., Ltd., a subsidiary of Alibaba Group, for about 28 billion RMB.", "During the year the company sold some properties to Zhang, making extraordinary profit for the loss-making company.", "In 2018, the listed company was renamed to Suning.com Co., Ltd. ()\nIn 2019, Suning.com acquired 80% stake of the Chinese division of Carrefour.", "Also in 2019, Suning.", "Com acquired 37 department stores from the Wanda Group for 2,7 billion RMB.", "Was ranked as the largest omnichannel retailer in China and as the most valuable retail brand in China by the World Brand Lab, with a total brand value of US$39,093 billion and operating income of over US$37 billion.", "As reported by the US magazine Fortune in 2019, it has a turnover of US$37 billion, and can count on 130,455 employees.", "As of September 30, 2019, the number of registered members of Suning.com's retail platform reached 470 million users.", "In February 2021, Shenzhen International and Shenzhen Kunpeng Equity Investment Management (both state-owned enterprises) invest in Suning.com at 6.92 yuan per share, for a total of approximately 14.8 billion yuan (US$2.28 billion), or 8% of the total stake.", "of their capital company (745 million shares) and 15% (1.397 billion shares), for a total of 23%.", "In May 2021, Suning.com released its report for the first quarter of 2021.", "Suning.com achieved operating profit of 54.05 billion yuan (approximately over US$8 billion) and net profit attributable to shareholders of listed companies reached 456 million yuan (over US$70 million).", "The Retail Cloud continued to develop in the first quarter, with 584 new stores opened and the scale of sales increased by 69% year on year (the 247 stores opened in June must be added for a total of 831 new stores opened since the beginning of the year).", "Two branches of the Jiangsu Province-based government agency that oversees major state-owned businesses agreed to set up a 20 billion yuan (US$3.1 billion) fund with Suning.com's parent company Suning Holdings Group.", "The fund would be used to invest in its best performing assets and assets, a move that should give the company more breathing room to deal with its heavy debt load.", "In June 2021, Zhang Jindong's company will in fact receive 3.2 billion yuan (US$500.6 million) from a state fund as it struggles to recover from a liquidity crisis.", "Suning.com said 5.59% of his shares will be transferred to a fund consisting of four state-owned enterprises ultimately controlled by the Jiangsu provincial government.", "The shares are controlled by an affiliate of Zhang Jindong, president of Suning.com, who currently holds 19.7% of the total shares.", "The transfer price will be 6.12 yuan per share, 90% of Tuesday's closing price.", "According to the agreement, Zhang will have the obligation to buy back the shares for sale by April 1, 2022, paying a consideration of 3.182 billion yuan, plus interest (equal to about 3.85% on an annual basis).", "In mid June 2021, a Beijing court froze 3 billion yuan worth of shares Zhang holds in the group's retail arm Suning.com Co. for three years.", "With most of Zhang Jindong shares pledged as collateral for loans, that could complicate his ability to raise cash and potentially derail a state-backed rescue.", "Concerns over Suning's cash flow initially surged to the fore in September, when Zhang waived his right to a 20 billion yuan payment from Evergrande Group.Suning.com has stopped trading in its shares, the stock has fallen by the daily limit of 10%.", "In early July 2021, it is announced that the company has reached an agreement with a group of investors, both private and government officials, who intervened on behalf of Suning.com.", "The transaction in question, which sees its core in the new \"New Retail Innovation Fund Phase II\" fund worth 8.83 billion yuan (US$1.36 billion), led by the state asset management committee of Nanjing and the government of Jiangsu province, will take over 16.96% of the company.", "The fund includes brands such as Alibaba Group, Haier, Midea Group, TCL and Xiaomi as protagonists.", "With this intervention, the shares of Zhang Jindong will drop from 20.96% to 17.62%, Suning Holdings Group's stake from 3.98% to 2.73%, Suning Appliance Group from 10.68% to 1.39% and the Tibet Trust's stake fell from 3.07% to zero.", "After a period of suspension on the stock exchange, from June 16 to July 5, the company's shares are up by a maximum of 10% after the dealer announces the financial transaction.", "On 12 July 2021, Suning.com announces that the company's board of directors will be reorganized and that the resigned founder and chairman Zhang Jindong will take up his new position as honorary chairman of the company's board of directors.", "The company said Ren Jun, a board member, will perform chairman duties temporarily.", "Zhang Jindong will continue as legal representative until when no replacement is found.", "For the same role there are a total of four candidates, Huang Mingduan, Xian Handi, Cao Qun and Zhang Kangyang.", "Through an official note published on July 29, 2021, Suning.com announced the new composition of the company's board of directors.", "The new Chairman of the board is Huang Mingduan, former CEO of \"Sun Art Retail Group\", a supermarket chain owned by Alibaba Group, replacing Suning.com interim chairman Ren Jun. Alibaba is the company led by Jack Ma and which, as part of the \"New New Retail Fund\", bought shares in the subsidiary Suning in early July.", "Steven Zhang, president of Suning International, president of Inter, vice president of Suning Holdings Group and son of Suning's number one, Zhang Jindong, was also appointed to the board of directors, together with Huang Mingduan, Xian Handi and Cao Qun, as a non-independent director of the company's seventh board of directors.", "On July 30 released results for the first half of 2021.", "Total operating revenue for the half-year period was about .Net income attributable to shareholders of the listed company stood at about .", "\"Suning.com\" Logistics is one of the leading retail logistics companies in China, with a delivery network covering 351 cities, 2858 districts and counties in China, with over 100,000 truck drivers working for the company.", "It has 5 warehouses just for regular deliveries in eastern China.", "The automatic warehouse in Nanjing covers more than 200,000 square meters, also the total area of the warehouse facility covers 9.64 million square meters.", "The size of the facilities justifies the number one position in the Chinese retail sector.", "Along with the size, is added the intelligent technology used by Suning.", "Over the years E-commerce platforms have revolutionized the way consumers shop, e-commerce has people ordering a product from the comfort of their home and quickly with home delivery.", "To date, with the Suning APP, it can count on over 600 million registered users.", "Suning has incorporated an intelligent system into its operations, their state-of-the-art logistics facility.", "The entire Nanjing Logistics Center is divided into various parts intended to perform a variety of services.", "The storage of goods in the center is also divided into various segments that separate the products according to type and size.", "Use Schaefer technologies in its own intelligent logistics center.", "the ASRS system developed by Schaefer automation system, a German brand of automation technology in the storage sector, expands to the automated archiving and retrieval system.", "The intelligent logistics center is almost fully automated with less human intervention which makes the storage process and the retrieval process for delivery extremely easy, fast and reliable.", "The system monitoring room has a huge screen with around 20 people working to keep the whole process smoother and faster.", "In the hall it has feeds from multiple cctv cameras positioned throughout the store, as well as feeds from various ASRS systems and manual worker feeds for a holistic approach to the entire logistics.", "The workers separate the products after receiving them from suppliers, storing them in small, medium and large piles and pallets.", "The workers have to scan the RFID code and then it goes for the final packaging before it can be delivered to the customers.", "The point that needs to be highlighted is the speed of the process because so many steps are covered in speed.", "Suning has a delivery of the products, purchased by the user, within twelve hours from the time of the order.", "During the COVID-19 pandemic in mainland China, logistics and distribution grew significantly under the catalysis of the \"rule of self-isolation\".", "According to large-scale consumption data in epidemic prevention published by Suning, the volume of orders in China for Suning Convenience Stores increased by 419.6% year on year, and the volume of \"order online and collect in store \"of the Food Market rose by more than 655%.", "In the epidemic, every residential property exercised a certain level of\" block \", and the traditional\" contactless distribution \"cannot meet the current situation.", "The advantages of unmanned technology are significant, such that it can improve the efficiency of the transfer between logistics warehouses and consumers.", "As a result, unmanned logistics can accelerate its development even after the outbreak.", "Automated Unmanned Logistics describes its operational process from when packages leave the warehouse without personnel, are quickly transported overland to the distribution center in a driverless truck, then in the last mile they are delivered to their destination by an automated truck or drone.", "In 2018, Suning had completed the actual verification of its \"Xinglong One\" driverless truck.", "Technically, \"Xinglong-1\" uses advanced artificial intelligence technology that assists radar, high-precision maps, cameras and sensors, and can accurately identify obstacles up to 300 meters away in high-speed scenarios.", "In addition, it can also control the vehicle for emergency stops or bypass obstacles with a response speed of 25ms, and the highest speed of safe automatic driving can reach 80 km per hour.", "During the outbreak, Suning Logistics launched the \"contactless distribution service\" with 5G driverless vehicles.", "In collaboration with \"Suning Convenience Store\", \"Suning Logistics\" quickly set up an unmanned delivery team that guarantees instant delivery service within 3 km radius, further reducing the risk of infection between consumer and courier, further reducing the risk of infection between consumer and courier, effectively implementing the \"self-isolation rule\".\nIn 2018, Suning used autonomous delivery robots, which transport daily essentials such as drinks, fruit and snacks from the local store to the residents.", "The new unmanned delivery robot called \"BIU\" can autonomously plan the route and avoid obstacles, deliver to the customer and return to service.", "The cooperation mode of \"courier delivery + robot delivery to the community\" opens the last 100 meters of distribution to the community during the outbreak, ensuring the safety and health of users and a high quality home service experience.", "The Suning.com company, in addition to the retail sector of household appliances and electronic products, is active in the automotive sector, luxury boats and aircraft of many categories, from business jets to civil helicopters.", "The Suning.com Auto Company (Suning Auto) division opened 20 auto supermarkets in 2018 and in the following years will increase the number of auto shows in various cities, such as Xi'an, Chongqing, Chengdu and Tianjin.", "In addition to Chinese domestic brands, there are foreign brands in the stores, including BMW, Audi and Maserati.", "It also provides accessories, financial services and used cars.", "In 2017, Suning invested US$200 million in favor of Chinese carmaker Byton, which produces electric vehicles, which unveiled its first concept car at the Consumer Electronics Show in Las Vegas in January 2018.", "In August 2020, Suning entered into an agreement with the Chinese giant NIO, a Chinese car manufacturer active since 2014 based in Shanghai, specialized in the design and development of electric vehicles and which, with its own team, also participates in the world championship of Formula E. They have established a long-term partnership to strengthen strategic cooperation in various fields, including channel expansion, product sales, brand promotion, B2B cooperation, technology products and development, and create development opportunities.", "In the \"Suning Plaza Auto\", in accordance with the Baojun brand, the Baojun E100 is for sale is a two-seater electric microcar, with two doors and a hatch in the rear, and a design similar to a Smart electric drive and is the first vehicle in Baojun's electric microcar series, then there is the E200 and E300 version.", "Suning, in a joint venture with Alibaba Group and Tencent together with automobile manufacturers Changan Automobile, Dongfeng Motor Corporation and FAW Group collaborate for a service in the ride-sharing sector, with an investment of US$1.5 billion.", "In 2014 Suning.com sponsored the Spanish club FC Barcelona.", "In January 2016, one of the shareholders of Suning Commerce, Suning Appliance Group, completed the purchase of the Chinese football club Jiangsu F.C.", "The Chinese name of the football club was then renamed as literally \"Jiangsu Suning.com team\".", "According to Suning Commerce, the company sponsored the football club in 2016.", "On 6 June 2016 chairman Zhang Jindong, via his own private holding company Suning Holdings Group, signed a contract to purchase the majority stake in Italian football club Inter Milan.", "The deal was approved by the extraordinary general meeting on 28 June 2016, which after the deal, Suning Holdings Group owned 68.55% shares.", "Suning.com, the online shopping website of Suning Commerce, became a sponsor of the Italian club.", "On 28 December 2016 the League of Legends e-sports team T.Bear Gaming, at the time competing in the LSPL (China's secondary league), was acquired by Suning.com and re-branded as Suning Gaming.", "Following the re-branding, the team qualified for the League of Legends Pro League by winning the 2017 LSPL spring finals.", "After the deal in July 2021, Suning's honorary chair, Zhang Jindong, Suning Holdings Group and Suning Appliance Group will hold a 21.74% in Suning.com, while Alibaba's Taobao will remain the retailer's second-largest shareholder with a 19.99 percent stake.", "The Suning-Taobao alliance was announced in 2015.", "The consortium will become the third largest shareholder with a 16.96-percent stake.", "Board of Directors in charge as of 2021:" ]

[ 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62 ]

[ "Suning.com Co., Ltd. formerly Suning Commerce Group Co., Ltd. is one of the largest non-government retailers in China, headquartered in Nanjing, Jiangsu Province.", "It was listed on the Shenzhen Stock Exchange in 2004." ]

[ "Hanoch's father Shalom Albeck was the editor of a number of works by \nRishonim including Raavan, Meiri on tractate Yevamot, and HaEshkol by Abraham ben Isaac of Narbonne.", "Hanoch studied at the Vienna rabbinical academy and he received rabbinical ordination in 1915.", "In 1921 he received a degree from the University of Vienna.", "Between 1926 and 1936 Albeck taught in the Hochschule für die Wissenschaft des Judentums in Berlin.", "Albeck married Hendel Weiss (the sister of Abraham Weiss), and the two had three children.", "Two of his children are Michael Albeck, a lecturer in organic chemistry, and Shalom Albeck, a lecturer in Jewish law (and husband of advocate Pliah Albeck), both at Bar Ilan University.", "His grandson is Amnon Albeck a Professor of Chemistry and University's Vice-Rector at Bar-Ilan University.", "Albeck's son in law, Yoseph Aryeh Bachrach, was killed in the 1948 Arab–Israeli War in the battle for Jerusalem, leaving behind a wife and two children.", "In 1935, Albeck immigrated to Mandatory Palestine where he was appointed as professor and head of the Talmud department at the Hebrew University in Jerusalem, a position he held for 25 years.", "Albeck, a religiously observant Jew, published a number of books in Hebrew and German on rabbinical literature, including \"Introduction to the Mishna\", \"Studies in Baraita and Tosephta\", \"Introduction to the Talmuds\", and others.", "In addition, he published numerous articles in the journal \"Tarbiẕ\".", "Albeck also wrote a simple and concise commentary on the Mishna, appending longer footnotes at the ends of each volume.", "Pinchas Kehati sometimes quotes this work in his own commentary on the Mishna.", "While the vocalization (niqqud) received special attention in Albeck's edition, the text did not merit such attention, and therefore Albeck's Mishna is not a fully scientific version of the latter.", "Albeck's version was written as a continuation and expansion of the uncompleted earlier work of Hayyim Nahman Bialik.\nAlbeck's teachers include David Zvi Miller and Avigdor Optowitzer.", "His students include Avraham Goldberg and Abraham Joshua Heschel, one of the foremost Jewish thinkers in the 20th century.", "In 1957 it was announced that Albeck was to receive the Israel prize; however, as a matter of principle Albeck refused to accept the award.", "In 1959 Albeck was elected as a member of the Israel Academy of Sciences and Humanities.", "In 1969 Albeck was awarded the Bialik Prize for Jewish thought." ]

[ 8, 9, 10, 11, 12, 13, 14, 15 ]

[ "He was a foremost scholar of the Mishna and one of the pioneers of the scientific approach to Mishna study." ]

[ "Tatum and Webster were established figures in their 40s when they assembled for this album on September 11, 1956.", "According to Ben Ratliff in \"Jazz:", "A Critic's Guide to the 100 Most Important Recordings\", Tatum was known for virtuoso solo performance, while Webster had mellowed from his days with Duke Ellington.", "Despite their differences, they were a good match.", "According to Benny Green in the liner notes, this was because of Webster's tone and professionalism.", "Critic Scott Yanow agrees that \"the combination works very well\".", "This was among the last recordings by Tatum, who died on November 5 of that year.", "The session was released in 1958 on an LP produced by Norman Granz for Verve Records under the title \"Art Tatum – Ben Webster Quartet\".", "By 1971, Granz had attempted to gain access to this and his other out-of-print collaborations with Art Tatum from Verve, even offering to buy the masters.", "He acquired the rights after the 1973 formation of his own label, Pablo Records, and reissued those albums in 1975 under \"The Tatum Group Masterpieces\" and \"The Tatum Solo Masterpieces\" as individual albums and as two boxed sets.", "One track from the session, \"All the Things You Are\", was later included in the 12-track CD \"The Best of the Pablo Group Masterpieces\".", "The album was reissued on January 31, 1992 with bonus tracks.", "The album was critically well received.", "In a 1994 review, \"The Hartford Courant\" described it as \"delectable\", with \"Webster's big, breathy tone\" wrapping \"Tatum's arabesques in a warm, loving embrace.\"", "\"The Washington Post\" characterized it as \"[a] great way to introduce two of the greats.", "\"\nThe album is included in several books on the top albums in jazz, including \"Jazz: A Critic's Guide to the 100 Most Important Recordings\", where it is listed at No. 42, and in \"The 101 Best Jazz Albums\", where author Leonard Lyons calls volume 8 the \"most exciting\" among the Group Masterpieces collection.", "\"The Penguin Guide to Jazz Recordings\" included the album in its suggested “core collection” of essential recordings.", "With volumes one and seven of the Group Masterpieces, it is recommended for inclusion in medium-sized or larger public libraries and all academic libraries by the Music Library Association in \"A Basic Music Library: Essential Scores and Sound Recordings\".", "# \"Gone With the Wind\" (Herb Magidson, Allie Wrubel) – 4:48\n# \"All the Things You Are\" (Oscar Hammerstein II, Jerome Kern) – 7:15 \n# \"Have You Met Miss Jones?\"", "(Richard Rodgers, Lorenz Hart) – 4:49\n# \"My One and Only Love\" (Robert Mellin, Guy Wood) – 6:15\n# \"Night and Day\" (Cole Porter) – 5:31\n# \"My Ideal\" (Newell Chase, Leo Robin, Richard A. Whiting) – 7:18\n# \"Where or When\" (Rodgers, Hart) – 6:28", "# \"Gone With the Wind\" (alternate take 1) (Magidson, Wrubel) – 4:53\n# \"Gone With the Wind\" (alternate take 2) (Magidson, Wrubel) – 4:51\n# \"Have You Met Miss Jones?\" (alternate take) (Rodgers, Hart) – 5:02" ]

[ 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 ]

[ "The 1956 session was originally released in 1958 on Verve Records album produced by Norman Granz as \"The Art Tatum - Ben Webster Quartet\", but Granz re-acquired the masters in the 1970s after the album was allowed to go out of print.", "He reissued the material as one of a series of eight Group Masterpieces featuring Tatum in collaboration with other artists, also issuing it as part of a boxed set, \"The Complete Pablo Group Masterpieces\".", "The album has been reissued on CD, including a January 31, 1992 version with bonus tracks." ]

[ "Tatum and Webster were established figures in their 40s when they assembled for this album on September 11, 1956.", "According to Ben Ratliff in \"Jazz:", "A Critic's Guide to the 100 Most Important Recordings\", Tatum was known for virtuoso solo performance, while Webster had mellowed from his days with Duke Ellington.", "Despite their differences, they were a good match.", "According to Benny Green in the liner notes, this was because of Webster's tone and professionalism.", "Critic Scott Yanow agrees that \"the combination works very well\".", "This was among the last recordings by Tatum, who died on November 5 of that year.", "The session was released in 1958 on an LP produced by Norman Granz for Verve Records under the title \"Art Tatum – Ben Webster Quartet\".", "By 1971, Granz had attempted to gain access to this and his other out-of-print collaborations with Art Tatum from Verve, even offering to buy the masters.", "He acquired the rights after the 1973 formation of his own label, Pablo Records, and reissued those albums in 1975 under \"The Tatum Group Masterpieces\" and \"The Tatum Solo Masterpieces\" as individual albums and as two boxed sets.", "One track from the session, \"All the Things You Are\", was later included in the 12-track CD \"The Best of the Pablo Group Masterpieces\".", "The album was reissued on January 31, 1992 with bonus tracks.", "The album was critically well received.", "In a 1994 review, \"The Hartford Courant\" described it as \"delectable\", with \"Webster's big, breathy tone\" wrapping \"Tatum's arabesques in a warm, loving embrace.\"", "\"The Washington Post\" characterized it as \"[a] great way to introduce two of the greats.", "\"\nThe album is included in several books on the top albums in jazz, including \"Jazz: A Critic's Guide to the 100 Most Important Recordings\", where it is listed at No. 42, and in \"The 101 Best Jazz Albums\", where author Leonard Lyons calls volume 8 the \"most exciting\" among the Group Masterpieces collection.", "\"The Penguin Guide to Jazz Recordings\" included the album in its suggested “core collection” of essential recordings.", "With volumes one and seven of the Group Masterpieces, it is recommended for inclusion in medium-sized or larger public libraries and all academic libraries by the Music Library Association in \"A Basic Music Library: Essential Scores and Sound Recordings\".", "# \"Gone With the Wind\" (Herb Magidson, Allie Wrubel) – 4:48\n# \"All the Things You Are\" (Oscar Hammerstein II, Jerome Kern) – 7:15 \n# \"Have You Met Miss Jones?\"", "(Richard Rodgers, Lorenz Hart) – 4:49\n# \"My One and Only Love\" (Robert Mellin, Guy Wood) – 6:15\n# \"Night and Day\" (Cole Porter) – 5:31\n# \"My Ideal\" (Newell Chase, Leo Robin, Richard A. Whiting) – 7:18\n# \"Where or When\" (Rodgers, Hart) – 6:28", "# \"Gone With the Wind\" (alternate take 1) (Magidson, Wrubel) – 4:53\n# \"Gone With the Wind\" (alternate take 2) (Magidson, Wrubel) – 4:51\n# \"Have You Met Miss Jones?\" (alternate take) (Rodgers, Hart) – 5:02" ]

[ 12, 13, 14, 15, 16, 17 ]

[ "The album was critically well-received, with critics singling out the combination of Webster's tone with Tatum's elaborate piano playing.", "The album is listed in several volumes as among the best in jazz and is recommended by the Music Library Association as an important piece for music libraries." ]

[ "ESGO stated the mission as following “ESGO strives to improve the health and well-being of women with gynaecological cancers through prevention, research, excellence in care and education.”", "ESGO's annual conference regularly attracts over 1,500 participants, and enables European health care professionals and researchers involved in the field of gynaecological oncology to network, discuss, debate, and disseminate new medical and scientific studies relating to the treatment and care of gynaecological cancer.", "In addition to its conferences, ESGO organizes a number of educational events, workshops and backed meetings throughout the year and provides travel grants to its members.", "ESGO is also active in developing educational tools such as videos, DVDs, and webcast lectures for the use of relevant health professionals.", "Currently, ESGO has several networks 1) European Network of Gynaecological Oncological Trial groups (ENGOT), 2) European Network of Young Gynaecological Oncologists (ENYGO), 3)European Network of Gynaecological Cancer Advocacy Groups (ENGAGe), 4) European Network of Individual Treatment in Endometrial Cancer ( ENITEC ), and 5)International Network on Cancer, Infertility and Pregnancy (INCIP).", "The European Network of Gynaecological Oncological Trial Groups (ENGOT), an integral part of ESGO, is active in coordinating and promoting clinical trials on patients with gynaecological cancers all over Europe.", "In cooperation with the European Board and College of Obstetrics and Gynaecology (EBCOG) and on behalf of the European Union of Medical Specialists (UEMS), ESGO provides certification for trained gynaecologic oncologists and also accredits relevant instructional institutions.", "ESGO's gynaecological oncology training and accreditation programmes have become recognized standards in a number of European countries.", "ESGO's peer-reviewed official medical journal, the \"International Journal of Gynecological Cancer\" (IJGC), is annually published nine times and covers research related to gynaecological cancer such as experimental studies, chemotherapy, radiotherapy, diagnostic techniques, pathology epidemiology and surgery.", "Prof. Dr. Pedro Ramirez, MD is the current editor-in-chief." ]

[ 1, 2, 3 ]

[ "The European Society of Gynaecological Oncology (ESGO) is a Europe-wide society of health care professionals and researchers specializing in the study, prevention, treatment and care of gynaecological cancers." ]

[ "The Zero S began shipping in volume in 2010, the first model year to include the Agni Motor, at which time the DS, a dual-sport model based on the S chassis became available.", "The XU, a smaller street bike with a removable battery, based on the same chassis as the Zero dirtbikes was produced from 2011 to 2013.", "In 2012, Zero introduced the ZF9 Power Pack with the Zero S & DS models making them the first production electric motorcycles that can exceed an EPA-estimated 100 miles on a single charge.", "In 2013 the Zero S and DS were completely redesigned.", "The battery capacity was increased to 11.4kWh, and a new brushless permanent magnet AC motor was introduced.", "In 2013 the Zero FX dual-sport model with modular removable power packs was introduced.", "CHAdeMO fast charging was also available on 2013 models.", "In 2014 the optional 2.8kWh \"Power Tank\" became available.", "2014 also saw the addition of the Zero SR to the range, a higher performance version of the Zero S, incorporating more powerful controller electrics and a motor with higher temperature magnets.", "The 2015 models had battery pack size increased to 12.5kWh, for a total possible maximum capacity of 15.3kWh including the optional Power Tank.", "Also introduced in 2015 were standard ABS brakes and Showa suspension.", "CHAdeMO fast charging was eliminated as an option, leaving instead an optional quick charger accessory at added cost.", "In 2016, Zero announced the DSR and FXS models.", "The DSR is based on the DS, but with the more powerful motor from the SR.", "The FXS is a supermoto version of the FX.", "Additional changes for the model year include the availability of a \"Charge Tank\" accessory, which is an on-board Level 2 charging system compatible with the J1772 plug.", "Battery pack size improved again to 13.0kWh (3.3kWh per FX power pack), for a total possible maximum capacity of 15.9kWh including the optional Power Tank.", "The air-cooled motors on the SR, DSR, and FXS were revised to reduce heat produced during high output.", "For 2017, all models have the interior-permanent-magnet (IPM) motor.", "All models also received a larger capacity controller which provides an increase in maximum torque and horsepower output, up to 116 lbs/ft on the SR and DSR models.", "All models but the S ZF13.0 (Already Installed) receive a wider, high-torque carbon fiber reinforced belt.", "Other changes for 2017 include a locking tank box and more durable paint on S/DS/SR/DSR models, and the ability for owners to update their bike's firmware through the mobile app.", "For 2018 Zero introduced the ZF14.4 battery, available for the S and D models (alongside the ZF7.2 battery) and the SR and DSR models (where it is the only available option).", "Until the introduction of the 2020 SR/F, traction control was absent across the lineup.", "For 2020, new trellis-framed motorcycles were introduced, the SR/f and the faired SR/s, with higher performance, as well as 6 kW and 12 kW onboard charging options.", "Zero Motorcycles also produces a line of electric motorcycles for police, authority, and military use.", "The fleet motorcycles are based upon the company's standard models but outfitted with equipment such as police lights, sirens, crash bars, and storage accessories.", "In 2016, the company celebrated its 10th anniversary.", "Zero's Lithium-ion power packs and motors were developed in-house, and are branded under the names \"Z-Force\" and \"ZF\" (even though ZF is since 1915 the well-established abbreviation of ZF Friedrichshafen, a spin-off from Zeppelin that nowadays also offers electric drive-trains and motorcycle parts).", "The Zero power packs use a cell configuration that operates at (nominally) 102 volts, which is well below the threshold of 200 V required for Combined Charging System (CCS) which is the most common DC fast charging standard, at least outside of Japan and China.", "Some electric motorcycle competitors like Energica and (Harley-Davidson)", "LiveWire offer CCS.", "In electric cars, 400 V are common, some new high performance vehicles use up to 924 V.\nThe motorcycles' propulsion is provided by a single electric, air-cooled, brushless, permanent-magnet 3-phase AC motor.", "The motor is coupled to the rear wheel by a belt or – optionally on the Zero FX – a chain.", "A controller manages the power delivery and comes in 420-amp, 550-amp, 660-amp, and 775-amp sizes depending on the year and model.", "Zero has made their electric powertrain systems available to commercial partners.", "Zero Motorcycles has had success racing at Pikes Peak.", "Zero has won the production electric motorcycle class in 2013, 2014, and 2015.", "In 2014 a Zero FX was the first production electric motorcycle to break the 12 minute mark.", "In 2012, Brandon Miller set a Bonneville Land Speed Record on a Zero S ZF6 model.", "He achieved an average speed of 101.652 mph over a one-mile course.", "This beat the previous record for modified production motorcycles weighing less than 150 kilograms by over 23 mph.", "Zero Motorcycles hosted an endurance racing event for electric motorcycles on April 4–5, 2009, called the 24 Hours of Electricross.", "This event was the largest electric motorcycle race to date.", "The 10 teams competed on Zero X electric motocross bikes.", "Team HotChalk set a Guinness world record for the furthest distance traveled on an all-electric off-road motorcycle in 24 hours at just over 500 miles.", "Racers have used Zero Motorcycles against gasoline motorcycles in a number of other forms of racing, including flat-track, hare scrambles, supermoto, and supercross.", "Zero's main competitors were the now defunct Victory Empulse (formerly Brammo), and halted Alta Motors, but current and upcoming models from Evoke, Lightning, and Energica compete with Zero's product lineup.", "Some of the larger OEMs have also released electric motorcycles and prototypes such as the Harley-Davidson LiveWire motorcycle and Yamaha's PES2 and PED2 concepts.", "All Zero Motorcycles models had a large number of recalls compared to Zero Motorcycles volumes (some years, up to 50% of the 2000 motorcycles sold have been subject to recalls) as well as many quality issues.", "Press articles also mentioned service issues and management turnover, as well as injuries leading to lawsuits." ]

[ 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27 ]

[ "Zero Motorcycles Inc. is an American manufacturer of electric motorcycles.", "Zero makes a line of electric motorcycles including the Zero S (street), SR (street racing), and FXS (supermoto), and the Zero DS (dual-sport) DSR (dual-sport racing), FX (motocross), and the new for 2020 SR/F." ]

[ "BASe Airlines was established in December 1991 by experienced aviation pilots and technicians.", "The company was based in Budapest, so Budapest-Ferihegy Airport was chosen as the basis for the operations.", "The flight operations began with two leased LET L-410 and included charter and freight flights.", "From that moment onwards, scheduled passenger flights to neighboring countries began, such as Austria, Ukraine and Croatia, under the call sign of the former AVIAEXPRESS.", "Starting in 1992, on behalf of foreign partners, night flights were made to Austrian, Slovak and Italian destinations from Budapest, Zagreb and Ljubljana.", "In addition to the operations mentioned above, between 1994 and 2006, BASe Airlines managed and operated eleven Hungarian National Health Service helicopters for HEMS (Helicopter Emergency Medical Service) tasks based on a network of six heliports, as well as a fixed wing aircraft for international air ambulance services.", "Starting in 1996, the operation of a special equipped L-410 UVP-E8 (aircraft for aerial works - Flight Inspection Service) by a contract with Budapest Airport Rt. has further improved BASe capabilities, now able to provide precision calibration/test flights of civil and tactical air navigation systems both in Hungary and abroad.", "The first \"Turbolet\" aircraft was purchased in 1997, followed by the second in 2000, and by the first helicopter.", "The same aircraft, as well as some leased Antonov An-26B, were also used for freight transport, both regular and charter, to destinations throughout Europe since 2002.", "At the same time BASe Airlines operated scheduled flights on behalf of Bosnian Airlines to Rome and Belgrade.", "According to the challenge of the tourism, BASe started to operate some seasonal flights from Budapest and other small Hungarian airports to famous tourist destinations in Croatia and Montenegro since 2003.", "With the first Embraer EMB 120, purchased in the summer of 2005, tourist flights have continued and increased, adding to the destinations also Tivat, Corfu and Burgas, in collaboration with the major Hungarian Tour Operators.", "Between 2006 and 2011, BASe Airlines flew on behalf of Air Moldova, in particular following the expansion of the fleet, which since 2008 has seen the purchase of two additional EMB-120s.", "In the same period BASe began to operate a helicopter Bell 206 for tourist flights and aerial work.", "In 2007, a contract was signed with the national airline Malév Hungarian Airlines to start running some of its regional flights.", "During the first season, BAS Airlines flew to Ljubljana and Timișoara on behalf of Malév.", "The BASe fleet includes the following aircraft types (at October 2018):" ]

[ 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 ]

[ "Budapest Aircraft Service Ltd. or BASe Airlines ( or BASe Kft), is a Hungarian charter airline based in Budapest, Hungary." ]

[ "The time between exposure to the virus and development of symptoms, called the incubation period, is 1–4 days, most commonly 1–2 days.", "Many infections, however, are asymptomatic.", "The onset of symptoms is sudden, and initial symptoms are predominately non-specific, including fever, chills, headaches, muscle pain or aching, a feeling of discomfort, loss of appetite, lack of energy/fatigue, and confusion.", "These symptoms are usually accompanied by respiratory symptoms such as a dry cough, sore or dry throat, hoarse voice, and a stuffy or runny nose.", "Coughing is the most common symptom.", "Gastrointestinal symptoms may also occur, including nausea, vomiting, diarrhea, and gastroenteritis, especially in children.", "The standard influenza symptoms typically last for 2–8 days.", "A 2021 study suggests influenza can cause long lasting symptoms in a similar way to long COVID.\nSymptomatic infections are usually mild and limited to the upper respiratory tract, but progression to pneumonia is relatively common.", "Pneumonia may be caused by the primary viral infection or by a secondary bacterial infection.", "Primary pneumonia is characterized by rapid progression of fever, cough, labored breathing, and low oxygen levels that cause bluish skin.", "It is especially common among those who have an underlying cardiovascular disease such as rheumatic heart disease.", "Secondary pneumonia typically has a period of improvement in symptoms for 1–3 weeks followed by recurrent fever, sputum production, and fluid buildup in the lungs, but can also occur just a few days after influenza symptoms appear.", "About a third of primary pneumonia cases are followed by secondary pneumonia, which is most frequently caused by the bacteria \"Streptococcus pneumoniae\" and \"Staphylococcus aureus\".", "Influenza viruses comprise four species.", "Each of the four species is the sole member of its own genus, and the four influenza genera comprise four of the seven genera in the family \"Orthomyxoviridae\".", "They are:\n\n\nIAV is responsible for most cases of severe illness as well as seasonal epidemics and occasional pandemics.", "It infects people of all ages but tends to disproportionately cause severe illness in the elderly, the very young, and those who have chronic health issues.", "Birds are the primary reservoir of IAV, especially aquatic birds such as ducks, geese, shorebirds, and gulls, but the virus also circulates among mammals, including pigs, horses, and marine mammals.", "IAV is classified into subtypes based on the viral proteins haemagglutinin (H) and neuraminidase (N).", "As of 2019, 18 H subtypes and 11 N subtypes have been identified.", "Most potential combinations have been reported in birds, but H17-18 and N10-11 have only been found in bats.", "Only H subtypes H1-3 and N subtypes N1-2 are known to have circulated in humans, the current IAV subtypes in circulation being H1N1 and H3N2.", "IAVs can be classified more specifically to also include natural host species, geographical origin, year of isolation, and strain number, such as H1N1/A/duck/Alberta/35/76.", "IBV mainly infects humans but has been identified in seals, horses, dogs, and pigs.", "IBV does not have subtypes like IAV but has two antigenically distinct lineages, termed the B/Victoria/2/1987-like and B/Yamagata/16/1988-like lineages, or simply (B/)Victoria(-like) and (B/)Yamagata(-like).", "Both lineages are in circulation in humans, disproportionately affecting children.", "IBVs contribute to seasonal epidemics alongside IAVs but have never been associated with a pandemic.", "ICV, like IBV, is primarily found in humans, though it also has been detected in pigs, feral dogs, dromedary camels, cattle, and dogs.", "ICV infection primarily affects children and is usually asymptomatic or has mild cold-like symptoms, though more severe symptoms such as gastroenteritis and pneumonia can occur.", "Unlike IAV and IBV, ICV has not been a major focus of research pertaining to antiviral drugs, vaccines, and other measures against influenza.", "ICV is subclassified into six genetic/antigenic lineages.", "IDV has been isolated from pigs and cattle, the latter being the natural reservoir.", "Infection has also been observed in humans, horses, dromedary camels, and small ruminants such as goats and sheep.", "IDV is distantly related to ICV.", "While cattle workers have occasionally tested positive to prior IDV infection, it is not known to cause disease in humans.", "ICV and IDV experience a slower rate of antigenic evolution than IAV and IBV.", "Because of this antigenic stability, relatively few novel lineages emerge.", "Influenza viruses have a negative-sense, single-stranded RNA genome that is segmented.", "The negative sense of the genome means it can be used as a template to synthesize messenger RNA (mRNA).", "IAV and IBV have eight genome segments that encode 10 major proteins.", "ICV and IDV have seven genome segments that encode nine major proteins.", "Three segments encode three subunits of an RNA-dependent RNA polymerase (RdRp) complex: PB1, a transcriptase, PB2, which recognizes 5' caps, and PA (P3 for ICV and IDV), an endonuclease.", "The matrix protein (M1) and membrane protein (M2) share a segment, as do the non-structural protein (NS1) and the nuclear export protein (NEP).", "For IAV and IBV, hemagglutinin (HA) and neuraminidase (NA) are encoded on one segment each, whereas ICV and IDV encode a hemagglutinin-esterase fusion (HEF) protein on one segment that merges the functions of HA and NA.", "The final genome segment encodes the viral nucleoprotein (NP).", "Influenza viruses also encode various accessory proteins, such as PB1-F2 and PA-X, that are expressed through alternative open reading frames and which are important in host defense suppression, virulence, and pathogenicity.", "The virus particle, called a virion, is pleomorphic and varies between being filamentous, bacilliform, or spherical in shape.", "Clinical isolates tend to be pleomorphic, whereas strains adapted to laboratory growth typically produce spherical virions.", "Filamentous virions are about 250 nanometers (nm) by 80 nm, bacilliform 120–250 by 95 nm, and spherical 120 nm in diameter.", "The virion consists of each segment of the genome bound to nucleoproteins in separate ribonucleoprotein (RNP) complexes for each segment, all of which are surrounded by a lipid bilayer membrane called the viral envelope.", "There is a copy of the RdRp, all subunits included, bound to each RNP.", "The envelope is reinforced structurally by matrix proteins on the interior that enclose the RNPs, and the envelope contains HA and NA (or HEF) proteins extending outward from the exterior surface of the envelope.", "HA and HEF proteins have a distinct \"head\" and \"stalk\" structure.", "M2 proteins form proton ion channels through the viral envelope that are required for viral entry and exit.", "IBVs contain a surface protein named NB that is anchored in the envelope, but its function is unknown.", "The viral life cycle begins by binding to a target cell.", "Binding is mediated by the viral HA proteins on the surface of the evelope, which bind to cells that contain sialic acid receptors on the surface of the cell membrane.", "For N1 subtypes with the \"G147R\" mutation and N2 subtypes, the NA protein can initiate entry.", "Prior to binding, NA proteins promote access to target cells by degrading mucous, which helps to remove extracellular decoy receptors that would impede access to target cells.", "After binding, the virus is internalized into the cell by an endosome that contains the virion inside it.", "The endosome is acidified by cellular vATPase to have lower pH, which triggers a conformational change in HA that allows fusion of the viral envelope with the endosomal membrane.", "At the same time, hydrogen ions diffuse into the virion through M2 ion channels, disrupting internal protein-protein interactions to release RNPs into the host cell's cytosol.", "The M1 protein shell surrounding RNPs is degraded, fully uncoating RNPs in the cytosol.", "RNPs are then imported into the nucleus with the help of viral localization signals.", "There, the viral RNA polymerase transcribes mRNA using the genomic negative-sense strand as a template.", "The polymerase snatches 5' caps for viral mRNA from cellular RNA to prime mRNA synthesis and the 3'-end of mRNA is polyadenylated at the end of transcription.", "Once viral mRNA is transcribed, it is exported out of the nucleus and translated by host ribosomes in a cap-dependent manner to synthesize viral proteins.", "RdRp also synthesizes complementary positive-sense strands of the viral genome in a complementary RNP complex which are then used as templates by viral polymerases to synthesize copies of the negative-sense genome.", "During these processes, RdRps of avian influenza viruses (AIVs) function optimally at a higher temperature than mammalian influenza viruses.", "Newly synthesized viral polymerase subunits and NP proteins are imported to the nucleus to further increase the rate of viral replication and form RNPs.", "HA, NA, and M2 proteins are trafficked with the aid of M1 and NEP proteins to the cell membrane through the Golgi apparatus and inserted into the cell's membrane.", "Viral non-structural proteins including NS1, PB1-F2, and PA-X regulate host cellular processes to disable antiviral responses.", "PB1-F2 aso interacts with PB1 to keep polymerases in the nucleus longer.", "M1 and NEP proteins localize to the nucleus during the later stages of infection, bind to viral RNPs and mediate their export to the cytoplasm where they migrate to the cell membrane with the aid of recycled endosomes and are bundled into the segments of the genome.", "Progenic viruses leave the cell by budding from the cell membrane, which is initiated by the accumulation of M1 proteins at the cytoplasmic side of the membrane.", "The viral genome is incorporated inside a viral envelope derived from portions of the cell membrane that have HA, NA, and M2 proteins.", "At the end of budding, HA proteins remain attached to cellular sialic acid until they are cleaved by the sialidase activity of NA proteins.", "The virion is then released from the cell.", "The sialidase activity of NA also cleaves any sialic acid residues from the viral surface, which helps prevent newly assembled viruses from aggregating near the cell surface and improving infectivity.", "Similar to other aspects of influenza replication, optimal NA activity is temperature- and pH-dependent.", "Ultimately, presence of large quantities of viral RNA in the cell triggers apoptosis, i.e. programmed cell death, which is initiated by cellular factors to restrict viral replication.", "Two key processes that influenza viruses evolve through are antigenic drift and antigenic shift.", "Antigenic drift is when an influenza virus's antigens change due to the gradual accumulation of mutations in the antigen's (HA or NA) gene.", "This can occur in response to evolutionary pressure exerted by the host immune response.", "Antigenic drift is especially common for the HA protein, in which just a few amino acid changes in the head region can constitute antigenic drift.", "The result is the production of novel strains that can evade pre-existing antibody-mediated immunity.", "Antigenic drift occurs in all influenza species but is slower in B than A and slowest in C and D. Antigenic drift is a major cause of seasonal influenza, and requires that flu vaccines be updated annually.", "HA is the main component of inactivated vaccines, so surveillance monitors antigenic drift of this antigen among circulating strains.", "Antigenic evolution of influenza viruses of humans appears to be faster than influenza viruses in swine and equines.", "In wild birds, within-subtype antigenic variation appears to be limited but has been observed in poultry.", "Antigenic shift is a sudden, drastic change in an influenza virus's antigen, usually HA.", "During antigenic shift, antigenically different strains that infect the same cell can reassort genome segments with each other, producing hybrid progeny.", "Since all influenza viruses have segmented genomes, all are capable of reassortment.", "Antigenic shift, however, only occurs among influenza viruses of the same genus and most commonly occurs among IAVs.", "In particular, reassortment is very common in AIVs, creating a large diversity of influenza viruses in birds, but is uncommon in human, equine, and canine lineages.", "Pigs, bats, and quails have receptors for both mammalian and avian IAVs, so they are potential \"mixing vessels\" for reassortment.", "If an animal strain reassorts with a human strain, then a novel strain can emerge that is capable of human-to-human transmission.", "This has caused pandemics, but only a limited number have occurred, so it is difficult to predict when the next will happen.", "People who are infected can transmit influenza viruses through breathing, talking, coughing, and sneezing, which spread respiratory droplets and aerosols that contain virus particles into the air.", "A person susceptible to infection can then contract influenza by coming into contact with these particles.", "Respiratory droplets are relatively large and travel less than two meters before falling onto nearby surfaces.", "Aerosols are smaller and remain suspended in the air longer, so they take longer to settle and can travel further than respiratory droplets.", "Inhalation of aerosols can lead to infection, but most transmission is in the area about two meters around an infected person via respiratory droplets that come into contact with mucosa of the upper respiratory tract.", "Transmission through contact with a person, bodily fluids, or intermediate objects (fomites) can also occur, such as through contaminated hands and surfaces since influenza viruses can survive for hours on non-porous surfaces.", "If one's hands are contaminated, then touching one's face can cause infection.", "Influenza is usually transmissible from one day before the onset of symptoms to 5–7 days after.", "In healthy adults, the virus is shed for up to 3–5 days.", "In children and the immunocompromised, the virus may be transmissible for several weeks.", "Children ages 2–17 are considered to be the primary and most efficient spreaders of influenza.", "Children who have not had multiple prior exposures to influenza viruses shed the virus at greater quantities and for a longer duration than other children.", "People who are at risk of exposure to influenza include health care workers, social care workers, and those who live with or care for people vulnerable to influenza.", "In long-term care facilities, the flu can spread rapidly after it is introduced.", "A variety of factors likely encourage influenza transmission, including lower temperature, lower absolute and relative humidity, less ultraviolet radiation from the Sun, and crowding.", "Influenza viruses that infect the upper respiratory tract like H1N1 tend to be more mild but more transmissible, whereas those that infect the lower respiratory tract like H5N1 tend to cause more severe illness but are less contagious.", "In humans, influenza viruses first cause infection by infecting epithelial cells in the respiratory tract.", "Illness during infection is primarily the result of lung inflammation and compromise caused by epithelial cell infection and death, combined with inflammation caused by the immune system's response to infection.", "Non-respiratory organs can become involved, but the mechanisms by which influenza is involved in these cases are unknown.", "Severe respiratory illness can be caused by multiple, non-exclusive mechanisms, including obstruction of the airways, loss of alveolar structure, loss of lung epithelial integrity due to epithelial cell infection and death, and degradation of the extracellular matrix that maintains lung structure.", "In particular, alveolar cell infection appears to drive severe symptoms since this results in impaired gas exchange and enables viruses to infect endothelial cells, which produce large quantities of pro-inflammatory cytokines.", "Pneumonia caused by influenza viruses is characterized by high levels of viral replication in the lower respiratory tract, accompanied by a strong pro-inflammatory response called a cytokine storm.", "Infection with H5N1 or H7N9 especially produces high levels of pro-inflammatory cytokines.", "In bacterial infections, early depletion of macrophages during influenza creates a favorable environment in the lungs for bacterial growth since these white blood cells are important in responding to bacterial infection.", "Host mechanisms to encourage tissue repair may inadvertently allow bacterial infection.", "Infection also induces production of systemic glucocorticoids that can reduce inflammation to preserve tissue integrity but allow increased bacterial growth.", "The pathophysiology of influenza is significantly influenced by which receptors influenza viruses bind to during entry into cells.", "Mammalian influenza viruses preferentially bind to sialic acids connected to the rest of the oligosaccharide by an α-2,6 link, most commonly found in various respiratory cells, such as respiratory and retinal epithelial cells.", "AIVs prefer sialic acids with an α-2,3 linkage, which are most common in birds in gastrointestinal epithelial cells and in humans in the lower respiratory tract.", "Furthermore, cleavage of the HA protein into HA, the binding subunit, and HA, the fusion subunit, is performed by different proteases, affecting which cells can be infected.", "For mammalian influenza viruses and low pathogenic AIVs, cleavage is extracellular, which limits infection to cells that have the appropriate proteases, whereas for highly pathogenic AIVs, cleavage is intracellular and performed by ubiquitous proteases, which allows for infection of a greater variety of cells, thereby contributing to more severe disease.", "Cells possess sensors to detect viral RNA, which can then induce interferon production.", "Interferons mediate expression of antiviral proteins and proteins that recruit immune cells to the infection site, and they also notify nearby uninfected cells of infection.", "Some infected cells release pro-inflammatory cytokines that recruit immune cells to the site of infection.", "Immune cells control viral infection by killing infected cells and phagocytizing viral particles and apoptotic cells.", "An exacerbated immune response, however, can harm the host organism through a cytokine storm.", "To counter the immune response, influenza viruses encode various non-structural proteins, including NS1, NEP, PB1-F2, and PA-X, that are involved in curtailing the host immune response by suppressing interferon production and host gene expression.", "B cells, a type of white blood cell, produce antibodies that bind to influenza antigens HA and NA (or HEF) and other proteins to a lesser degree.", "Once bound to these proteins, antibodies block virions from binding to cellular receptors, neutralizing the virus.", "In humans, a sizeable antibody response occurs ~1 week after viral exposure.", "This antibody response is typically robust and long-lasting, especially for ICV and IDV.", "In other words, people exposed to a certain strain in childhood still possess antibodies to that strain at a reasonable level later in life, which can provide some protection to related strains.", "There is, however, an \"original antigenic sin\", in which the first HA subtype a person is exposed to influences the antibody-based immune response to future infections and vaccines.", "Annual vaccination is the primary and most effective way to prevent influenza and influenza-associated complications, especially for high-risk groups.", "Vaccines against the flu are trivalent or quadrivalent, providing protection against an H1N1 strain, an H3N2 strain, and one or two IBV strains corresponding to the two IBV lineages.", "Two types of vaccines are in use: inactivated vaccines that contain \"killed\" (i.e. inactivated) viruses and live attenuated influenza vaccines (LAIVs) that contain weakened viruses.", "There are three types of inactivated vaccines: whole virus, split virus, in which the virus is disrupted by a detergent, and subunit, which only contains the viral antigens HA and NA.", "Most flu vaccines are inactivated and administered via intramuscular injection.", "LAIVs are sprayed into the nasal cavity.", "Vaccination recommendations vary by country.", "Some recommend vaccination for all people above a certain age, such as 6 months, whereas other countries recommendation is limited for high at risk groups, such as pregnant women, young children (excluding newborns), the elderly, people with chronic medical conditions, health care workers, people who come into contact with high-risk people, and people who transmit the virus easily.", "Young infants cannot receive flu vaccines for safety reasons, but they can inherit passive immunity from their mother if inactivated vaccines are administered to the mother during pregnancy.", "Influenza vaccination also helps to reduce the probability of reassortment.", "In general, influenza vaccines are only effective if there is an antigenic match between vaccine strains and circulating strains.", "Additionally, most commercially available flu vaccines are manufactured by propagation of influenza viruses in embryonated chicken eggs, taking 6–8 months.", "Flu seasons are different in the northern and southern hemisphere, so the WHO meets twice a year, one for each hemisphere, to discuss which strains should be included in flu vaccines based on observation from HA inhibition assays.", "Other manufacturing methods include an MDCK cell culture-based inactivated vaccine and a recombinant subunit vaccine manufactured from baculovirus overexpression in insect cells.", "Influenza can be prevented or reduced in severity by post-exposure prophylaxis with the antiviral drugs oseltamivir, which can be taken orally by those at least three months old, and zanamivir, which can be inhaled by those above seven years of age.", "Chemoprophylaxis is most useful for individuals at high-risk of developing complications and those who cannot receive the flu vaccine due to contraindications or lack of effectiveness.", "Post-exposure chemoprophylaxis is only recommended if oseltamivir is taken within 48 hours of contact with a confirmed or suspected influenza case and zanamivir within 36 hours.", "It is recommended that it be offered to people who have yet to receive a vaccine for the current flu season, who have been vaccinated less than two week since contact, if there is a significant mismatch between vaccine and circulating strains, or during an outbreak in a closed setting regardless of vaccination history.", "Hand hygiene is important in reducing the spread of influenza.", "This includes frequent hand washing with soap and water, using alcohol-based hand sanitizers, and not touching one's eyes, nose, and mouth with one's hands.", "Covering one's nose and mouth when coughing or sneezing is important.", "Other methods to limit influenza transmission include staying home when sick, avoiding contact with others until one day after symptoms end, and disinfecting surfaces likely to be contaminated by the virus, such as doorknobs.", "Health education through media and posters is often used to remind people of the aforementioned etiquette and hygiene.", "There is uncertainty about the use of masks since research thus far has not shown a significant reduction in seasonal influenza with mask usage.", "Likewise, the effectiveness of screening at points of entry into countries is not well researched.", "Social distancing measures such as school closures, avoiding contact with infected people via isolation or quarantine, and limiting mass gatherings may reduce transmission, but these measures are often expensive, unpopular, and difficult to implement.", "Consequently, the commonly recommended methods of infection control are respiratory etiquette, hand hygiene, and mask wearing, which are inexpensive and easy to perform.", "Pharmaceutical measures are effective but may not be available in the early stages of an outbreak.", "In health care settings, infected individuals may be cohorted or assigned to individual rooms.", "Protective clothing such as masks, gloves, and gowns is recommended when coming into contact with infected individuals if there is a risk of exposure to infected bodily fluids.", "Keeping patients in negative pressure rooms and avoiding aerosol-producing activities may help, but special air handling and ventilation systems are not considered necessary to prevent the spread of influenza in the air.", "In residential homes, new admissions may need to be closed until the spread of influenza is controlled.", "When discharging patients to care homes, it is important to take care if there is a known influenza outbreak.", "Since influenza viruses circulate in animals such as birds and pigs, prevention of transmission from these animals is important.", "Water treatment, indoor raising of animals, quarantining sick animals, vaccination, and biosecurity are the primary measures used.", "Placing poultry houses and piggeries on high ground away from high-density farms, backyard farms, live poultry markets, and bodies of water helps to minimize contact with wild birds.", "Closure of live poultry markets appears to the most effective measure and has shown to be effective at controlling the spread of H5N1, H7N9, and H9N2.", "Other biosecurity measures include cleaning and disinfecting facilities and vehicles, banning visits to poultry farms, not bringing birds intended for slaughter back to farms, changing clothes, disinfecting foot baths, and treating food and water.", "If live poultry markets are not closed, then \"clean days\" when unsold poultry is removed and facilities are disinfected and \"no carry-over\" policies to eliminate infectious material before new poultry arrive can be used to reduce the spread of influenza viruses.", "If a novel influenza viruses has breached the aforementioned biosecurity measures, then rapid detection to stamp it out via quarantining, decontamination, and culling may be necessary to prevent the virus from becoming endemic.", "Vaccines exist for avian H5, H7, and H9 subtypes that are used in some countries.", "In China, for example, vaccination of domestic birds against H7N9 successfully limited its spread, indicating that vaccination may be an effective strategy if used in combination with other measures to limit transmission.", "In pigs and horses, management of influenza is dependent on vaccination with biosecurity.", "Diagnosis based on symptoms is fairly accurate in otherwise healthy people during seasonal epidemics and should be suspected in cases of pneumonia, acute respiratory distress syndrome (ARDS), sepsis, or if encephalitis, myocarditis, or breaking down of muscle tissue occur.", "Because influenza is similar to other viral respiratory tract illnesses, laboratory diagnosis is necessary for confirmation.", "Common ways of collecting samples for testing include nasal and throat swabs.", "Samples may be taken from the lower respiratory tract if infection has cleared the upper but not lower respiratory tract.", "Influenza testing is recommended for anyone hospitalized with symptoms resembling influenza during flu season or who is connected to an influenza case.", "For severe cases, earlier diagnosis improves patient outcome.", "Diagnostic methods that can identify influenza include viral cultures, antibody- and antigen-detecting tests, and nucleic acid-based tests.", "Viruses can be grown in a culture of mammalian cells or embryonated eggs for 3–10 days to monitor cytopathic effect.", "Final confirmation can then be done via antibody staining, hemadsorption using red blood cells, or immunofluorescence microscopy.", "Shell vial cultures, which can identify infection via immunostaining before a cytopathic effect appears, are more sensitive than traditional cultures with results in 1–3 days.", "Cultures can be used to characterize novel viruses, observe sensitivity to antiviral drugs, and monitor antigenic drift, but they are relatively slow and require specialized skills and equipment.", "Serological assays can be used to detect an antibody response to influenza after natural infection or vaccination.", "Common serological assays include hemagglutination inhibition assays that detect HA-specific antibodies, virus neutralization assays that check whether antibodies have neutralized the virus, and enzyme-linked immunoabsorbant assays.", "These methods tend to be relatively inexpensive and fast but are less reliable than nucleic-acid based tests.", "Direct fluorescent or immunofluorescent antibody (DFA/IFA) tests involve staining respiratory epithelial cells in samples with fluorescently-labeled influenza-specific antibodies, followed by examination under a fluorescent microscope.", "They can differentiate between IAV and IBV but can't subtype IAV.", "Rapid influenza diagnostic tests (RIDTs) are a simple way of obtaining assay results, are low cost, and produce results quickly, at less than 30 minutes, so they are commonly used, but they can't distinguish between IAV and IBV or between IAV subtypes and are not as sensitive as nucleic-acid based tests.", "Nucleic acid-based tests (NATs) amplify and detect viral nucleic acid.", "Most of these tests take a few hours, but rapid molecular assays are as fast as RIDTs.", "Among NATs, reverse transcription polymerase chain reaction (RT-PCR) is the most traditional and considered the gold standard for diagnosing influenza because it is fast and can subtype IAV, but it is relatively expensive and more prone to false-positives than cultures.", "Other NATs that have been used include loop-mediated isothermal amplification-based assays, simple amplification-based assays, and nucleic acid sequence-based amplification.", "Nucleic acid sequencing methods can identify infection by obtaining the nucleic acid sequence of viral samples to identify the virus and antiviral drug resistance.", "The traditional method is Sanger sequencing, but it has been largely replaced by next-generation methods that have greater sequencing speed and throughput.", "Treatment of influenza in cases of mild or moderate illness is supportive and includes anti-fever medications such as acetaminophen and ibuprofen, adequate fluid intake to avoid dehydration, and resting at home.", "Cough drops and throat sprays may be beneficial for sore throat.", "It is recommended to avoid alcohol and tobacco use while sick with the flu.", "Aspirin is not recommended to treat influenza in children due to an elevated risk of developing Reye syndrome.", "Corticosteroids likewise are not recommended except when treating septic shock or an underlying medical condition, such as chronic obstructive pulmonary disease or asthma exacerbation, since they are associated with increased mortality.", "If a secondary bacterial infection occurs, then treatment with antibiotics may be necessary.", "Antiviral drugs are primarily used to treat severely ill patients, especially those with compromised immune systems.", "Antivirals are most effective when started in the first 48 hours after symptoms appear.", "Later administration may still be beneficial for those who have underlying immune defects, those with more severe symptoms, or those who have a higher risk of developing complications if these individuals are still shedding the virus.", "Antiviral treatment is also recommended if a person is hospitalized with suspected influenza instead of waiting for test results to return and if symptoms are worsening.", "Most antiviral drugs against influenza fall into two categories: neuraminidase (NA) inhibitors and M2 inhibitors.", "Baloxavir marboxil is a notable exception, which targets the endonuclease activity of the viral RNA polymerase and can be used as an alternative to NA and M2 inhibitors for IAV and IBV.", "NA inhibitors target the enzymatic activity of NA receptors, mimicking the binding of sialic acid in the active site of NA on IAV and IBV virions so that viral release from infected cells and the rate of viral replication are impaired.", "NA inhibitors include oseltamivir, which is consumed orally in a prodrug form and converted to its active form in the liver, and zanamivir, which is a powder that is inhaled nasally.", "Oseltamivir and zanamivir are effective for prophylaxis and post-exposure prophylaxis, and research overall indicates that NA inhibitors are effective at reducing rates of complications, hospitalization, and mortality and the duration of illness.", "Additionally, the earlier NA inhibitors are provided, the better the outcome, though late administration can still be beneficial in severe cases.", "Other NA inhibitors include laninamivir and peramivir, the latter of which can be used as an alternative to oseltamivir for people who cannot tolerate or absorb it.", "The adamantanes amantadine and rimantadine are orally administered drugs that block the influenza virus's M2 ion channel, preventing viral uncoating.", "These drugs are only functional against IAV but are no longer recommended for use because of widespread resistance to them among IAVs.", "Adamantane resistance first emerged in H3N2 in 2003, becoming worldwide by 2008.", "Oseltamivir resistance is no longer widespread because the 2009 pandemic H1N1 strain (H1N1 pdm09), which is resistant to adamantanes, seemingly replaced resistant strains in circulation.", "Since the 2009 pandemic, oseltamivir resistance has mainly been observed in patients undergoing therapy, especially the immunocompromised and young children.", "Oseltamivir resistance is usually reported in H1N1, but has been reported in H3N2 and IBVs less commonly.", "Because of this, oseltamivir is recommended as the first drug of choice for immunocompetent people, whereas for the immunocompromised, oseltamivir is recommended against H3N2 and IBV and zanamivir against H1N1 pdm09.", "Zanamivir resistance is observed less frequently, and resistance to peramivir and baloxavir marboxil is possible.", "In healthy individuals, influenza infection is usually self-limiting and rarely fatal.", "Symptoms usually last for 2–8 days.", "Influenza can cause people to miss work or school, and it is associated with decreased job performance and, in older adults, reduced independence.", "Fatigue and malaise may last for several weeks after recovery, and healthy adults may experience pulmonary abnormalities that can take several weeks to resolve.", "Complications and mortality primarily occur in high-risk populations and those who are hospitalized.", "Severe disease and mortality are usually attributable to pneumonia from the primary viral infection or a secondary bacterial infection, which can progress to ARDS.", "Other respiratory complications that may occur include sinusitis, bronchitis, bronchiolitis, excess fluid buildup in the lungs, and exacerbation of chronic bronchitis and asthma.", "Middle ear infection and croup may occur, most commonly in children.", "Secondary \"S. aureus\" infection has been observed, primarily in children, to cause toxic shock syndrome after influenza, with hypotension, fever, and reddening and peeling of the skin.", "Complications affecting the cardiovascular system are rare and include pericarditis, fulminant myocarditis with a fast, slow, or irregular heartbeat, and exacerbation of pre-existing cardiovascular disease.", "Inflammation or swelling of muscles accompanied by muscle tissue breaking down occurs rarely, usually in children, which presents as extreme tenderness and muscle pain in the legs and a reluctance to walk for 2–3 days.", "Influenza can affect pregnancy, including causing smaller neonatal size, increased risk of premature birth, and an increased risk of child death shortly before or after birth.", "Neurological complications have been associated with influenza on rare occasions, including aseptic meningitis, encephalitis, disseminated encephalomyelitis, transverse myelitis, and Guillain–Barré syndrome.", "Additionally, febrile seizures and Reye syndrome can occur, most commonly in children.", "Influenza-associated encephalopathy can occur directly from central nervous system infection from the presence of the virus in blood and presents as suddent onset of fever with convulsions, followed by rapid progression to coma.", "An atypical form of encephalitis called encephalitis lethargica, characterized by headache, drowsiness, and coma, may rarely occur sometime after infection.", "In survivors of influenza-associated encephalopathy, neurological defects may occur.", "Primarily in children, in severe cases the immune system may rarely dramatically overproduce white blood cells that release cytokines, causing severe inflammation.", "People who are at least 65 years of age, due to a weakened immune system from aging or a chronic illness, are a high-risk group for developing complications, as are children less than one year of age and children who have not been previously exposed to influenza viruses multiple times.", "Pregnant women are at an elevated risk, which increases by trimester and lasts up to two weeks after childbirth.", "Obesity, in particular a body mass index greater than 35–40, is associated with greater amounts of viral replication, increased severity of secondary bacterial infection, and reduced vaccination efficacy.", "People who have underlying health conditions are also considered at-risk, including those who have congenital or chronic heart problems or lung (e.g. asthma), kidney, liver, blood, neurological, or metabolic (e.g. diabetes) disorders, as are people who are immunocompromised from chemotherapy, asplenia, prolonged steroid treatment, splenic dysfunction, or HIV infection.", "Current or past tobacco use also places a person at risk.", "The role of genetics in influenza is not well researched, but it may be a factor in influenza mortality.", "Influenza is typically characterized by seasonal epidemics and sporadic pandemics.", "Most of the burden of influenza is a result of flu seasons caused by IAV and IBV.", "Among IAV subtypes, H1N1 and H3N2 currently circulate in humans and are responsible for seasonal influenza.", "Cases disproportionately occur in children, but most severe causes are among the elderly, the very young, and the immunocompromised.", "In a typical year, influenza viruses infect 5–15% of the global population, causing 3–5 million cases of severe illness annually and accounting for 290,000–650,000 deaths each year due to respiratory illness.", "5–10% of adults and 20–30% of children contract influenza each year.", "The reported number of influenza cases is usually much lower than the actual number of cases.", "During seasonal epidemics, it is estimated that about 80% of otherwise healthy people who have a cough or sore throat have the flu.", "Approximately 30–40% of people hospitalized for influenza develop pneumonia, and about 5% of all severe pneumonia cases in hospitals are due to influenza, which is also the most common cause of ARDS in adults.", "In children, influenza is one of the two most common causes of ARDS, the other being the respiratory syncytial virus.", "About 3–5% of children each year develop otitis media due to influenza.", "Adults who develop organ failure from influenza and children who have PIM scores and acute renal failure have higher rates of mortality.", "During seasonal influenza, mortality is concentrated in the very young and the elderly, whereas during flu pandemics, young adults are often affected at a high rate.", "In temperate regions, the number of influenza cases varies from season to season.", "Lower vitamin D levels, presumably due to less sunlight, lower humidity, lower temperature, and minor changes in virus proteins caused by antigenic drift contribute to annual epidemics that peak during the winter season.", "In the northern hemisphere, this is from October to May (more narrowly December to April), and in the southern hemisphere, this is from May to October (more narrowly June to September).", "There are therefore two distinct influenza seasons every year in temperate regions, one in the northern hemisphere and one in the southern hemisphere.", "In tropical and subtropical regions, seasonality is more complex and appears to be affected by various climatic factors such as minimum temperature, hours of sunshine, maximum rainfall, and high humidity.", "Influenza may therefore occur year-round in these regions.", "Influenza epidemics in modern times have the tendency to start in the eastern or southern hemisphere, with Asia being a key reservoir of influenza viruses.", "IAV and IBV co-circulate, so the two have the same patterns of transmission.", "The seasonality of ICV, however, is poorly understood.", "ICV infection is most common in children under the age of 2, and by adulthood most people have been exposed to it.", "ICV-associated hospitalization most commonly occurs in children under the age of 3 and is frequently accompanied by co-infection with another virus or a bacterium, which may increase the severity of disease.", "When considering all hospitalizations for respiratory illness among young children, ICV appears to account for only a small percentage of such cases.", "Large outbreaks of ICV infection can occur, so incidence varies significantly.", "Outbreaks of influenza caused by novel influenza viruses are common.", "Depending on the level of pre-existing immunity in the population, novel influenza viruses can spread rapidly and cause pandemics with millions of deaths.", "These pandemics, in contrast to seasonal influenza, are caused by antigenic shifts involving animal influenza viruses.", "To date, all known flu pandemics have been caused by IAVs, and they follow the same pattern of spreading from an origin point to the rest of the world over the course of multiple waves in a year.", "Pandemic strains tend to be associated with higher rates of pneumonia in otherwise healthy individuals.", "Generally after each influenza pandemic, the pandemic strain continues to circulate as the cause of seasonal influenza, replacing prior strains.", "From 1700 to 1889, influenza pandemics occurred about once every 50–60 years.", "Since then, pandemics have occurred about once every 10–50 years, so they may be getting more frequent over time.", "It is impossible to know when an influenza virus first infected humans or when the first influenza pandemic occurred.", "Possibly the first influenza epidemic occurred around 6,000 BC in China, and possible descriptions of influenza exist in Greek writings from the 5th century BC.", "In both 1173–1174 AD and 1387 AD, epidemics occurred across Europe that were named \"influenza\".", "Whether these epidemics and others were caused by influenza is unclear since there was no consistent naming pattern for epidemic respiratory diseases at that time, and \"influenza\" didn't become completely attached to respiratory disease until centuries later.", "Influenza may have been brought to the Americas as early as 1493, when an epidemic disease resembling influenza killed most of the population of the Antilles.", "The first convincing record of an influenza pandemic was chronicled in 1510; it began in East Asia before spreading to North Africa and then Europe.", "Following the pandemic, seasonal influenza occurred, with subsequent pandemics in 1557 and 1580.", "The flu pandemic in 1557 was potentially the first time influenza was connected to miscarriage and death of pregnant women.", "The 1580 flu pandemic originated in Asia during summer, spread to Africa, then Europe, and finally America.", "By the end of the 16th century, influenza was likely beginning to become understood as a specific, recognizable disease with epidemic and endemic forms.", "In 1648, it was discovered that horses also experience influenza.", "Influenza data after 1700 is more informative, so it is easier to identify flu pandemics after this point, each of which incrementally increased understanding of influenza.", "The first flu pandemic of the 18th century started in 1729 in Russia in spring, spreading worldwide over the course of three years with distinct waves, the later ones being more lethal.", "The second flu pandemic of the 18th century was in 1781–1782, starting in China in autumn.", "From this pandemic, influenza became associated with sudden outbreaks of febrile illness.", "The next flu pandemic was from 1830 to 1833, beginning in China in winter.", "This pandemic had a high attack rate, but the mortality rate was low.", "A minor influenza pandemic occurred from 1847 to 1851 at the same time as the third cholera pandemic and was the first flu pandemic to occur with vital statistics being recorded, so influenza mortality was clearly recorded for the first time.", "Highly pathogenic avian influenza was recognized in 1878 and was soon linked to transmission to humans.", "By the time of the 1889 pandemic, which may have been caused by an H2N2 strain, the flu had become an easily recognizable disease.", "Initially, the microbial agent responsible for influenza was incorrently identified in 1892 by R. F. J. Pfeiffer as the bacteria species \"Haemophilus influenzae\", which retains \"influenza\" in its name.", "In the following years, the field of virology began to form as viruses were identified as the cause of many diseases.", "From 1901 to 1903, Italian and Austrian researchers were able to show that avian influenza, then called \"fowl plague\", was caused by a microscopic agent smaller than bacteria by using filters with pores too small for bacteria to pass through.", "The fundamental differences between viruses and bacteria, however, were not yet fully understood.", "From 1918 to 1920, the Spanish flu pandemic became the most devastating influenza pandemic and one of the deadliest pandemics in history.", "The pandemic, probably caused by H1N1, likely began in the USA before spreading worldwide by soldiers during and after the First World War.", "The initial wave in the first half of 1918 was relatively minor and resembled past flu pandemics, but the second wave later that year had a much higher mortality rate, accounting for most deaths.", "A third wave with lower mortality occurred in many places a few months after the second.", "By the end of 1920, it is estimated that about a third to half of all people in the world had been infected, with tens of millions of deaths, disproportionately young adults.", "During the 1918 pandemic, the respiratory route of transmission was clearly identified and influenza was shown to be caused by a \"filter passer\", not a bacterium, but there remained a lack of agreement about influenza's cause for another decade and research on influenza declined.", "After the pandemic, H1N1 circulated in humans in seasonal form up until the next pandemic.", "In 1931, Richard Shope published three papers identifying a virus as the cause of swine influenza, a then newly recognized disease among pigs that was first characterized during the second wave of the 1918 pandemic.", "Shope's research reinvigorated research on human influenza, and many advances in virology, serology, immunology, experimental animal models, vaccinology, and immunotherapy have since arisen from influenza research.", "Just two years after influenza viruses were discovered, in 1933, IAV was identified as the agent responsible for human influenza.", "Subtypes of IAV were discovered throughout the 1930s, and IBV was discovered in 1940.", "During the Second World War, the US government worked on developing inactivated vaccines for influenza, resulting in the first influenza vaccine being licensed in 1945 in the United States.", "ICV was discovered two years later in 1947.", "In 1955, avian influenza was confirmed to be caused by IAV.", "Four influenza pandemics have occurred since WWII, each less severe than the 1918 pandemic.", "The first of these was the Asian flu from 1957 to 1958, caused by an H2N2 strain and beginning in China's Yunnan province.", "The number of deaths probably exceeded one million, mostly among the very young and very old.", "Notably, the 1957 pandemic was the first flu pandemic to occur in the presence of a global surveillance system and laboratories able to study the novel influenza virus.", "After the pandemic, H2N2 was the IAV subtype responsible for seasonal influenza.", "The first antiviral drug against influenza, amantadine, was approved for use in 1966, with additional antiviral drugs being used since the 1990s.", "In 1968, H3N2 was introduced into humans as a result of a reassortment between an avian H3N2 strain and an H2N2 strain that was circulating in humans.", "The novel H3N2 strain first emerged in Hong Kong and spread worldwide, causing the Hong Kong flu pandemic, which resulted in 500,000–2,000,000 deaths.", "This was the first pandemic to spread significantly by air travel.", "H2N2 and H3N2 co-circulated after the pandemic until 1971 when H2N2 waned in prevalence and was completely replaced by H3N2.", "In 1977, H1N1 reemerged in humans, possibly after it was released from a freezer in a laboratory accident, and caused a pseudo-pandemic.", "Whether the 1977 \"pandemic\" deserves to be included in the natural history of flu pandemics is debatable.", "This H1N1 strain was antigenically similar to the H1N1 strains that circulated prior to 1957.", "Since 1977, both H1N1 and H3N2 have circulated in humans as part of seasonal influenza.", "In 1980, the current classification system used to subtype influenza viruses was introduced.", "At some point, IBV diverged into two lineages, named the B/Victoria-like and B/Yamagata-like lineages, both of which have been circulating in humans since 1983.", "In 1996, HPAI H5N1 was detected in Guangdong, China and a year later emerged in poultry in Hong Kong, gradually spreading worldwide from there.", "A small H5N1 outbreak in humans in Hong Kong occurred then, and sporadic human cases have occurred since 1997, carrying a high case fatality rate.", "The most recent flu pandemic was the 2009 swine flu pandemic, which originated in Mexico and resulted in hundreds of thousands of deaths.", "It was caused by a novel H1N1 strain that was a reassortment of human, swine, and avian influenza viruses.", "The 2009 pandemic had the effect of replacing prior H1N1 strains in circulation with the novel strain but not any other influenza viruses.", "Consequently, H1N1, H3N2, and both IBV lineages have been in circulation in seasonal form since the 2009 pandemic.", "In 2011, IDV was discovered in pigs in Oklahoma, USA, and cattle were later identified as the primary reservoir of IDV.", "In the same year, avian H7N9 was detected in China and began to cause human infections in 2013, starting in Shanghai and Anhui and remaining mostly in China.", "HPAI H7N9 emerged sometime in 2016 and has occasionally infected humans incidentally.", "Other AIVs have less commonly infected humans since the 1990s, including H5N6, H6N1, H7N2-4, H7N7, and H10N7-8, and HPAI H subtypes such as H5N1-3, H5N5-6, and H5N8 have begun to spread throughout much of the world since the 2010s.", "Future flu pandemics, which may be caused by an influenza virus of avian origin, are viewed as almost inevitable, and increased globalization has made it easier for novel viruses to spread, so there are continual efforts to prepare for future pandemics and improve the prevention and treatment of influenza.", "The word \"influenza\" comes from the Italian word \"influenza\", from medieval Latin \"influentia\", originally meaning \"visitation\" or \"influence\".", "Terms such as \"influenza di freddo\", meaning \"influence of the cold\", and \"influenza di stelle\", meaning \"influence of the stars\" are attested from the 14th century.", "The latter referred to the disease's cause, which at the time was ascribed by some to unfavorable astrological conditions.", "As early as 1504, \"influenza\" began to mean a \"visitation\" or \"outbreak\" of any disease affecting many people in a single place at once.", "During an outbreak of influenza in 1743 that started in Italy and spread throughout Europe, the word reached the English language and was anglicized in pronunciation.", "Since the mid-1800s, \"influenza\" has also been used to refer to severe colds.", "The shortened form of the word, \"(the) flu\", is first attested in 1839 as \"flue\" with the spelling \"flu\" first attested in 1893.", "Other names that have been used for influenza include \"epidemic catarrh\", \"la grippe\" from French, \"sweating sickness\", and, especially when referring to the 1918 pandemic strain, \"Spanish fever\".", "Influenza research is wide-ranging and includes efforts to understand how influenza viruses enter hosts, the relationship between influenza viruses and bacteria, how influenza symptoms progress, and what make some influenza viruses deadlier than others.", "Non-structural proteins encoded by influenza viruses are periodically discovered and their functions are continually under research.", "Past pandemics, and especially the 1918 pandemic, are the subject of much research to understand flu pandemics.", "As part of pandemic preparedness, the Global Influenza Surveillance and Response System is a global network of laboratories that monitors influenza transmission and epidemiology.", "Additional areas of research include ways to improve the diagnosis, treatment, and prevention of influenza.", "Existing diagnostic methods have a variety of limitations coupled with their advantages.", "For example, NATs have high sensitivity and specificity but are impractical in under-resourced regions due to their high cost, complexity, maintenance, and training required.", "Low-cost, portable RIDTs can rapidly diagnose influenza but have highly variable sensitivity and are unable to subtype IAV.", "As a result of these limitations and others, research into new diagnostic methods revolves around producing new methods that are cost-effective, less labor-intensive, and less complex than existing methods while also being able to differentiate influenza species and IAV subtypes.", "One approach in development are lab-on-a-chips, which are diagnostic devices that make use of a variety of diagnostic tests, such as RT-PCR and serological assays, in microchip form.", "These chips have many potential advantages, including high reaction efficiency, low energy consumption, and low waste generation.", "New antiviral drugs are also in development due to the elimination of adamantines as viable drugs and concerns over oseltamivir resistance.", "These include: NA inhibitors that can be injected intravenously, such as intravenous formulations of zanamivir; favipiravir, which is a polymerase inhibitor used against several RNA viruses; pimodivir, which prevents cap-binding required during viral transcription; and nitazoxanide, which inhibits HA maturation.", "Reducing excess inflammation in the respiratory tract is also subject to much research since this is one of the primary mechanisms of influenza pathology.", "Other forms of therapy in development include monoclonal and polyclonal antibodies that target viral proteins, convalescent plasma, different approaches to modify the host antiviral response, and stem cell-based therapies to repair lung damage.", "Much research on LAIVs focuses on identifying genome sequences that can be deleted to create harmless influenza viruses in vaccines that still confer immunity.", "The high variability and rapid evolution of influenza virus antigens, however, is a major obstacle in developing effective vaccines.", "Furthermore, it is hard to predict which strains will be in circulation during the next flu season, manufacturing a sufficient quantity of flu vaccines for the next season is difficult, LAIVs have limited efficacy, and repeated annual vaccination potentially has diminished efficacy.", "For these reasons, \"broadly-reactive\" or \"universal\" flu vaccines are being researched that can provide protection against many or all influenza viruses.", "Approaches to develop such a vaccine include HA stalk-based methods such as chimeras that have the same stalk but different heads, HA head-based methods such as computationally optimized broadly neutralizing antigens, anti-idiotypic antibodies, and vaccines to elicit immune responses to highly conserved viral proteins.", "mRNA vaccines to provide protection against influenza are also under research.", "Aquatic birds such as ducks, geese, shorebirds, and gulls are the primary reservoir of IAVs.", "In birds, AIVs may be either low pathogenic avian influenza (LPAI) viruses that produce little to no symptoms or highly pathogenic avian influenza (HPAI) viruses that cause severe illness.", "Symptoms of HPAI infection include lack of energy and appetite, decreased egg production, soft-shelled or misshapen eggs, swelling of the head, comb, wattles, and hocks, purple discoloration of wattles, combs, and legs, nasal discharge, coughing, sneezing, incoordination, and diarrhea.", "Birds infected with an HPAI virus may also die suddenly without any signs of infection.", "The distinction between LPAI and HPAI can generally be made based on how lethal an AIV is to chickens.", "At the genetic level, an AIV can be usually be identified as an HPAI virus if it has a multibasic cleavage site in the HA protein, which contains additional residues in the HA gene.", "Most AIVs are LPAI.", "Notable HPAI viruses include HPAI H5N1 and HPAI H7N9.", "HPAI viruses have been a major disease burden in the 21st century, resulting in the death of large numbers of birds.", "In H7N9's case, some circulating strains were originally LPAI but became HPAI by acquiring the HA multibasic cleavage site.", "Avian H9N2 is also of concern because although it is LPAI, it is a common donor of genes to H5N1 and H7N9 during reassortment.", "Migratory birds can spread influenza across long distances.", "An example of this was when an H5N1 strain in 2005 infected birds at Qinghai Lake, China, which is a stopover and breeding site for many migratory birds, subsequently spreading the virus to more than 20 countries across Asia, Europe, and the Middle East.", "AIVs can be transmitted from wild birds to domestic free-range ducks and in turn to poultry through contaminated water, aerosols, and fomites.", "Ducks therefore act as key intermediates between wild and domestic birds.", "Transmission to poultry typically occurs in backyard farming and live animal markets where multiple species interact with each other.", "From there, AIVs can spread to poultry farms in the absence of adequate biosecurity.", "Among poultry, HPAI transmission occurs through aerosols and contaminated feces, cages, feed, and dead animals.", "Back-transmission of HPAI viruses from poultry to wild birds has occurred and is implicated in mass die-offs and intercontinental spread.", "AIVs have occasionally infected humans through aerosols, fomites, and contaminated water.", "Direction transmission from wild birds is rare.", "Instead, most transmission involves domestic poultry, mainly chickens, ducks, and geese but also a variety of other birds such as guinea fowl, partridge, pheasants, and quails.", "The primary risk factor for infection with AIVs is exposure to birds in farms and live poultry markets.", "Typically, infection with an AIV has an incubation period of 3–5 days but can be up to 9 days.", "H5N1 and H7N9 cause severe lower respiratory tract illness, whereas other AIVs such as H9N2 cause a more mild upper respiratory tract illness, commonly with conjunctivitis.", "Limited transmission of avian H2, H5-7, H9, and H10 subtypes from one person to another through respiratory droplets, aerosols, and fomites has occurred, but sustained human-to-human transmission of AIVs has not occurred.", "Before 2013, H5N1 was the most common AIV to infect humans.", "Since then, H7N9 has been responsible for most human cases.", "Influenza in pigs is a respiratory disease similar to influenza in humans and is found worldwide.", "Asymptomatic infections are common.", "Symptoms typically appear 1–3 days after infection and include fever, lethargy, anorexia, weight loss, labored breathing, coughing, sneezing, and nasal discharge.", "In sows, pregnancy may be aborted.", "Complications include secondary infections and potentially fatal bronchopneumonia.", "Pigs become contagious within a day of infection and typically spread the virus for 7–10 days, which can spread rapidly within a herd.", "Pigs usually recover from infection within 3–7 days after symptoms appear.", "Prevention and control measures include inactivated vaccines and culling infected herds.", "The influenza viruses usually responsible for swine flu are IAV subtypes H1N1, H1N2, and H3N2.", "Some IAVs can be transmitted via aerosols from pigs to humans and vice versa.", "Furthermore, pigs, along with bats and quails, are recognized as a mixing vessel of influenza viruses because they have both α-2,3 and α-2,6 sialic acid receptors in their respiratory tract.", "Because of that, both avian and mammalian influenza viruses can infect pigs.", "If co-infection occurs, then reassortment is possible.", "A notable example of this was the reassortment of a swine, avian, and human influenza virus in 2009, resulting in a novel H1N1 strain that caused the 2009 flu pandemic.", "Spillover events from humans to pigs, however, appear to be more common than from pigs to humans.", "Influenza viruses have been found in many other animals, including cattle, horses, dogs, cats, and marine mammals.", "Nearly all IAVs are apparently descended from ancestral viruses in birds.", "The exception are bat influenza-like viruses, which have an uncertain origin.", "These bat viruses have HA and NA subtypes H17, H18, N10, and N11.", "H17N10 and H18N11 are unable to reassort with other IAVs, but they are still able to replicate in other mammals.", "AIVs sometimes crossover into mammals.", "For example, in late 2016 to early 2017, an avian H7N2 strain was found to be infecting cats in New York.", "Equine IAVs include H7N7 and two lineages of H3N8.", "H7N7, however, has not been detected in horses since the late 1970s, so it may have become extinct in horses.", "H3N8 in equines spreads via aerosols and causes respiratory illness.", "Equine H3N8 perferentially binds to α-2,3 sialic acids, so horses are usually considered dead-end hosts, but transmission to dogs and camels has occurred, raising concerns that horses may be mixing vessels for reassortment.", "In canines, the only IAVs in circulation are equine-derived H3N8 and avian-derived H3N2.", "Canine H3N8 has not been observed to reassort with other subtypes.", "H3N2 has a much broader host range and can reassort with H1N1 and H5N1.", "An isolated case of H6N1 likely from a chicken was found infecting a dog, so other AIVs may emerge in canines.", "Other mammals to be infected by IAVs include H7N7 and H4N5 in seals, H1N3 in whales, and H10N4 and H3N2 in minks.", "Various mutations have been identified that are associated with AIVs adapting to mammals.", "Since HA proteins vary in which sialic acids they bind to, mutations in the HA receptor binding site can allow AIVs to infect mammals.", "Other mutations include mutations affecting which sialic acids NA proteins cleave and a mutation in the PB2 polymerase subunit that improves tolerance of lower temperatures in mammalian respiratory tracts and enhances RNP assembly by stabilizing NP and PB2 binding.", "IBV is mainly found in humans but has also been detected in pigs, dogs, horses, and seals.", "Likewise, ICV primarily infects humans but has been observed in pigs, dogs, cattle, and dromedary camels.", "IDV causes an influenza-like illness in pigs but its impact in its natural reservoir, cattle, is relatively unknown.", "It may cause respiratory disease resembling human influenza on its own, or it may be part of a bovine respiratory disease (BRD) complex with other pathogens during co-infection.", "BRD is a concern for the cattle industry, so IDV's possible involvement in BRD has led to research on vaccines for cattle that can provide protection against IDV.", "Two antigenic lineages are in circulation: D/swine/Oklahoma/1334/2011 (D/OK) and D/bovine/Oklahoma/660/2013 (D/660)." ]

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[ "Symptoms range from mild to severe and often include fever, runny nose, sore throat, muscle pain, headache, coughing, and fatigue.", "These symptoms begin from one to four days after exposure to the virus (typically two days) and last for about 2–8 days.", "Diarrhea and vomiting can occur, particularly in children.", "Influenza may progress to pneumonia, which can be caused by the virus or by a subsequent bacterial infection." ]

[ "The time between exposure to the virus and development of symptoms, called the incubation period, is 1–4 days, most commonly 1–2 days.", "Many infections, however, are asymptomatic.", "The onset of symptoms is sudden, and initial symptoms are predominately non-specific, including fever, chills, headaches, muscle pain or aching, a feeling of discomfort, loss of appetite, lack of energy/fatigue, and confusion.", "These symptoms are usually accompanied by respiratory symptoms such as a dry cough, sore or dry throat, hoarse voice, and a stuffy or runny nose.", "Coughing is the most common symptom.", "Gastrointestinal symptoms may also occur, including nausea, vomiting, diarrhea, and gastroenteritis, especially in children.", "The standard influenza symptoms typically last for 2–8 days.", "A 2021 study suggests influenza can cause long lasting symptoms in a similar way to long COVID.\nSymptomatic infections are usually mild and limited to the upper respiratory tract, but progression to pneumonia is relatively common.", "Pneumonia may be caused by the primary viral infection or by a secondary bacterial infection.", "Primary pneumonia is characterized by rapid progression of fever, cough, labored breathing, and low oxygen levels that cause bluish skin.", "It is especially common among those who have an underlying cardiovascular disease such as rheumatic heart disease.", "Secondary pneumonia typically has a period of improvement in symptoms for 1–3 weeks followed by recurrent fever, sputum production, and fluid buildup in the lungs, but can also occur just a few days after influenza symptoms appear.", "About a third of primary pneumonia cases are followed by secondary pneumonia, which is most frequently caused by the bacteria \"Streptococcus pneumoniae\" and \"Staphylococcus aureus\".", "Influenza viruses comprise four species.", "Each of the four species is the sole member of its own genus, and the four influenza genera comprise four of the seven genera in the family \"Orthomyxoviridae\".", "They are:\n\n\nIAV is responsible for most cases of severe illness as well as seasonal epidemics and occasional pandemics.", "It infects people of all ages but tends to disproportionately cause severe illness in the elderly, the very young, and those who have chronic health issues.", "Birds are the primary reservoir of IAV, especially aquatic birds such as ducks, geese, shorebirds, and gulls, but the virus also circulates among mammals, including pigs, horses, and marine mammals.", "IAV is classified into subtypes based on the viral proteins haemagglutinin (H) and neuraminidase (N).", "As of 2019, 18 H subtypes and 11 N subtypes have been identified.", "Most potential combinations have been reported in birds, but H17-18 and N10-11 have only been found in bats.", "Only H subtypes H1-3 and N subtypes N1-2 are known to have circulated in humans, the current IAV subtypes in circulation being H1N1 and H3N2.", "IAVs can be classified more specifically to also include natural host species, geographical origin, year of isolation, and strain number, such as H1N1/A/duck/Alberta/35/76.", "IBV mainly infects humans but has been identified in seals, horses, dogs, and pigs.", "IBV does not have subtypes like IAV but has two antigenically distinct lineages, termed the B/Victoria/2/1987-like and B/Yamagata/16/1988-like lineages, or simply (B/)Victoria(-like) and (B/)Yamagata(-like).", "Both lineages are in circulation in humans, disproportionately affecting children.", "IBVs contribute to seasonal epidemics alongside IAVs but have never been associated with a pandemic.", "ICV, like IBV, is primarily found in humans, though it also has been detected in pigs, feral dogs, dromedary camels, cattle, and dogs.", "ICV infection primarily affects children and is usually asymptomatic or has mild cold-like symptoms, though more severe symptoms such as gastroenteritis and pneumonia can occur.", "Unlike IAV and IBV, ICV has not been a major focus of research pertaining to antiviral drugs, vaccines, and other measures against influenza.", "ICV is subclassified into six genetic/antigenic lineages.", "IDV has been isolated from pigs and cattle, the latter being the natural reservoir.", "Infection has also been observed in humans, horses, dromedary camels, and small ruminants such as goats and sheep.", "IDV is distantly related to ICV.", "While cattle workers have occasionally tested positive to prior IDV infection, it is not known to cause disease in humans.", "ICV and IDV experience a slower rate of antigenic evolution than IAV and IBV.", "Because of this antigenic stability, relatively few novel lineages emerge.", "Influenza viruses have a negative-sense, single-stranded RNA genome that is segmented.", "The negative sense of the genome means it can be used as a template to synthesize messenger RNA (mRNA).", "IAV and IBV have eight genome segments that encode 10 major proteins.", "ICV and IDV have seven genome segments that encode nine major proteins.", "Three segments encode three subunits of an RNA-dependent RNA polymerase (RdRp) complex: PB1, a transcriptase, PB2, which recognizes 5' caps, and PA (P3 for ICV and IDV), an endonuclease.", "The matrix protein (M1) and membrane protein (M2) share a segment, as do the non-structural protein (NS1) and the nuclear export protein (NEP).", "For IAV and IBV, hemagglutinin (HA) and neuraminidase (NA) are encoded on one segment each, whereas ICV and IDV encode a hemagglutinin-esterase fusion (HEF) protein on one segment that merges the functions of HA and NA.", "The final genome segment encodes the viral nucleoprotein (NP).", "Influenza viruses also encode various accessory proteins, such as PB1-F2 and PA-X, that are expressed through alternative open reading frames and which are important in host defense suppression, virulence, and pathogenicity.", "The virus particle, called a virion, is pleomorphic and varies between being filamentous, bacilliform, or spherical in shape.", "Clinical isolates tend to be pleomorphic, whereas strains adapted to laboratory growth typically produce spherical virions.", "Filamentous virions are about 250 nanometers (nm) by 80 nm, bacilliform 120–250 by 95 nm, and spherical 120 nm in diameter.", "The virion consists of each segment of the genome bound to nucleoproteins in separate ribonucleoprotein (RNP) complexes for each segment, all of which are surrounded by a lipid bilayer membrane called the viral envelope.", "There is a copy of the RdRp, all subunits included, bound to each RNP.", "The envelope is reinforced structurally by matrix proteins on the interior that enclose the RNPs, and the envelope contains HA and NA (or HEF) proteins extending outward from the exterior surface of the envelope.", "HA and HEF proteins have a distinct \"head\" and \"stalk\" structure.", "M2 proteins form proton ion channels through the viral envelope that are required for viral entry and exit.", "IBVs contain a surface protein named NB that is anchored in the envelope, but its function is unknown.", "The viral life cycle begins by binding to a target cell.", "Binding is mediated by the viral HA proteins on the surface of the evelope, which bind to cells that contain sialic acid receptors on the surface of the cell membrane.", "For N1 subtypes with the \"G147R\" mutation and N2 subtypes, the NA protein can initiate entry.", "Prior to binding, NA proteins promote access to target cells by degrading mucous, which helps to remove extracellular decoy receptors that would impede access to target cells.", "After binding, the virus is internalized into the cell by an endosome that contains the virion inside it.", "The endosome is acidified by cellular vATPase to have lower pH, which triggers a conformational change in HA that allows fusion of the viral envelope with the endosomal membrane.", "At the same time, hydrogen ions diffuse into the virion through M2 ion channels, disrupting internal protein-protein interactions to release RNPs into the host cell's cytosol.", "The M1 protein shell surrounding RNPs is degraded, fully uncoating RNPs in the cytosol.", "RNPs are then imported into the nucleus with the help of viral localization signals.", "There, the viral RNA polymerase transcribes mRNA using the genomic negative-sense strand as a template.", "The polymerase snatches 5' caps for viral mRNA from cellular RNA to prime mRNA synthesis and the 3'-end of mRNA is polyadenylated at the end of transcription.", "Once viral mRNA is transcribed, it is exported out of the nucleus and translated by host ribosomes in a cap-dependent manner to synthesize viral proteins.", "RdRp also synthesizes complementary positive-sense strands of the viral genome in a complementary RNP complex which are then used as templates by viral polymerases to synthesize copies of the negative-sense genome.", "During these processes, RdRps of avian influenza viruses (AIVs) function optimally at a higher temperature than mammalian influenza viruses.", "Newly synthesized viral polymerase subunits and NP proteins are imported to the nucleus to further increase the rate of viral replication and form RNPs.", "HA, NA, and M2 proteins are trafficked with the aid of M1 and NEP proteins to the cell membrane through the Golgi apparatus and inserted into the cell's membrane.", "Viral non-structural proteins including NS1, PB1-F2, and PA-X regulate host cellular processes to disable antiviral responses.", "PB1-F2 aso interacts with PB1 to keep polymerases in the nucleus longer.", "M1 and NEP proteins localize to the nucleus during the later stages of infection, bind to viral RNPs and mediate their export to the cytoplasm where they migrate to the cell membrane with the aid of recycled endosomes and are bundled into the segments of the genome.", "Progenic viruses leave the cell by budding from the cell membrane, which is initiated by the accumulation of M1 proteins at the cytoplasmic side of the membrane.", "The viral genome is incorporated inside a viral envelope derived from portions of the cell membrane that have HA, NA, and M2 proteins.", "At the end of budding, HA proteins remain attached to cellular sialic acid until they are cleaved by the sialidase activity of NA proteins.", "The virion is then released from the cell.", "The sialidase activity of NA also cleaves any sialic acid residues from the viral surface, which helps prevent newly assembled viruses from aggregating near the cell surface and improving infectivity.", "Similar to other aspects of influenza replication, optimal NA activity is temperature- and pH-dependent.", "Ultimately, presence of large quantities of viral RNA in the cell triggers apoptosis, i.e. programmed cell death, which is initiated by cellular factors to restrict viral replication.", "Two key processes that influenza viruses evolve through are antigenic drift and antigenic shift.", "Antigenic drift is when an influenza virus's antigens change due to the gradual accumulation of mutations in the antigen's (HA or NA) gene.", "This can occur in response to evolutionary pressure exerted by the host immune response.", "Antigenic drift is especially common for the HA protein, in which just a few amino acid changes in the head region can constitute antigenic drift.", "The result is the production of novel strains that can evade pre-existing antibody-mediated immunity.", "Antigenic drift occurs in all influenza species but is slower in B than A and slowest in C and D. Antigenic drift is a major cause of seasonal influenza, and requires that flu vaccines be updated annually.", "HA is the main component of inactivated vaccines, so surveillance monitors antigenic drift of this antigen among circulating strains.", "Antigenic evolution of influenza viruses of humans appears to be faster than influenza viruses in swine and equines.", "In wild birds, within-subtype antigenic variation appears to be limited but has been observed in poultry.", "Antigenic shift is a sudden, drastic change in an influenza virus's antigen, usually HA.", "During antigenic shift, antigenically different strains that infect the same cell can reassort genome segments with each other, producing hybrid progeny.", "Since all influenza viruses have segmented genomes, all are capable of reassortment.", "Antigenic shift, however, only occurs among influenza viruses of the same genus and most commonly occurs among IAVs.", "In particular, reassortment is very common in AIVs, creating a large diversity of influenza viruses in birds, but is uncommon in human, equine, and canine lineages.", "Pigs, bats, and quails have receptors for both mammalian and avian IAVs, so they are potential \"mixing vessels\" for reassortment.", "If an animal strain reassorts with a human strain, then a novel strain can emerge that is capable of human-to-human transmission.", "This has caused pandemics, but only a limited number have occurred, so it is difficult to predict when the next will happen.", "People who are infected can transmit influenza viruses through breathing, talking, coughing, and sneezing, which spread respiratory droplets and aerosols that contain virus particles into the air.", "A person susceptible to infection can then contract influenza by coming into contact with these particles.", "Respiratory droplets are relatively large and travel less than two meters before falling onto nearby surfaces.", "Aerosols are smaller and remain suspended in the air longer, so they take longer to settle and can travel further than respiratory droplets.", "Inhalation of aerosols can lead to infection, but most transmission is in the area about two meters around an infected person via respiratory droplets that come into contact with mucosa of the upper respiratory tract.", "Transmission through contact with a person, bodily fluids, or intermediate objects (fomites) can also occur, such as through contaminated hands and surfaces since influenza viruses can survive for hours on non-porous surfaces.", "If one's hands are contaminated, then touching one's face can cause infection.", "Influenza is usually transmissible from one day before the onset of symptoms to 5–7 days after.", "In healthy adults, the virus is shed for up to 3–5 days.", "In children and the immunocompromised, the virus may be transmissible for several weeks.", "Children ages 2–17 are considered to be the primary and most efficient spreaders of influenza.", "Children who have not had multiple prior exposures to influenza viruses shed the virus at greater quantities and for a longer duration than other children.", "People who are at risk of exposure to influenza include health care workers, social care workers, and those who live with or care for people vulnerable to influenza.", "In long-term care facilities, the flu can spread rapidly after it is introduced.", "A variety of factors likely encourage influenza transmission, including lower temperature, lower absolute and relative humidity, less ultraviolet radiation from the Sun, and crowding.", "Influenza viruses that infect the upper respiratory tract like H1N1 tend to be more mild but more transmissible, whereas those that infect the lower respiratory tract like H5N1 tend to cause more severe illness but are less contagious.", "In humans, influenza viruses first cause infection by infecting epithelial cells in the respiratory tract.", "Illness during infection is primarily the result of lung inflammation and compromise caused by epithelial cell infection and death, combined with inflammation caused by the immune system's response to infection.", "Non-respiratory organs can become involved, but the mechanisms by which influenza is involved in these cases are unknown.", "Severe respiratory illness can be caused by multiple, non-exclusive mechanisms, including obstruction of the airways, loss of alveolar structure, loss of lung epithelial integrity due to epithelial cell infection and death, and degradation of the extracellular matrix that maintains lung structure.", "In particular, alveolar cell infection appears to drive severe symptoms since this results in impaired gas exchange and enables viruses to infect endothelial cells, which produce large quantities of pro-inflammatory cytokines.", "Pneumonia caused by influenza viruses is characterized by high levels of viral replication in the lower respiratory tract, accompanied by a strong pro-inflammatory response called a cytokine storm.", "Infection with H5N1 or H7N9 especially produces high levels of pro-inflammatory cytokines.", "In bacterial infections, early depletion of macrophages during influenza creates a favorable environment in the lungs for bacterial growth since these white blood cells are important in responding to bacterial infection.", "Host mechanisms to encourage tissue repair may inadvertently allow bacterial infection.", "Infection also induces production of systemic glucocorticoids that can reduce inflammation to preserve tissue integrity but allow increased bacterial growth.", "The pathophysiology of influenza is significantly influenced by which receptors influenza viruses bind to during entry into cells.", "Mammalian influenza viruses preferentially bind to sialic acids connected to the rest of the oligosaccharide by an α-2,6 link, most commonly found in various respiratory cells, such as respiratory and retinal epithelial cells.", "AIVs prefer sialic acids with an α-2,3 linkage, which are most common in birds in gastrointestinal epithelial cells and in humans in the lower respiratory tract.", "Furthermore, cleavage of the HA protein into HA, the binding subunit, and HA, the fusion subunit, is performed by different proteases, affecting which cells can be infected.", "For mammalian influenza viruses and low pathogenic AIVs, cleavage is extracellular, which limits infection to cells that have the appropriate proteases, whereas for highly pathogenic AIVs, cleavage is intracellular and performed by ubiquitous proteases, which allows for infection of a greater variety of cells, thereby contributing to more severe disease.", "Cells possess sensors to detect viral RNA, which can then induce interferon production.", "Interferons mediate expression of antiviral proteins and proteins that recruit immune cells to the infection site, and they also notify nearby uninfected cells of infection.", "Some infected cells release pro-inflammatory cytokines that recruit immune cells to the site of infection.", "Immune cells control viral infection by killing infected cells and phagocytizing viral particles and apoptotic cells.", "An exacerbated immune response, however, can harm the host organism through a cytokine storm.", "To counter the immune response, influenza viruses encode various non-structural proteins, including NS1, NEP, PB1-F2, and PA-X, that are involved in curtailing the host immune response by suppressing interferon production and host gene expression.", "B cells, a type of white blood cell, produce antibodies that bind to influenza antigens HA and NA (or HEF) and other proteins to a lesser degree.", "Once bound to these proteins, antibodies block virions from binding to cellular receptors, neutralizing the virus.", "In humans, a sizeable antibody response occurs ~1 week after viral exposure.", "This antibody response is typically robust and long-lasting, especially for ICV and IDV.", "In other words, people exposed to a certain strain in childhood still possess antibodies to that strain at a reasonable level later in life, which can provide some protection to related strains.", "There is, however, an \"original antigenic sin\", in which the first HA subtype a person is exposed to influences the antibody-based immune response to future infections and vaccines.", "Annual vaccination is the primary and most effective way to prevent influenza and influenza-associated complications, especially for high-risk groups.", "Vaccines against the flu are trivalent or quadrivalent, providing protection against an H1N1 strain, an H3N2 strain, and one or two IBV strains corresponding to the two IBV lineages.", "Two types of vaccines are in use: inactivated vaccines that contain \"killed\" (i.e. inactivated) viruses and live attenuated influenza vaccines (LAIVs) that contain weakened viruses.", "There are three types of inactivated vaccines: whole virus, split virus, in which the virus is disrupted by a detergent, and subunit, which only contains the viral antigens HA and NA.", "Most flu vaccines are inactivated and administered via intramuscular injection.", "LAIVs are sprayed into the nasal cavity.", "Vaccination recommendations vary by country.", "Some recommend vaccination for all people above a certain age, such as 6 months, whereas other countries recommendation is limited for high at risk groups, such as pregnant women, young children (excluding newborns), the elderly, people with chronic medical conditions, health care workers, people who come into contact with high-risk people, and people who transmit the virus easily.", "Young infants cannot receive flu vaccines for safety reasons, but they can inherit passive immunity from their mother if inactivated vaccines are administered to the mother during pregnancy.", "Influenza vaccination also helps to reduce the probability of reassortment.", "In general, influenza vaccines are only effective if there is an antigenic match between vaccine strains and circulating strains.", "Additionally, most commercially available flu vaccines are manufactured by propagation of influenza viruses in embryonated chicken eggs, taking 6–8 months.", "Flu seasons are different in the northern and southern hemisphere, so the WHO meets twice a year, one for each hemisphere, to discuss which strains should be included in flu vaccines based on observation from HA inhibition assays.", "Other manufacturing methods include an MDCK cell culture-based inactivated vaccine and a recombinant subunit vaccine manufactured from baculovirus overexpression in insect cells.", "Influenza can be prevented or reduced in severity by post-exposure prophylaxis with the antiviral drugs oseltamivir, which can be taken orally by those at least three months old, and zanamivir, which can be inhaled by those above seven years of age.", "Chemoprophylaxis is most useful for individuals at high-risk of developing complications and those who cannot receive the flu vaccine due to contraindications or lack of effectiveness.", "Post-exposure chemoprophylaxis is only recommended if oseltamivir is taken within 48 hours of contact with a confirmed or suspected influenza case and zanamivir within 36 hours.", "It is recommended that it be offered to people who have yet to receive a vaccine for the current flu season, who have been vaccinated less than two week since contact, if there is a significant mismatch between vaccine and circulating strains, or during an outbreak in a closed setting regardless of vaccination history.", "Hand hygiene is important in reducing the spread of influenza.", "This includes frequent hand washing with soap and water, using alcohol-based hand sanitizers, and not touching one's eyes, nose, and mouth with one's hands.", "Covering one's nose and mouth when coughing or sneezing is important.", "Other methods to limit influenza transmission include staying home when sick, avoiding contact with others until one day after symptoms end, and disinfecting surfaces likely to be contaminated by the virus, such as doorknobs.", "Health education through media and posters is often used to remind people of the aforementioned etiquette and hygiene.", "There is uncertainty about the use of masks since research thus far has not shown a significant reduction in seasonal influenza with mask usage.", "Likewise, the effectiveness of screening at points of entry into countries is not well researched.", "Social distancing measures such as school closures, avoiding contact with infected people via isolation or quarantine, and limiting mass gatherings may reduce transmission, but these measures are often expensive, unpopular, and difficult to implement.", "Consequently, the commonly recommended methods of infection control are respiratory etiquette, hand hygiene, and mask wearing, which are inexpensive and easy to perform.", "Pharmaceutical measures are effective but may not be available in the early stages of an outbreak.", "In health care settings, infected individuals may be cohorted or assigned to individual rooms.", "Protective clothing such as masks, gloves, and gowns is recommended when coming into contact with infected individuals if there is a risk of exposure to infected bodily fluids.", "Keeping patients in negative pressure rooms and avoiding aerosol-producing activities may help, but special air handling and ventilation systems are not considered necessary to prevent the spread of influenza in the air.", "In residential homes, new admissions may need to be closed until the spread of influenza is controlled.", "When discharging patients to care homes, it is important to take care if there is a known influenza outbreak.", "Since influenza viruses circulate in animals such as birds and pigs, prevention of transmission from these animals is important.", "Water treatment, indoor raising of animals, quarantining sick animals, vaccination, and biosecurity are the primary measures used.", "Placing poultry houses and piggeries on high ground away from high-density farms, backyard farms, live poultry markets, and bodies of water helps to minimize contact with wild birds.", "Closure of live poultry markets appears to the most effective measure and has shown to be effective at controlling the spread of H5N1, H7N9, and H9N2.", "Other biosecurity measures include cleaning and disinfecting facilities and vehicles, banning visits to poultry farms, not bringing birds intended for slaughter back to farms, changing clothes, disinfecting foot baths, and treating food and water.", "If live poultry markets are not closed, then \"clean days\" when unsold poultry is removed and facilities are disinfected and \"no carry-over\" policies to eliminate infectious material before new poultry arrive can be used to reduce the spread of influenza viruses.", "If a novel influenza viruses has breached the aforementioned biosecurity measures, then rapid detection to stamp it out via quarantining, decontamination, and culling may be necessary to prevent the virus from becoming endemic.", "Vaccines exist for avian H5, H7, and H9 subtypes that are used in some countries.", "In China, for example, vaccination of domestic birds against H7N9 successfully limited its spread, indicating that vaccination may be an effective strategy if used in combination with other measures to limit transmission.", "In pigs and horses, management of influenza is dependent on vaccination with biosecurity.", "Diagnosis based on symptoms is fairly accurate in otherwise healthy people during seasonal epidemics and should be suspected in cases of pneumonia, acute respiratory distress syndrome (ARDS), sepsis, or if encephalitis, myocarditis, or breaking down of muscle tissue occur.", "Because influenza is similar to other viral respiratory tract illnesses, laboratory diagnosis is necessary for confirmation.", "Common ways of collecting samples for testing include nasal and throat swabs.", "Samples may be taken from the lower respiratory tract if infection has cleared the upper but not lower respiratory tract.", "Influenza testing is recommended for anyone hospitalized with symptoms resembling influenza during flu season or who is connected to an influenza case.", "For severe cases, earlier diagnosis improves patient outcome.", "Diagnostic methods that can identify influenza include viral cultures, antibody- and antigen-detecting tests, and nucleic acid-based tests.", "Viruses can be grown in a culture of mammalian cells or embryonated eggs for 3–10 days to monitor cytopathic effect.", "Final confirmation can then be done via antibody staining, hemadsorption using red blood cells, or immunofluorescence microscopy.", "Shell vial cultures, which can identify infection via immunostaining before a cytopathic effect appears, are more sensitive than traditional cultures with results in 1–3 days.", "Cultures can be used to characterize novel viruses, observe sensitivity to antiviral drugs, and monitor antigenic drift, but they are relatively slow and require specialized skills and equipment.", "Serological assays can be used to detect an antibody response to influenza after natural infection or vaccination.", "Common serological assays include hemagglutination inhibition assays that detect HA-specific antibodies, virus neutralization assays that check whether antibodies have neutralized the virus, and enzyme-linked immunoabsorbant assays.", "These methods tend to be relatively inexpensive and fast but are less reliable than nucleic-acid based tests.", "Direct fluorescent or immunofluorescent antibody (DFA/IFA) tests involve staining respiratory epithelial cells in samples with fluorescently-labeled influenza-specific antibodies, followed by examination under a fluorescent microscope.", "They can differentiate between IAV and IBV but can't subtype IAV.", "Rapid influenza diagnostic tests (RIDTs) are a simple way of obtaining assay results, are low cost, and produce results quickly, at less than 30 minutes, so they are commonly used, but they can't distinguish between IAV and IBV or between IAV subtypes and are not as sensitive as nucleic-acid based tests.", "Nucleic acid-based tests (NATs) amplify and detect viral nucleic acid.", "Most of these tests take a few hours, but rapid molecular assays are as fast as RIDTs.", "Among NATs, reverse transcription polymerase chain reaction (RT-PCR) is the most traditional and considered the gold standard for diagnosing influenza because it is fast and can subtype IAV, but it is relatively expensive and more prone to false-positives than cultures.", "Other NATs that have been used include loop-mediated isothermal amplification-based assays, simple amplification-based assays, and nucleic acid sequence-based amplification.", "Nucleic acid sequencing methods can identify infection by obtaining the nucleic acid sequence of viral samples to identify the virus and antiviral drug resistance.", "The traditional method is Sanger sequencing, but it has been largely replaced by next-generation methods that have greater sequencing speed and throughput.", "Treatment of influenza in cases of mild or moderate illness is supportive and includes anti-fever medications such as acetaminophen and ibuprofen, adequate fluid intake to avoid dehydration, and resting at home.", "Cough drops and throat sprays may be beneficial for sore throat.", "It is recommended to avoid alcohol and tobacco use while sick with the flu.", "Aspirin is not recommended to treat influenza in children due to an elevated risk of developing Reye syndrome.", "Corticosteroids likewise are not recommended except when treating septic shock or an underlying medical condition, such as chronic obstructive pulmonary disease or asthma exacerbation, since they are associated with increased mortality.", "If a secondary bacterial infection occurs, then treatment with antibiotics may be necessary.", "Antiviral drugs are primarily used to treat severely ill patients, especially those with compromised immune systems.", "Antivirals are most effective when started in the first 48 hours after symptoms appear.", "Later administration may still be beneficial for those who have underlying immune defects, those with more severe symptoms, or those who have a higher risk of developing complications if these individuals are still shedding the virus.", "Antiviral treatment is also recommended if a person is hospitalized with suspected influenza instead of waiting for test results to return and if symptoms are worsening.", "Most antiviral drugs against influenza fall into two categories: neuraminidase (NA) inhibitors and M2 inhibitors.", "Baloxavir marboxil is a notable exception, which targets the endonuclease activity of the viral RNA polymerase and can be used as an alternative to NA and M2 inhibitors for IAV and IBV.", "NA inhibitors target the enzymatic activity of NA receptors, mimicking the binding of sialic acid in the active site of NA on IAV and IBV virions so that viral release from infected cells and the rate of viral replication are impaired.", "NA inhibitors include oseltamivir, which is consumed orally in a prodrug form and converted to its active form in the liver, and zanamivir, which is a powder that is inhaled nasally.", "Oseltamivir and zanamivir are effective for prophylaxis and post-exposure prophylaxis, and research overall indicates that NA inhibitors are effective at reducing rates of complications, hospitalization, and mortality and the duration of illness.", "Additionally, the earlier NA inhibitors are provided, the better the outcome, though late administration can still be beneficial in severe cases.", "Other NA inhibitors include laninamivir and peramivir, the latter of which can be used as an alternative to oseltamivir for people who cannot tolerate or absorb it.", "The adamantanes amantadine and rimantadine are orally administered drugs that block the influenza virus's M2 ion channel, preventing viral uncoating.", "These drugs are only functional against IAV but are no longer recommended for use because of widespread resistance to them among IAVs.", "Adamantane resistance first emerged in H3N2 in 2003, becoming worldwide by 2008.", "Oseltamivir resistance is no longer widespread because the 2009 pandemic H1N1 strain (H1N1 pdm09), which is resistant to adamantanes, seemingly replaced resistant strains in circulation.", "Since the 2009 pandemic, oseltamivir resistance has mainly been observed in patients undergoing therapy, especially the immunocompromised and young children.", "Oseltamivir resistance is usually reported in H1N1, but has been reported in H3N2 and IBVs less commonly.", "Because of this, oseltamivir is recommended as the first drug of choice for immunocompetent people, whereas for the immunocompromised, oseltamivir is recommended against H3N2 and IBV and zanamivir against H1N1 pdm09.", "Zanamivir resistance is observed less frequently, and resistance to peramivir and baloxavir marboxil is possible.", "In healthy individuals, influenza infection is usually self-limiting and rarely fatal.", "Symptoms usually last for 2–8 days.", "Influenza can cause people to miss work or school, and it is associated with decreased job performance and, in older adults, reduced independence.", "Fatigue and malaise may last for several weeks after recovery, and healthy adults may experience pulmonary abnormalities that can take several weeks to resolve.", "Complications and mortality primarily occur in high-risk populations and those who are hospitalized.", "Severe disease and mortality are usually attributable to pneumonia from the primary viral infection or a secondary bacterial infection, which can progress to ARDS.", "Other respiratory complications that may occur include sinusitis, bronchitis, bronchiolitis, excess fluid buildup in the lungs, and exacerbation of chronic bronchitis and asthma.", "Middle ear infection and croup may occur, most commonly in children.", "Secondary \"S. aureus\" infection has been observed, primarily in children, to cause toxic shock syndrome after influenza, with hypotension, fever, and reddening and peeling of the skin.", "Complications affecting the cardiovascular system are rare and include pericarditis, fulminant myocarditis with a fast, slow, or irregular heartbeat, and exacerbation of pre-existing cardiovascular disease.", "Inflammation or swelling of muscles accompanied by muscle tissue breaking down occurs rarely, usually in children, which presents as extreme tenderness and muscle pain in the legs and a reluctance to walk for 2–3 days.", "Influenza can affect pregnancy, including causing smaller neonatal size, increased risk of premature birth, and an increased risk of child death shortly before or after birth.", "Neurological complications have been associated with influenza on rare occasions, including aseptic meningitis, encephalitis, disseminated encephalomyelitis, transverse myelitis, and Guillain–Barré syndrome.", "Additionally, febrile seizures and Reye syndrome can occur, most commonly in children.", "Influenza-associated encephalopathy can occur directly from central nervous system infection from the presence of the virus in blood and presents as suddent onset of fever with convulsions, followed by rapid progression to coma.", "An atypical form of encephalitis called encephalitis lethargica, characterized by headache, drowsiness, and coma, may rarely occur sometime after infection.", "In survivors of influenza-associated encephalopathy, neurological defects may occur.", "Primarily in children, in severe cases the immune system may rarely dramatically overproduce white blood cells that release cytokines, causing severe inflammation.", "People who are at least 65 years of age, due to a weakened immune system from aging or a chronic illness, are a high-risk group for developing complications, as are children less than one year of age and children who have not been previously exposed to influenza viruses multiple times.", "Pregnant women are at an elevated risk, which increases by trimester and lasts up to two weeks after childbirth.", "Obesity, in particular a body mass index greater than 35–40, is associated with greater amounts of viral replication, increased severity of secondary bacterial infection, and reduced vaccination efficacy.", "People who have underlying health conditions are also considered at-risk, including those who have congenital or chronic heart problems or lung (e.g. asthma), kidney, liver, blood, neurological, or metabolic (e.g. diabetes) disorders, as are people who are immunocompromised from chemotherapy, asplenia, prolonged steroid treatment, splenic dysfunction, or HIV infection.", "Current or past tobacco use also places a person at risk.", "The role of genetics in influenza is not well researched, but it may be a factor in influenza mortality.", "Influenza is typically characterized by seasonal epidemics and sporadic pandemics.", "Most of the burden of influenza is a result of flu seasons caused by IAV and IBV.", "Among IAV subtypes, H1N1 and H3N2 currently circulate in humans and are responsible for seasonal influenza.", "Cases disproportionately occur in children, but most severe causes are among the elderly, the very young, and the immunocompromised.", "In a typical year, influenza viruses infect 5–15% of the global population, causing 3–5 million cases of severe illness annually and accounting for 290,000–650,000 deaths each year due to respiratory illness.", "5–10% of adults and 20–30% of children contract influenza each year.", "The reported number of influenza cases is usually much lower than the actual number of cases.", "During seasonal epidemics, it is estimated that about 80% of otherwise healthy people who have a cough or sore throat have the flu.", "Approximately 30–40% of people hospitalized for influenza develop pneumonia, and about 5% of all severe pneumonia cases in hospitals are due to influenza, which is also the most common cause of ARDS in adults.", "In children, influenza is one of the two most common causes of ARDS, the other being the respiratory syncytial virus.", "About 3–5% of children each year develop otitis media due to influenza.", "Adults who develop organ failure from influenza and children who have PIM scores and acute renal failure have higher rates of mortality.", "During seasonal influenza, mortality is concentrated in the very young and the elderly, whereas during flu pandemics, young adults are often affected at a high rate.", "In temperate regions, the number of influenza cases varies from season to season.", "Lower vitamin D levels, presumably due to less sunlight, lower humidity, lower temperature, and minor changes in virus proteins caused by antigenic drift contribute to annual epidemics that peak during the winter season.", "In the northern hemisphere, this is from October to May (more narrowly December to April), and in the southern hemisphere, this is from May to October (more narrowly June to September).", "There are therefore two distinct influenza seasons every year in temperate regions, one in the northern hemisphere and one in the southern hemisphere.", "In tropical and subtropical regions, seasonality is more complex and appears to be affected by various climatic factors such as minimum temperature, hours of sunshine, maximum rainfall, and high humidity.", "Influenza may therefore occur year-round in these regions.", "Influenza epidemics in modern times have the tendency to start in the eastern or southern hemisphere, with Asia being a key reservoir of influenza viruses.", "IAV and IBV co-circulate, so the two have the same patterns of transmission.", "The seasonality of ICV, however, is poorly understood.", "ICV infection is most common in children under the age of 2, and by adulthood most people have been exposed to it.", "ICV-associated hospitalization most commonly occurs in children under the age of 3 and is frequently accompanied by co-infection with another virus or a bacterium, which may increase the severity of disease.", "When considering all hospitalizations for respiratory illness among young children, ICV appears to account for only a small percentage of such cases.", "Large outbreaks of ICV infection can occur, so incidence varies significantly.", "Outbreaks of influenza caused by novel influenza viruses are common.", "Depending on the level of pre-existing immunity in the population, novel influenza viruses can spread rapidly and cause pandemics with millions of deaths.", "These pandemics, in contrast to seasonal influenza, are caused by antigenic shifts involving animal influenza viruses.", "To date, all known flu pandemics have been caused by IAVs, and they follow the same pattern of spreading from an origin point to the rest of the world over the course of multiple waves in a year.", "Pandemic strains tend to be associated with higher rates of pneumonia in otherwise healthy individuals.", "Generally after each influenza pandemic, the pandemic strain continues to circulate as the cause of seasonal influenza, replacing prior strains.", "From 1700 to 1889, influenza pandemics occurred about once every 50–60 years.", "Since then, pandemics have occurred about once every 10–50 years, so they may be getting more frequent over time.", "It is impossible to know when an influenza virus first infected humans or when the first influenza pandemic occurred.", "Possibly the first influenza epidemic occurred around 6,000 BC in China, and possible descriptions of influenza exist in Greek writings from the 5th century BC.", "In both 1173–1174 AD and 1387 AD, epidemics occurred across Europe that were named \"influenza\".", "Whether these epidemics and others were caused by influenza is unclear since there was no consistent naming pattern for epidemic respiratory diseases at that time, and \"influenza\" didn't become completely attached to respiratory disease until centuries later.", "Influenza may have been brought to the Americas as early as 1493, when an epidemic disease resembling influenza killed most of the population of the Antilles.", "The first convincing record of an influenza pandemic was chronicled in 1510; it began in East Asia before spreading to North Africa and then Europe.", "Following the pandemic, seasonal influenza occurred, with subsequent pandemics in 1557 and 1580.", "The flu pandemic in 1557 was potentially the first time influenza was connected to miscarriage and death of pregnant women.", "The 1580 flu pandemic originated in Asia during summer, spread to Africa, then Europe, and finally America.", "By the end of the 16th century, influenza was likely beginning to become understood as a specific, recognizable disease with epidemic and endemic forms.", "In 1648, it was discovered that horses also experience influenza.", "Influenza data after 1700 is more informative, so it is easier to identify flu pandemics after this point, each of which incrementally increased understanding of influenza.", "The first flu pandemic of the 18th century started in 1729 in Russia in spring, spreading worldwide over the course of three years with distinct waves, the later ones being more lethal.", "The second flu pandemic of the 18th century was in 1781–1782, starting in China in autumn.", "From this pandemic, influenza became associated with sudden outbreaks of febrile illness.", "The next flu pandemic was from 1830 to 1833, beginning in China in winter.", "This pandemic had a high attack rate, but the mortality rate was low.", "A minor influenza pandemic occurred from 1847 to 1851 at the same time as the third cholera pandemic and was the first flu pandemic to occur with vital statistics being recorded, so influenza mortality was clearly recorded for the first time.", "Highly pathogenic avian influenza was recognized in 1878 and was soon linked to transmission to humans.", "By the time of the 1889 pandemic, which may have been caused by an H2N2 strain, the flu had become an easily recognizable disease.", "Initially, the microbial agent responsible for influenza was incorrently identified in 1892 by R. F. J. Pfeiffer as the bacteria species \"Haemophilus influenzae\", which retains \"influenza\" in its name.", "In the following years, the field of virology began to form as viruses were identified as the cause of many diseases.", "From 1901 to 1903, Italian and Austrian researchers were able to show that avian influenza, then called \"fowl plague\", was caused by a microscopic agent smaller than bacteria by using filters with pores too small for bacteria to pass through.", "The fundamental differences between viruses and bacteria, however, were not yet fully understood.", "From 1918 to 1920, the Spanish flu pandemic became the most devastating influenza pandemic and one of the deadliest pandemics in history.", "The pandemic, probably caused by H1N1, likely began in the USA before spreading worldwide by soldiers during and after the First World War.", "The initial wave in the first half of 1918 was relatively minor and resembled past flu pandemics, but the second wave later that year had a much higher mortality rate, accounting for most deaths.", "A third wave with lower mortality occurred in many places a few months after the second.", "By the end of 1920, it is estimated that about a third to half of all people in the world had been infected, with tens of millions of deaths, disproportionately young adults.", "During the 1918 pandemic, the respiratory route of transmission was clearly identified and influenza was shown to be caused by a \"filter passer\", not a bacterium, but there remained a lack of agreement about influenza's cause for another decade and research on influenza declined.", "After the pandemic, H1N1 circulated in humans in seasonal form up until the next pandemic.", "In 1931, Richard Shope published three papers identifying a virus as the cause of swine influenza, a then newly recognized disease among pigs that was first characterized during the second wave of the 1918 pandemic.", "Shope's research reinvigorated research on human influenza, and many advances in virology, serology, immunology, experimental animal models, vaccinology, and immunotherapy have since arisen from influenza research.", "Just two years after influenza viruses were discovered, in 1933, IAV was identified as the agent responsible for human influenza.", "Subtypes of IAV were discovered throughout the 1930s, and IBV was discovered in 1940.", "During the Second World War, the US government worked on developing inactivated vaccines for influenza, resulting in the first influenza vaccine being licensed in 1945 in the United States.", "ICV was discovered two years later in 1947.", "In 1955, avian influenza was confirmed to be caused by IAV.", "Four influenza pandemics have occurred since WWII, each less severe than the 1918 pandemic.", "The first of these was the Asian flu from 1957 to 1958, caused by an H2N2 strain and beginning in China's Yunnan province.", "The number of deaths probably exceeded one million, mostly among the very young and very old.", "Notably, the 1957 pandemic was the first flu pandemic to occur in the presence of a global surveillance system and laboratories able to study the novel influenza virus.", "After the pandemic, H2N2 was the IAV subtype responsible for seasonal influenza.", "The first antiviral drug against influenza, amantadine, was approved for use in 1966, with additional antiviral drugs being used since the 1990s.", "In 1968, H3N2 was introduced into humans as a result of a reassortment between an avian H3N2 strain and an H2N2 strain that was circulating in humans.", "The novel H3N2 strain first emerged in Hong Kong and spread worldwide, causing the Hong Kong flu pandemic, which resulted in 500,000–2,000,000 deaths.", "This was the first pandemic to spread significantly by air travel.", "H2N2 and H3N2 co-circulated after the pandemic until 1971 when H2N2 waned in prevalence and was completely replaced by H3N2.", "In 1977, H1N1 reemerged in humans, possibly after it was released from a freezer in a laboratory accident, and caused a pseudo-pandemic.", "Whether the 1977 \"pandemic\" deserves to be included in the natural history of flu pandemics is debatable.", "This H1N1 strain was antigenically similar to the H1N1 strains that circulated prior to 1957.", "Since 1977, both H1N1 and H3N2 have circulated in humans as part of seasonal influenza.", "In 1980, the current classification system used to subtype influenza viruses was introduced.", "At some point, IBV diverged into two lineages, named the B/Victoria-like and B/Yamagata-like lineages, both of which have been circulating in humans since 1983.", "In 1996, HPAI H5N1 was detected in Guangdong, China and a year later emerged in poultry in Hong Kong, gradually spreading worldwide from there.", "A small H5N1 outbreak in humans in Hong Kong occurred then, and sporadic human cases have occurred since 1997, carrying a high case fatality rate.", "The most recent flu pandemic was the 2009 swine flu pandemic, which originated in Mexico and resulted in hundreds of thousands of deaths.", "It was caused by a novel H1N1 strain that was a reassortment of human, swine, and avian influenza viruses.", "The 2009 pandemic had the effect of replacing prior H1N1 strains in circulation with the novel strain but not any other influenza viruses.", "Consequently, H1N1, H3N2, and both IBV lineages have been in circulation in seasonal form since the 2009 pandemic.", "In 2011, IDV was discovered in pigs in Oklahoma, USA, and cattle were later identified as the primary reservoir of IDV.", "In the same year, avian H7N9 was detected in China and began to cause human infections in 2013, starting in Shanghai and Anhui and remaining mostly in China.", "HPAI H7N9 emerged sometime in 2016 and has occasionally infected humans incidentally.", "Other AIVs have less commonly infected humans since the 1990s, including H5N6, H6N1, H7N2-4, H7N7, and H10N7-8, and HPAI H subtypes such as H5N1-3, H5N5-6, and H5N8 have begun to spread throughout much of the world since the 2010s.", "Future flu pandemics, which may be caused by an influenza virus of avian origin, are viewed as almost inevitable, and increased globalization has made it easier for novel viruses to spread, so there are continual efforts to prepare for future pandemics and improve the prevention and treatment of influenza.", "The word \"influenza\" comes from the Italian word \"influenza\", from medieval Latin \"influentia\", originally meaning \"visitation\" or \"influence\".", "Terms such as \"influenza di freddo\", meaning \"influence of the cold\", and \"influenza di stelle\", meaning \"influence of the stars\" are attested from the 14th century.", "The latter referred to the disease's cause, which at the time was ascribed by some to unfavorable astrological conditions.", "As early as 1504, \"influenza\" began to mean a \"visitation\" or \"outbreak\" of any disease affecting many people in a single place at once.", "During an outbreak of influenza in 1743 that started in Italy and spread throughout Europe, the word reached the English language and was anglicized in pronunciation.", "Since the mid-1800s, \"influenza\" has also been used to refer to severe colds.", "The shortened form of the word, \"(the) flu\", is first attested in 1839 as \"flue\" with the spelling \"flu\" first attested in 1893.", "Other names that have been used for influenza include \"epidemic catarrh\", \"la grippe\" from French, \"sweating sickness\", and, especially when referring to the 1918 pandemic strain, \"Spanish fever\".", "Influenza research is wide-ranging and includes efforts to understand how influenza viruses enter hosts, the relationship between influenza viruses and bacteria, how influenza symptoms progress, and what make some influenza viruses deadlier than others.", "Non-structural proteins encoded by influenza viruses are periodically discovered and their functions are continually under research.", "Past pandemics, and especially the 1918 pandemic, are the subject of much research to understand flu pandemics.", "As part of pandemic preparedness, the Global Influenza Surveillance and Response System is a global network of laboratories that monitors influenza transmission and epidemiology.", "Additional areas of research include ways to improve the diagnosis, treatment, and prevention of influenza.", "Existing diagnostic methods have a variety of limitations coupled with their advantages.", "For example, NATs have high sensitivity and specificity but are impractical in under-resourced regions due to their high cost, complexity, maintenance, and training required.", "Low-cost, portable RIDTs can rapidly diagnose influenza but have highly variable sensitivity and are unable to subtype IAV.", "As a result of these limitations and others, research into new diagnostic methods revolves around producing new methods that are cost-effective, less labor-intensive, and less complex than existing methods while also being able to differentiate influenza species and IAV subtypes.", "One approach in development are lab-on-a-chips, which are diagnostic devices that make use of a variety of diagnostic tests, such as RT-PCR and serological assays, in microchip form.", "These chips have many potential advantages, including high reaction efficiency, low energy consumption, and low waste generation.", "New antiviral drugs are also in development due to the elimination of adamantines as viable drugs and concerns over oseltamivir resistance.", "These include: NA inhibitors that can be injected intravenously, such as intravenous formulations of zanamivir; favipiravir, which is a polymerase inhibitor used against several RNA viruses; pimodivir, which prevents cap-binding required during viral transcription; and nitazoxanide, which inhibits HA maturation.", "Reducing excess inflammation in the respiratory tract is also subject to much research since this is one of the primary mechanisms of influenza pathology.", "Other forms of therapy in development include monoclonal and polyclonal antibodies that target viral proteins, convalescent plasma, different approaches to modify the host antiviral response, and stem cell-based therapies to repair lung damage.", "Much research on LAIVs focuses on identifying genome sequences that can be deleted to create harmless influenza viruses in vaccines that still confer immunity.", "The high variability and rapid evolution of influenza virus antigens, however, is a major obstacle in developing effective vaccines.", "Furthermore, it is hard to predict which strains will be in circulation during the next flu season, manufacturing a sufficient quantity of flu vaccines for the next season is difficult, LAIVs have limited efficacy, and repeated annual vaccination potentially has diminished efficacy.", "For these reasons, \"broadly-reactive\" or \"universal\" flu vaccines are being researched that can provide protection against many or all influenza viruses.", "Approaches to develop such a vaccine include HA stalk-based methods such as chimeras that have the same stalk but different heads, HA head-based methods such as computationally optimized broadly neutralizing antigens, anti-idiotypic antibodies, and vaccines to elicit immune responses to highly conserved viral proteins.", "mRNA vaccines to provide protection against influenza are also under research.", "Aquatic birds such as ducks, geese, shorebirds, and gulls are the primary reservoir of IAVs.", "In birds, AIVs may be either low pathogenic avian influenza (LPAI) viruses that produce little to no symptoms or highly pathogenic avian influenza (HPAI) viruses that cause severe illness.", "Symptoms of HPAI infection include lack of energy and appetite, decreased egg production, soft-shelled or misshapen eggs, swelling of the head, comb, wattles, and hocks, purple discoloration of wattles, combs, and legs, nasal discharge, coughing, sneezing, incoordination, and diarrhea.", "Birds infected with an HPAI virus may also die suddenly without any signs of infection.", "The distinction between LPAI and HPAI can generally be made based on how lethal an AIV is to chickens.", "At the genetic level, an AIV can be usually be identified as an HPAI virus if it has a multibasic cleavage site in the HA protein, which contains additional residues in the HA gene.", "Most AIVs are LPAI.", "Notable HPAI viruses include HPAI H5N1 and HPAI H7N9.", "HPAI viruses have been a major disease burden in the 21st century, resulting in the death of large numbers of birds.", "In H7N9's case, some circulating strains were originally LPAI but became HPAI by acquiring the HA multibasic cleavage site.", "Avian H9N2 is also of concern because although it is LPAI, it is a common donor of genes to H5N1 and H7N9 during reassortment.", "Migratory birds can spread influenza across long distances.", "An example of this was when an H5N1 strain in 2005 infected birds at Qinghai Lake, China, which is a stopover and breeding site for many migratory birds, subsequently spreading the virus to more than 20 countries across Asia, Europe, and the Middle East.", "AIVs can be transmitted from wild birds to domestic free-range ducks and in turn to poultry through contaminated water, aerosols, and fomites.", "Ducks therefore act as key intermediates between wild and domestic birds.", "Transmission to poultry typically occurs in backyard farming and live animal markets where multiple species interact with each other.", "From there, AIVs can spread to poultry farms in the absence of adequate biosecurity.", "Among poultry, HPAI transmission occurs through aerosols and contaminated feces, cages, feed, and dead animals.", "Back-transmission of HPAI viruses from poultry to wild birds has occurred and is implicated in mass die-offs and intercontinental spread.", "AIVs have occasionally infected humans through aerosols, fomites, and contaminated water.", "Direction transmission from wild birds is rare.", "Instead, most transmission involves domestic poultry, mainly chickens, ducks, and geese but also a variety of other birds such as guinea fowl, partridge, pheasants, and quails.", "The primary risk factor for infection with AIVs is exposure to birds in farms and live poultry markets.", "Typically, infection with an AIV has an incubation period of 3–5 days but can be up to 9 days.", "H5N1 and H7N9 cause severe lower respiratory tract illness, whereas other AIVs such as H9N2 cause a more mild upper respiratory tract illness, commonly with conjunctivitis.", "Limited transmission of avian H2, H5-7, H9, and H10 subtypes from one person to another through respiratory droplets, aerosols, and fomites has occurred, but sustained human-to-human transmission of AIVs has not occurred.", "Before 2013, H5N1 was the most common AIV to infect humans.", "Since then, H7N9 has been responsible for most human cases.", "Influenza in pigs is a respiratory disease similar to influenza in humans and is found worldwide.", "Asymptomatic infections are common.", "Symptoms typically appear 1–3 days after infection and include fever, lethargy, anorexia, weight loss, labored breathing, coughing, sneezing, and nasal discharge.", "In sows, pregnancy may be aborted.", "Complications include secondary infections and potentially fatal bronchopneumonia.", "Pigs become contagious within a day of infection and typically spread the virus for 7–10 days, which can spread rapidly within a herd.", "Pigs usually recover from infection within 3–7 days after symptoms appear.", "Prevention and control measures include inactivated vaccines and culling infected herds.", "The influenza viruses usually responsible for swine flu are IAV subtypes H1N1, H1N2, and H3N2.", "Some IAVs can be transmitted via aerosols from pigs to humans and vice versa.", "Furthermore, pigs, along with bats and quails, are recognized as a mixing vessel of influenza viruses because they have both α-2,3 and α-2,6 sialic acid receptors in their respiratory tract.", "Because of that, both avian and mammalian influenza viruses can infect pigs.", "If co-infection occurs, then reassortment is possible.", "A notable example of this was the reassortment of a swine, avian, and human influenza virus in 2009, resulting in a novel H1N1 strain that caused the 2009 flu pandemic.", "Spillover events from humans to pigs, however, appear to be more common than from pigs to humans.", "Influenza viruses have been found in many other animals, including cattle, horses, dogs, cats, and marine mammals.", "Nearly all IAVs are apparently descended from ancestral viruses in birds.", "The exception are bat influenza-like viruses, which have an uncertain origin.", "These bat viruses have HA and NA subtypes H17, H18, N10, and N11.", "H17N10 and H18N11 are unable to reassort with other IAVs, but they are still able to replicate in other mammals.", "AIVs sometimes crossover into mammals.", "For example, in late 2016 to early 2017, an avian H7N2 strain was found to be infecting cats in New York.", "Equine IAVs include H7N7 and two lineages of H3N8.", "H7N7, however, has not been detected in horses since the late 1970s, so it may have become extinct in horses.", "H3N8 in equines spreads via aerosols and causes respiratory illness.", "Equine H3N8 perferentially binds to α-2,3 sialic acids, so horses are usually considered dead-end hosts, but transmission to dogs and camels has occurred, raising concerns that horses may be mixing vessels for reassortment.", "In canines, the only IAVs in circulation are equine-derived H3N8 and avian-derived H3N2.", "Canine H3N8 has not been observed to reassort with other subtypes.", "H3N2 has a much broader host range and can reassort with H1N1 and H5N1.", "An isolated case of H6N1 likely from a chicken was found infecting a dog, so other AIVs may emerge in canines.", "Other mammals to be infected by IAVs include H7N7 and H4N5 in seals, H1N3 in whales, and H10N4 and H3N2 in minks.", "Various mutations have been identified that are associated with AIVs adapting to mammals.", "Since HA proteins vary in which sialic acids they bind to, mutations in the HA receptor binding site can allow AIVs to infect mammals.", "Other mutations include mutations affecting which sialic acids NA proteins cleave and a mutation in the PB2 polymerase subunit that improves tolerance of lower temperatures in mammalian respiratory tracts and enhances RNP assembly by stabilizing NP and PB2 binding.", "IBV is mainly found in humans but has also been detected in pigs, dogs, horses, and seals.", "Likewise, ICV primarily infects humans but has been observed in pigs, dogs, cattle, and dromedary camels.", "IDV causes an influenza-like illness in pigs but its impact in its natural reservoir, cattle, is relatively unknown.", "It may cause respiratory disease resembling human influenza on its own, or it may be part of a bovine respiratory disease (BRD) complex with other pathogens during co-infection.", "BRD is a concern for the cattle industry, so IDV's possible involvement in BRD has led to research on vaccines for cattle that can provide protection against IDV.", "Two antigenic lineages are in circulation: D/swine/Oklahoma/1334/2011 (D/OK) and D/bovine/Oklahoma/660/2013 (D/660)." ]

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[ "There are four types of influenza virus, termed influenza viruses A, B, C, and D. Aquatic birds are the primary source of \"Influenza A virus\" (IAV), which is also widespread in various mammals, including humans and pigs.", "\"Influenza B virus\" (IBV) and \"Influenza C virus\" (ICV) primarily infect humans, and \"Influenza D virus\" (IDV) is found in cattle and pigs.", "IAV and IBV circulate in humans and cause seasonal epidemics, and ICV causes a mild infection, primarily in children.", "IDV can infect humans but is not known to cause illness.", "Annual vaccination can help to provide protection against influenza.", "Influenza viruses, particularly IAV, evolve quickly, so flu vaccines are updated regularly to match which influenza strains are in circulation.", "Vaccines currently in use provide protection against IAV subtypes H1N1 and H3N2 and one or two IBV subtypes." ]

[ "The time between exposure to the virus and development of symptoms, called the incubation period, is 1–4 days, most commonly 1–2 days.", "Many infections, however, are asymptomatic.", "The onset of symptoms is sudden, and initial symptoms are predominately non-specific, including fever, chills, headaches, muscle pain or aching, a feeling of discomfort, loss of appetite, lack of energy/fatigue, and confusion.", "These symptoms are usually accompanied by respiratory symptoms such as a dry cough, sore or dry throat, hoarse voice, and a stuffy or runny nose.", "Coughing is the most common symptom.", "Gastrointestinal symptoms may also occur, including nausea, vomiting, diarrhea, and gastroenteritis, especially in children.", "The standard influenza symptoms typically last for 2–8 days.", "A 2021 study suggests influenza can cause long lasting symptoms in a similar way to long COVID.\nSymptomatic infections are usually mild and limited to the upper respiratory tract, but progression to pneumonia is relatively common.", "Pneumonia may be caused by the primary viral infection or by a secondary bacterial infection.", "Primary pneumonia is characterized by rapid progression of fever, cough, labored breathing, and low oxygen levels that cause bluish skin.", "It is especially common among those who have an underlying cardiovascular disease such as rheumatic heart disease.", "Secondary pneumonia typically has a period of improvement in symptoms for 1–3 weeks followed by recurrent fever, sputum production, and fluid buildup in the lungs, but can also occur just a few days after influenza symptoms appear.", "About a third of primary pneumonia cases are followed by secondary pneumonia, which is most frequently caused by the bacteria \"Streptococcus pneumoniae\" and \"Staphylococcus aureus\".", "Influenza viruses comprise four species.", "Each of the four species is the sole member of its own genus, and the four influenza genera comprise four of the seven genera in the family \"Orthomyxoviridae\".", "They are:\n\n\nIAV is responsible for most cases of severe illness as well as seasonal epidemics and occasional pandemics.", "It infects people of all ages but tends to disproportionately cause severe illness in the elderly, the very young, and those who have chronic health issues.", "Birds are the primary reservoir of IAV, especially aquatic birds such as ducks, geese, shorebirds, and gulls, but the virus also circulates among mammals, including pigs, horses, and marine mammals.", "IAV is classified into subtypes based on the viral proteins haemagglutinin (H) and neuraminidase (N).", "As of 2019, 18 H subtypes and 11 N subtypes have been identified.", "Most potential combinations have been reported in birds, but H17-18 and N10-11 have only been found in bats.", "Only H subtypes H1-3 and N subtypes N1-2 are known to have circulated in humans, the current IAV subtypes in circulation being H1N1 and H3N2.", "IAVs can be classified more specifically to also include natural host species, geographical origin, year of isolation, and strain number, such as H1N1/A/duck/Alberta/35/76.", "IBV mainly infects humans but has been identified in seals, horses, dogs, and pigs.", "IBV does not have subtypes like IAV but has two antigenically distinct lineages, termed the B/Victoria/2/1987-like and B/Yamagata/16/1988-like lineages, or simply (B/)Victoria(-like) and (B/)Yamagata(-like).", "Both lineages are in circulation in humans, disproportionately affecting children.", "IBVs contribute to seasonal epidemics alongside IAVs but have never been associated with a pandemic.", "ICV, like IBV, is primarily found in humans, though it also has been detected in pigs, feral dogs, dromedary camels, cattle, and dogs.", "ICV infection primarily affects children and is usually asymptomatic or has mild cold-like symptoms, though more severe symptoms such as gastroenteritis and pneumonia can occur.", "Unlike IAV and IBV, ICV has not been a major focus of research pertaining to antiviral drugs, vaccines, and other measures against influenza.", "ICV is subclassified into six genetic/antigenic lineages.", "IDV has been isolated from pigs and cattle, the latter being the natural reservoir.", "Infection has also been observed in humans, horses, dromedary camels, and small ruminants such as goats and sheep.", "IDV is distantly related to ICV.", "While cattle workers have occasionally tested positive to prior IDV infection, it is not known to cause disease in humans.", "ICV and IDV experience a slower rate of antigenic evolution than IAV and IBV.", "Because of this antigenic stability, relatively few novel lineages emerge.", "Influenza viruses have a negative-sense, single-stranded RNA genome that is segmented.", "The negative sense of the genome means it can be used as a template to synthesize messenger RNA (mRNA).", "IAV and IBV have eight genome segments that encode 10 major proteins.", "ICV and IDV have seven genome segments that encode nine major proteins.", "Three segments encode three subunits of an RNA-dependent RNA polymerase (RdRp) complex: PB1, a transcriptase, PB2, which recognizes 5' caps, and PA (P3 for ICV and IDV), an endonuclease.", "The matrix protein (M1) and membrane protein (M2) share a segment, as do the non-structural protein (NS1) and the nuclear export protein (NEP).", "For IAV and IBV, hemagglutinin (HA) and neuraminidase (NA) are encoded on one segment each, whereas ICV and IDV encode a hemagglutinin-esterase fusion (HEF) protein on one segment that merges the functions of HA and NA.", "The final genome segment encodes the viral nucleoprotein (NP).", "Influenza viruses also encode various accessory proteins, such as PB1-F2 and PA-X, that are expressed through alternative open reading frames and which are important in host defense suppression, virulence, and pathogenicity.", "The virus particle, called a virion, is pleomorphic and varies between being filamentous, bacilliform, or spherical in shape.", "Clinical isolates tend to be pleomorphic, whereas strains adapted to laboratory growth typically produce spherical virions.", "Filamentous virions are about 250 nanometers (nm) by 80 nm, bacilliform 120–250 by 95 nm, and spherical 120 nm in diameter.", "The virion consists of each segment of the genome bound to nucleoproteins in separate ribonucleoprotein (RNP) complexes for each segment, all of which are surrounded by a lipid bilayer membrane called the viral envelope.", "There is a copy of the RdRp, all subunits included, bound to each RNP.", "The envelope is reinforced structurally by matrix proteins on the interior that enclose the RNPs, and the envelope contains HA and NA (or HEF) proteins extending outward from the exterior surface of the envelope.", "HA and HEF proteins have a distinct \"head\" and \"stalk\" structure.", "M2 proteins form proton ion channels through the viral envelope that are required for viral entry and exit.", "IBVs contain a surface protein named NB that is anchored in the envelope, but its function is unknown.", "The viral life cycle begins by binding to a target cell.", "Binding is mediated by the viral HA proteins on the surface of the evelope, which bind to cells that contain sialic acid receptors on the surface of the cell membrane.", "For N1 subtypes with the \"G147R\" mutation and N2 subtypes, the NA protein can initiate entry.", "Prior to binding, NA proteins promote access to target cells by degrading mucous, which helps to remove extracellular decoy receptors that would impede access to target cells.", "After binding, the virus is internalized into the cell by an endosome that contains the virion inside it.", "The endosome is acidified by cellular vATPase to have lower pH, which triggers a conformational change in HA that allows fusion of the viral envelope with the endosomal membrane.", "At the same time, hydrogen ions diffuse into the virion through M2 ion channels, disrupting internal protein-protein interactions to release RNPs into the host cell's cytosol.", "The M1 protein shell surrounding RNPs is degraded, fully uncoating RNPs in the cytosol.", "RNPs are then imported into the nucleus with the help of viral localization signals.", "There, the viral RNA polymerase transcribes mRNA using the genomic negative-sense strand as a template.", "The polymerase snatches 5' caps for viral mRNA from cellular RNA to prime mRNA synthesis and the 3'-end of mRNA is polyadenylated at the end of transcription.", "Once viral mRNA is transcribed, it is exported out of the nucleus and translated by host ribosomes in a cap-dependent manner to synthesize viral proteins.", "RdRp also synthesizes complementary positive-sense strands of the viral genome in a complementary RNP complex which are then used as templates by viral polymerases to synthesize copies of the negative-sense genome.", "During these processes, RdRps of avian influenza viruses (AIVs) function optimally at a higher temperature than mammalian influenza viruses.", "Newly synthesized viral polymerase subunits and NP proteins are imported to the nucleus to further increase the rate of viral replication and form RNPs.", "HA, NA, and M2 proteins are trafficked with the aid of M1 and NEP proteins to the cell membrane through the Golgi apparatus and inserted into the cell's membrane.", "Viral non-structural proteins including NS1, PB1-F2, and PA-X regulate host cellular processes to disable antiviral responses.", "PB1-F2 aso interacts with PB1 to keep polymerases in the nucleus longer.", "M1 and NEP proteins localize to the nucleus during the later stages of infection, bind to viral RNPs and mediate their export to the cytoplasm where they migrate to the cell membrane with the aid of recycled endosomes and are bundled into the segments of the genome.", "Progenic viruses leave the cell by budding from the cell membrane, which is initiated by the accumulation of M1 proteins at the cytoplasmic side of the membrane.", "The viral genome is incorporated inside a viral envelope derived from portions of the cell membrane that have HA, NA, and M2 proteins.", "At the end of budding, HA proteins remain attached to cellular sialic acid until they are cleaved by the sialidase activity of NA proteins.", "The virion is then released from the cell.", "The sialidase activity of NA also cleaves any sialic acid residues from the viral surface, which helps prevent newly assembled viruses from aggregating near the cell surface and improving infectivity.", "Similar to other aspects of influenza replication, optimal NA activity is temperature- and pH-dependent.", "Ultimately, presence of large quantities of viral RNA in the cell triggers apoptosis, i.e. programmed cell death, which is initiated by cellular factors to restrict viral replication.", "Two key processes that influenza viruses evolve through are antigenic drift and antigenic shift.", "Antigenic drift is when an influenza virus's antigens change due to the gradual accumulation of mutations in the antigen's (HA or NA) gene.", "This can occur in response to evolutionary pressure exerted by the host immune response.", "Antigenic drift is especially common for the HA protein, in which just a few amino acid changes in the head region can constitute antigenic drift.", "The result is the production of novel strains that can evade pre-existing antibody-mediated immunity.", "Antigenic drift occurs in all influenza species but is slower in B than A and slowest in C and D. Antigenic drift is a major cause of seasonal influenza, and requires that flu vaccines be updated annually.", "HA is the main component of inactivated vaccines, so surveillance monitors antigenic drift of this antigen among circulating strains.", "Antigenic evolution of influenza viruses of humans appears to be faster than influenza viruses in swine and equines.", "In wild birds, within-subtype antigenic variation appears to be limited but has been observed in poultry.", "Antigenic shift is a sudden, drastic change in an influenza virus's antigen, usually HA.", "During antigenic shift, antigenically different strains that infect the same cell can reassort genome segments with each other, producing hybrid progeny.", "Since all influenza viruses have segmented genomes, all are capable of reassortment.", "Antigenic shift, however, only occurs among influenza viruses of the same genus and most commonly occurs among IAVs.", "In particular, reassortment is very common in AIVs, creating a large diversity of influenza viruses in birds, but is uncommon in human, equine, and canine lineages.", "Pigs, bats, and quails have receptors for both mammalian and avian IAVs, so they are potential \"mixing vessels\" for reassortment.", "If an animal strain reassorts with a human strain, then a novel strain can emerge that is capable of human-to-human transmission.", "This has caused pandemics, but only a limited number have occurred, so it is difficult to predict when the next will happen.", "People who are infected can transmit influenza viruses through breathing, talking, coughing, and sneezing, which spread respiratory droplets and aerosols that contain virus particles into the air.", "A person susceptible to infection can then contract influenza by coming into contact with these particles.", "Respiratory droplets are relatively large and travel less than two meters before falling onto nearby surfaces.", "Aerosols are smaller and remain suspended in the air longer, so they take longer to settle and can travel further than respiratory droplets.", "Inhalation of aerosols can lead to infection, but most transmission is in the area about two meters around an infected person via respiratory droplets that come into contact with mucosa of the upper respiratory tract.", "Transmission through contact with a person, bodily fluids, or intermediate objects (fomites) can also occur, such as through contaminated hands and surfaces since influenza viruses can survive for hours on non-porous surfaces.", "If one's hands are contaminated, then touching one's face can cause infection.", "Influenza is usually transmissible from one day before the onset of symptoms to 5–7 days after.", "In healthy adults, the virus is shed for up to 3–5 days.", "In children and the immunocompromised, the virus may be transmissible for several weeks.", "Children ages 2–17 are considered to be the primary and most efficient spreaders of influenza.", "Children who have not had multiple prior exposures to influenza viruses shed the virus at greater quantities and for a longer duration than other children.", "People who are at risk of exposure to influenza include health care workers, social care workers, and those who live with or care for people vulnerable to influenza.", "In long-term care facilities, the flu can spread rapidly after it is introduced.", "A variety of factors likely encourage influenza transmission, including lower temperature, lower absolute and relative humidity, less ultraviolet radiation from the Sun, and crowding.", "Influenza viruses that infect the upper respiratory tract like H1N1 tend to be more mild but more transmissible, whereas those that infect the lower respiratory tract like H5N1 tend to cause more severe illness but are less contagious.", "In humans, influenza viruses first cause infection by infecting epithelial cells in the respiratory tract.", "Illness during infection is primarily the result of lung inflammation and compromise caused by epithelial cell infection and death, combined with inflammation caused by the immune system's response to infection.", "Non-respiratory organs can become involved, but the mechanisms by which influenza is involved in these cases are unknown.", "Severe respiratory illness can be caused by multiple, non-exclusive mechanisms, including obstruction of the airways, loss of alveolar structure, loss of lung epithelial integrity due to epithelial cell infection and death, and degradation of the extracellular matrix that maintains lung structure.", "In particular, alveolar cell infection appears to drive severe symptoms since this results in impaired gas exchange and enables viruses to infect endothelial cells, which produce large quantities of pro-inflammatory cytokines.", "Pneumonia caused by influenza viruses is characterized by high levels of viral replication in the lower respiratory tract, accompanied by a strong pro-inflammatory response called a cytokine storm.", "Infection with H5N1 or H7N9 especially produces high levels of pro-inflammatory cytokines.", "In bacterial infections, early depletion of macrophages during influenza creates a favorable environment in the lungs for bacterial growth since these white blood cells are important in responding to bacterial infection.", "Host mechanisms to encourage tissue repair may inadvertently allow bacterial infection.", "Infection also induces production of systemic glucocorticoids that can reduce inflammation to preserve tissue integrity but allow increased bacterial growth.", "The pathophysiology of influenza is significantly influenced by which receptors influenza viruses bind to during entry into cells.", "Mammalian influenza viruses preferentially bind to sialic acids connected to the rest of the oligosaccharide by an α-2,6 link, most commonly found in various respiratory cells, such as respiratory and retinal epithelial cells.", "AIVs prefer sialic acids with an α-2,3 linkage, which are most common in birds in gastrointestinal epithelial cells and in humans in the lower respiratory tract.", "Furthermore, cleavage of the HA protein into HA, the binding subunit, and HA, the fusion subunit, is performed by different proteases, affecting which cells can be infected.", "For mammalian influenza viruses and low pathogenic AIVs, cleavage is extracellular, which limits infection to cells that have the appropriate proteases, whereas for highly pathogenic AIVs, cleavage is intracellular and performed by ubiquitous proteases, which allows for infection of a greater variety of cells, thereby contributing to more severe disease.", "Cells possess sensors to detect viral RNA, which can then induce interferon production.", "Interferons mediate expression of antiviral proteins and proteins that recruit immune cells to the infection site, and they also notify nearby uninfected cells of infection.", "Some infected cells release pro-inflammatory cytokines that recruit immune cells to the site of infection.", "Immune cells control viral infection by killing infected cells and phagocytizing viral particles and apoptotic cells.", "An exacerbated immune response, however, can harm the host organism through a cytokine storm.", "To counter the immune response, influenza viruses encode various non-structural proteins, including NS1, NEP, PB1-F2, and PA-X, that are involved in curtailing the host immune response by suppressing interferon production and host gene expression.", "B cells, a type of white blood cell, produce antibodies that bind to influenza antigens HA and NA (or HEF) and other proteins to a lesser degree.", "Once bound to these proteins, antibodies block virions from binding to cellular receptors, neutralizing the virus.", "In humans, a sizeable antibody response occurs ~1 week after viral exposure.", "This antibody response is typically robust and long-lasting, especially for ICV and IDV.", "In other words, people exposed to a certain strain in childhood still possess antibodies to that strain at a reasonable level later in life, which can provide some protection to related strains.", "There is, however, an \"original antigenic sin\", in which the first HA subtype a person is exposed to influences the antibody-based immune response to future infections and vaccines.", "Annual vaccination is the primary and most effective way to prevent influenza and influenza-associated complications, especially for high-risk groups.", "Vaccines against the flu are trivalent or quadrivalent, providing protection against an H1N1 strain, an H3N2 strain, and one or two IBV strains corresponding to the two IBV lineages.", "Two types of vaccines are in use: inactivated vaccines that contain \"killed\" (i.e. inactivated) viruses and live attenuated influenza vaccines (LAIVs) that contain weakened viruses.", "There are three types of inactivated vaccines: whole virus, split virus, in which the virus is disrupted by a detergent, and subunit, which only contains the viral antigens HA and NA.", "Most flu vaccines are inactivated and administered via intramuscular injection.", "LAIVs are sprayed into the nasal cavity.", "Vaccination recommendations vary by country.", "Some recommend vaccination for all people above a certain age, such as 6 months, whereas other countries recommendation is limited for high at risk groups, such as pregnant women, young children (excluding newborns), the elderly, people with chronic medical conditions, health care workers, people who come into contact with high-risk people, and people who transmit the virus easily.", "Young infants cannot receive flu vaccines for safety reasons, but they can inherit passive immunity from their mother if inactivated vaccines are administered to the mother during pregnancy.", "Influenza vaccination also helps to reduce the probability of reassortment.", "In general, influenza vaccines are only effective if there is an antigenic match between vaccine strains and circulating strains.", "Additionally, most commercially available flu vaccines are manufactured by propagation of influenza viruses in embryonated chicken eggs, taking 6–8 months.", "Flu seasons are different in the northern and southern hemisphere, so the WHO meets twice a year, one for each hemisphere, to discuss which strains should be included in flu vaccines based on observation from HA inhibition assays.", "Other manufacturing methods include an MDCK cell culture-based inactivated vaccine and a recombinant subunit vaccine manufactured from baculovirus overexpression in insect cells.", "Influenza can be prevented or reduced in severity by post-exposure prophylaxis with the antiviral drugs oseltamivir, which can be taken orally by those at least three months old, and zanamivir, which can be inhaled by those above seven years of age.", "Chemoprophylaxis is most useful for individuals at high-risk of developing complications and those who cannot receive the flu vaccine due to contraindications or lack of effectiveness.", "Post-exposure chemoprophylaxis is only recommended if oseltamivir is taken within 48 hours of contact with a confirmed or suspected influenza case and zanamivir within 36 hours.", "It is recommended that it be offered to people who have yet to receive a vaccine for the current flu season, who have been vaccinated less than two week since contact, if there is a significant mismatch between vaccine and circulating strains, or during an outbreak in a closed setting regardless of vaccination history.", "Hand hygiene is important in reducing the spread of influenza.", "This includes frequent hand washing with soap and water, using alcohol-based hand sanitizers, and not touching one's eyes, nose, and mouth with one's hands.", "Covering one's nose and mouth when coughing or sneezing is important.", "Other methods to limit influenza transmission include staying home when sick, avoiding contact with others until one day after symptoms end, and disinfecting surfaces likely to be contaminated by the virus, such as doorknobs.", "Health education through media and posters is often used to remind people of the aforementioned etiquette and hygiene.", "There is uncertainty about the use of masks since research thus far has not shown a significant reduction in seasonal influenza with mask usage.", "Likewise, the effectiveness of screening at points of entry into countries is not well researched.", "Social distancing measures such as school closures, avoiding contact with infected people via isolation or quarantine, and limiting mass gatherings may reduce transmission, but these measures are often expensive, unpopular, and difficult to implement.", "Consequently, the commonly recommended methods of infection control are respiratory etiquette, hand hygiene, and mask wearing, which are inexpensive and easy to perform.", "Pharmaceutical measures are effective but may not be available in the early stages of an outbreak.", "In health care settings, infected individuals may be cohorted or assigned to individual rooms.", "Protective clothing such as masks, gloves, and gowns is recommended when coming into contact with infected individuals if there is a risk of exposure to infected bodily fluids.", "Keeping patients in negative pressure rooms and avoiding aerosol-producing activities may help, but special air handling and ventilation systems are not considered necessary to prevent the spread of influenza in the air.", "In residential homes, new admissions may need to be closed until the spread of influenza is controlled.", "When discharging patients to care homes, it is important to take care if there is a known influenza outbreak.", "Since influenza viruses circulate in animals such as birds and pigs, prevention of transmission from these animals is important.", "Water treatment, indoor raising of animals, quarantining sick animals, vaccination, and biosecurity are the primary measures used.", "Placing poultry houses and piggeries on high ground away from high-density farms, backyard farms, live poultry markets, and bodies of water helps to minimize contact with wild birds.", "Closure of live poultry markets appears to the most effective measure and has shown to be effective at controlling the spread of H5N1, H7N9, and H9N2.", "Other biosecurity measures include cleaning and disinfecting facilities and vehicles, banning visits to poultry farms, not bringing birds intended for slaughter back to farms, changing clothes, disinfecting foot baths, and treating food and water.", "If live poultry markets are not closed, then \"clean days\" when unsold poultry is removed and facilities are disinfected and \"no carry-over\" policies to eliminate infectious material before new poultry arrive can be used to reduce the spread of influenza viruses.", "If a novel influenza viruses has breached the aforementioned biosecurity measures, then rapid detection to stamp it out via quarantining, decontamination, and culling may be necessary to prevent the virus from becoming endemic.", "Vaccines exist for avian H5, H7, and H9 subtypes that are used in some countries.", "In China, for example, vaccination of domestic birds against H7N9 successfully limited its spread, indicating that vaccination may be an effective strategy if used in combination with other measures to limit transmission.", "In pigs and horses, management of influenza is dependent on vaccination with biosecurity.", "Diagnosis based on symptoms is fairly accurate in otherwise healthy people during seasonal epidemics and should be suspected in cases of pneumonia, acute respiratory distress syndrome (ARDS), sepsis, or if encephalitis, myocarditis, or breaking down of muscle tissue occur.", "Because influenza is similar to other viral respiratory tract illnesses, laboratory diagnosis is necessary for confirmation.", "Common ways of collecting samples for testing include nasal and throat swabs.", "Samples may be taken from the lower respiratory tract if infection has cleared the upper but not lower respiratory tract.", "Influenza testing is recommended for anyone hospitalized with symptoms resembling influenza during flu season or who is connected to an influenza case.", "For severe cases, earlier diagnosis improves patient outcome.", "Diagnostic methods that can identify influenza include viral cultures, antibody- and antigen-detecting tests, and nucleic acid-based tests.", "Viruses can be grown in a culture of mammalian cells or embryonated eggs for 3–10 days to monitor cytopathic effect.", "Final confirmation can then be done via antibody staining, hemadsorption using red blood cells, or immunofluorescence microscopy.", "Shell vial cultures, which can identify infection via immunostaining before a cytopathic effect appears, are more sensitive than traditional cultures with results in 1–3 days.", "Cultures can be used to characterize novel viruses, observe sensitivity to antiviral drugs, and monitor antigenic drift, but they are relatively slow and require specialized skills and equipment.", "Serological assays can be used to detect an antibody response to influenza after natural infection or vaccination.", "Common serological assays include hemagglutination inhibition assays that detect HA-specific antibodies, virus neutralization assays that check whether antibodies have neutralized the virus, and enzyme-linked immunoabsorbant assays.", "These methods tend to be relatively inexpensive and fast but are less reliable than nucleic-acid based tests.", "Direct fluorescent or immunofluorescent antibody (DFA/IFA) tests involve staining respiratory epithelial cells in samples with fluorescently-labeled influenza-specific antibodies, followed by examination under a fluorescent microscope.", "They can differentiate between IAV and IBV but can't subtype IAV.", "Rapid influenza diagnostic tests (RIDTs) are a simple way of obtaining assay results, are low cost, and produce results quickly, at less than 30 minutes, so they are commonly used, but they can't distinguish between IAV and IBV or between IAV subtypes and are not as sensitive as nucleic-acid based tests.", "Nucleic acid-based tests (NATs) amplify and detect viral nucleic acid.", "Most of these tests take a few hours, but rapid molecular assays are as fast as RIDTs.", "Among NATs, reverse transcription polymerase chain reaction (RT-PCR) is the most traditional and considered the gold standard for diagnosing influenza because it is fast and can subtype IAV, but it is relatively expensive and more prone to false-positives than cultures.", "Other NATs that have been used include loop-mediated isothermal amplification-based assays, simple amplification-based assays, and nucleic acid sequence-based amplification.", "Nucleic acid sequencing methods can identify infection by obtaining the nucleic acid sequence of viral samples to identify the virus and antiviral drug resistance.", "The traditional method is Sanger sequencing, but it has been largely replaced by next-generation methods that have greater sequencing speed and throughput.", "Treatment of influenza in cases of mild or moderate illness is supportive and includes anti-fever medications such as acetaminophen and ibuprofen, adequate fluid intake to avoid dehydration, and resting at home.", "Cough drops and throat sprays may be beneficial for sore throat.", "It is recommended to avoid alcohol and tobacco use while sick with the flu.", "Aspirin is not recommended to treat influenza in children due to an elevated risk of developing Reye syndrome.", "Corticosteroids likewise are not recommended except when treating septic shock or an underlying medical condition, such as chronic obstructive pulmonary disease or asthma exacerbation, since they are associated with increased mortality.", "If a secondary bacterial infection occurs, then treatment with antibiotics may be necessary.", "Antiviral drugs are primarily used to treat severely ill patients, especially those with compromised immune systems.", "Antivirals are most effective when started in the first 48 hours after symptoms appear.", "Later administration may still be beneficial for those who have underlying immune defects, those with more severe symptoms, or those who have a higher risk of developing complications if these individuals are still shedding the virus.", "Antiviral treatment is also recommended if a person is hospitalized with suspected influenza instead of waiting for test results to return and if symptoms are worsening.", "Most antiviral drugs against influenza fall into two categories: neuraminidase (NA) inhibitors and M2 inhibitors.", "Baloxavir marboxil is a notable exception, which targets the endonuclease activity of the viral RNA polymerase and can be used as an alternative to NA and M2 inhibitors for IAV and IBV.", "NA inhibitors target the enzymatic activity of NA receptors, mimicking the binding of sialic acid in the active site of NA on IAV and IBV virions so that viral release from infected cells and the rate of viral replication are impaired.", "NA inhibitors include oseltamivir, which is consumed orally in a prodrug form and converted to its active form in the liver, and zanamivir, which is a powder that is inhaled nasally.", "Oseltamivir and zanamivir are effective for prophylaxis and post-exposure prophylaxis, and research overall indicates that NA inhibitors are effective at reducing rates of complications, hospitalization, and mortality and the duration of illness.", "Additionally, the earlier NA inhibitors are provided, the better the outcome, though late administration can still be beneficial in severe cases.", "Other NA inhibitors include laninamivir and peramivir, the latter of which can be used as an alternative to oseltamivir for people who cannot tolerate or absorb it.", "The adamantanes amantadine and rimantadine are orally administered drugs that block the influenza virus's M2 ion channel, preventing viral uncoating.", "These drugs are only functional against IAV but are no longer recommended for use because of widespread resistance to them among IAVs.", "Adamantane resistance first emerged in H3N2 in 2003, becoming worldwide by 2008.", "Oseltamivir resistance is no longer widespread because the 2009 pandemic H1N1 strain (H1N1 pdm09), which is resistant to adamantanes, seemingly replaced resistant strains in circulation.", "Since the 2009 pandemic, oseltamivir resistance has mainly been observed in patients undergoing therapy, especially the immunocompromised and young children.", "Oseltamivir resistance is usually reported in H1N1, but has been reported in H3N2 and IBVs less commonly.", "Because of this, oseltamivir is recommended as the first drug of choice for immunocompetent people, whereas for the immunocompromised, oseltamivir is recommended against H3N2 and IBV and zanamivir against H1N1 pdm09.", "Zanamivir resistance is observed less frequently, and resistance to peramivir and baloxavir marboxil is possible.", "In healthy individuals, influenza infection is usually self-limiting and rarely fatal.", "Symptoms usually last for 2–8 days.", "Influenza can cause people to miss work or school, and it is associated with decreased job performance and, in older adults, reduced independence.", "Fatigue and malaise may last for several weeks after recovery, and healthy adults may experience pulmonary abnormalities that can take several weeks to resolve.", "Complications and mortality primarily occur in high-risk populations and those who are hospitalized.", "Severe disease and mortality are usually attributable to pneumonia from the primary viral infection or a secondary bacterial infection, which can progress to ARDS.", "Other respiratory complications that may occur include sinusitis, bronchitis, bronchiolitis, excess fluid buildup in the lungs, and exacerbation of chronic bronchitis and asthma.", "Middle ear infection and croup may occur, most commonly in children.", "Secondary \"S. aureus\" infection has been observed, primarily in children, to cause toxic shock syndrome after influenza, with hypotension, fever, and reddening and peeling of the skin.", "Complications affecting the cardiovascular system are rare and include pericarditis, fulminant myocarditis with a fast, slow, or irregular heartbeat, and exacerbation of pre-existing cardiovascular disease.", "Inflammation or swelling of muscles accompanied by muscle tissue breaking down occurs rarely, usually in children, which presents as extreme tenderness and muscle pain in the legs and a reluctance to walk for 2–3 days.", "Influenza can affect pregnancy, including causing smaller neonatal size, increased risk of premature birth, and an increased risk of child death shortly before or after birth.", "Neurological complications have been associated with influenza on rare occasions, including aseptic meningitis, encephalitis, disseminated encephalomyelitis, transverse myelitis, and Guillain–Barré syndrome.", "Additionally, febrile seizures and Reye syndrome can occur, most commonly in children.", "Influenza-associated encephalopathy can occur directly from central nervous system infection from the presence of the virus in blood and presents as suddent onset of fever with convulsions, followed by rapid progression to coma.", "An atypical form of encephalitis called encephalitis lethargica, characterized by headache, drowsiness, and coma, may rarely occur sometime after infection.", "In survivors of influenza-associated encephalopathy, neurological defects may occur.", "Primarily in children, in severe cases the immune system may rarely dramatically overproduce white blood cells that release cytokines, causing severe inflammation.", "People who are at least 65 years of age, due to a weakened immune system from aging or a chronic illness, are a high-risk group for developing complications, as are children less than one year of age and children who have not been previously exposed to influenza viruses multiple times.", "Pregnant women are at an elevated risk, which increases by trimester and lasts up to two weeks after childbirth.", "Obesity, in particular a body mass index greater than 35–40, is associated with greater amounts of viral replication, increased severity of secondary bacterial infection, and reduced vaccination efficacy.", "People who have underlying health conditions are also considered at-risk, including those who have congenital or chronic heart problems or lung (e.g. asthma), kidney, liver, blood, neurological, or metabolic (e.g. diabetes) disorders, as are people who are immunocompromised from chemotherapy, asplenia, prolonged steroid treatment, splenic dysfunction, or HIV infection.", "Current or past tobacco use also places a person at risk.", "The role of genetics in influenza is not well researched, but it may be a factor in influenza mortality.", "Influenza is typically characterized by seasonal epidemics and sporadic pandemics.", "Most of the burden of influenza is a result of flu seasons caused by IAV and IBV.", "Among IAV subtypes, H1N1 and H3N2 currently circulate in humans and are responsible for seasonal influenza.", "Cases disproportionately occur in children, but most severe causes are among the elderly, the very young, and the immunocompromised.", "In a typical year, influenza viruses infect 5–15% of the global population, causing 3–5 million cases of severe illness annually and accounting for 290,000–650,000 deaths each year due to respiratory illness.", "5–10% of adults and 20–30% of children contract influenza each year.", "The reported number of influenza cases is usually much lower than the actual number of cases.", "During seasonal epidemics, it is estimated that about 80% of otherwise healthy people who have a cough or sore throat have the flu.", "Approximately 30–40% of people hospitalized for influenza develop pneumonia, and about 5% of all severe pneumonia cases in hospitals are due to influenza, which is also the most common cause of ARDS in adults.", "In children, influenza is one of the two most common causes of ARDS, the other being the respiratory syncytial virus.", "About 3–5% of children each year develop otitis media due to influenza.", "Adults who develop organ failure from influenza and children who have PIM scores and acute renal failure have higher rates of mortality.", "During seasonal influenza, mortality is concentrated in the very young and the elderly, whereas during flu pandemics, young adults are often affected at a high rate.", "In temperate regions, the number of influenza cases varies from season to season.", "Lower vitamin D levels, presumably due to less sunlight, lower humidity, lower temperature, and minor changes in virus proteins caused by antigenic drift contribute to annual epidemics that peak during the winter season.", "In the northern hemisphere, this is from October to May (more narrowly December to April), and in the southern hemisphere, this is from May to October (more narrowly June to September).", "There are therefore two distinct influenza seasons every year in temperate regions, one in the northern hemisphere and one in the southern hemisphere.", "In tropical and subtropical regions, seasonality is more complex and appears to be affected by various climatic factors such as minimum temperature, hours of sunshine, maximum rainfall, and high humidity.", "Influenza may therefore occur year-round in these regions.", "Influenza epidemics in modern times have the tendency to start in the eastern or southern hemisphere, with Asia being a key reservoir of influenza viruses.", "IAV and IBV co-circulate, so the two have the same patterns of transmission.", "The seasonality of ICV, however, is poorly understood.", "ICV infection is most common in children under the age of 2, and by adulthood most people have been exposed to it.", "ICV-associated hospitalization most commonly occurs in children under the age of 3 and is frequently accompanied by co-infection with another virus or a bacterium, which may increase the severity of disease.", "When considering all hospitalizations for respiratory illness among young children, ICV appears to account for only a small percentage of such cases.", "Large outbreaks of ICV infection can occur, so incidence varies significantly.", "Outbreaks of influenza caused by novel influenza viruses are common.", "Depending on the level of pre-existing immunity in the population, novel influenza viruses can spread rapidly and cause pandemics with millions of deaths.", "These pandemics, in contrast to seasonal influenza, are caused by antigenic shifts involving animal influenza viruses.", "To date, all known flu pandemics have been caused by IAVs, and they follow the same pattern of spreading from an origin point to the rest of the world over the course of multiple waves in a year.", "Pandemic strains tend to be associated with higher rates of pneumonia in otherwise healthy individuals.", "Generally after each influenza pandemic, the pandemic strain continues to circulate as the cause of seasonal influenza, replacing prior strains.", "From 1700 to 1889, influenza pandemics occurred about once every 50–60 years.", "Since then, pandemics have occurred about once every 10–50 years, so they may be getting more frequent over time.", "It is impossible to know when an influenza virus first infected humans or when the first influenza pandemic occurred.", "Possibly the first influenza epidemic occurred around 6,000 BC in China, and possible descriptions of influenza exist in Greek writings from the 5th century BC.", "In both 1173–1174 AD and 1387 AD, epidemics occurred across Europe that were named \"influenza\".", "Whether these epidemics and others were caused by influenza is unclear since there was no consistent naming pattern for epidemic respiratory diseases at that time, and \"influenza\" didn't become completely attached to respiratory disease until centuries later.", "Influenza may have been brought to the Americas as early as 1493, when an epidemic disease resembling influenza killed most of the population of the Antilles.", "The first convincing record of an influenza pandemic was chronicled in 1510; it began in East Asia before spreading to North Africa and then Europe.", "Following the pandemic, seasonal influenza occurred, with subsequent pandemics in 1557 and 1580.", "The flu pandemic in 1557 was potentially the first time influenza was connected to miscarriage and death of pregnant women.", "The 1580 flu pandemic originated in Asia during summer, spread to Africa, then Europe, and finally America.", "By the end of the 16th century, influenza was likely beginning to become understood as a specific, recognizable disease with epidemic and endemic forms.", "In 1648, it was discovered that horses also experience influenza.", "Influenza data after 1700 is more informative, so it is easier to identify flu pandemics after this point, each of which incrementally increased understanding of influenza.", "The first flu pandemic of the 18th century started in 1729 in Russia in spring, spreading worldwide over the course of three years with distinct waves, the later ones being more lethal.", "The second flu pandemic of the 18th century was in 1781–1782, starting in China in autumn.", "From this pandemic, influenza became associated with sudden outbreaks of febrile illness.", "The next flu pandemic was from 1830 to 1833, beginning in China in winter.", "This pandemic had a high attack rate, but the mortality rate was low.", "A minor influenza pandemic occurred from 1847 to 1851 at the same time as the third cholera pandemic and was the first flu pandemic to occur with vital statistics being recorded, so influenza mortality was clearly recorded for the first time.", "Highly pathogenic avian influenza was recognized in 1878 and was soon linked to transmission to humans.", "By the time of the 1889 pandemic, which may have been caused by an H2N2 strain, the flu had become an easily recognizable disease.", "Initially, the microbial agent responsible for influenza was incorrently identified in 1892 by R. F. J. Pfeiffer as the bacteria species \"Haemophilus influenzae\", which retains \"influenza\" in its name.", "In the following years, the field of virology began to form as viruses were identified as the cause of many diseases.", "From 1901 to 1903, Italian and Austrian researchers were able to show that avian influenza, then called \"fowl plague\", was caused by a microscopic agent smaller than bacteria by using filters with pores too small for bacteria to pass through.", "The fundamental differences between viruses and bacteria, however, were not yet fully understood.", "From 1918 to 1920, the Spanish flu pandemic became the most devastating influenza pandemic and one of the deadliest pandemics in history.", "The pandemic, probably caused by H1N1, likely began in the USA before spreading worldwide by soldiers during and after the First World War.", "The initial wave in the first half of 1918 was relatively minor and resembled past flu pandemics, but the second wave later that year had a much higher mortality rate, accounting for most deaths.", "A third wave with lower mortality occurred in many places a few months after the second.", "By the end of 1920, it is estimated that about a third to half of all people in the world had been infected, with tens of millions of deaths, disproportionately young adults.", "During the 1918 pandemic, the respiratory route of transmission was clearly identified and influenza was shown to be caused by a \"filter passer\", not a bacterium, but there remained a lack of agreement about influenza's cause for another decade and research on influenza declined.", "After the pandemic, H1N1 circulated in humans in seasonal form up until the next pandemic.", "In 1931, Richard Shope published three papers identifying a virus as the cause of swine influenza, a then newly recognized disease among pigs that was first characterized during the second wave of the 1918 pandemic.", "Shope's research reinvigorated research on human influenza, and many advances in virology, serology, immunology, experimental animal models, vaccinology, and immunotherapy have since arisen from influenza research.", "Just two years after influenza viruses were discovered, in 1933, IAV was identified as the agent responsible for human influenza.", "Subtypes of IAV were discovered throughout the 1930s, and IBV was discovered in 1940.", "During the Second World War, the US government worked on developing inactivated vaccines for influenza, resulting in the first influenza vaccine being licensed in 1945 in the United States.", "ICV was discovered two years later in 1947.", "In 1955, avian influenza was confirmed to be caused by IAV.", "Four influenza pandemics have occurred since WWII, each less severe than the 1918 pandemic.", "The first of these was the Asian flu from 1957 to 1958, caused by an H2N2 strain and beginning in China's Yunnan province.", "The number of deaths probably exceeded one million, mostly among the very young and very old.", "Notably, the 1957 pandemic was the first flu pandemic to occur in the presence of a global surveillance system and laboratories able to study the novel influenza virus.", "After the pandemic, H2N2 was the IAV subtype responsible for seasonal influenza.", "The first antiviral drug against influenza, amantadine, was approved for use in 1966, with additional antiviral drugs being used since the 1990s.", "In 1968, H3N2 was introduced into humans as a result of a reassortment between an avian H3N2 strain and an H2N2 strain that was circulating in humans.", "The novel H3N2 strain first emerged in Hong Kong and spread worldwide, causing the Hong Kong flu pandemic, which resulted in 500,000–2,000,000 deaths.", "This was the first pandemic to spread significantly by air travel.", "H2N2 and H3N2 co-circulated after the pandemic until 1971 when H2N2 waned in prevalence and was completely replaced by H3N2.", "In 1977, H1N1 reemerged in humans, possibly after it was released from a freezer in a laboratory accident, and caused a pseudo-pandemic.", "Whether the 1977 \"pandemic\" deserves to be included in the natural history of flu pandemics is debatable.", "This H1N1 strain was antigenically similar to the H1N1 strains that circulated prior to 1957.", "Since 1977, both H1N1 and H3N2 have circulated in humans as part of seasonal influenza.", "In 1980, the current classification system used to subtype influenza viruses was introduced.", "At some point, IBV diverged into two lineages, named the B/Victoria-like and B/Yamagata-like lineages, both of which have been circulating in humans since 1983.", "In 1996, HPAI H5N1 was detected in Guangdong, China and a year later emerged in poultry in Hong Kong, gradually spreading worldwide from there.", "A small H5N1 outbreak in humans in Hong Kong occurred then, and sporadic human cases have occurred since 1997, carrying a high case fatality rate.", "The most recent flu pandemic was the 2009 swine flu pandemic, which originated in Mexico and resulted in hundreds of thousands of deaths.", "It was caused by a novel H1N1 strain that was a reassortment of human, swine, and avian influenza viruses.", "The 2009 pandemic had the effect of replacing prior H1N1 strains in circulation with the novel strain but not any other influenza viruses.", "Consequently, H1N1, H3N2, and both IBV lineages have been in circulation in seasonal form since the 2009 pandemic.", "In 2011, IDV was discovered in pigs in Oklahoma, USA, and cattle were later identified as the primary reservoir of IDV.", "In the same year, avian H7N9 was detected in China and began to cause human infections in 2013, starting in Shanghai and Anhui and remaining mostly in China.", "HPAI H7N9 emerged sometime in 2016 and has occasionally infected humans incidentally.", "Other AIVs have less commonly infected humans since the 1990s, including H5N6, H6N1, H7N2-4, H7N7, and H10N7-8, and HPAI H subtypes such as H5N1-3, H5N5-6, and H5N8 have begun to spread throughout much of the world since the 2010s.", "Future flu pandemics, which may be caused by an influenza virus of avian origin, are viewed as almost inevitable, and increased globalization has made it easier for novel viruses to spread, so there are continual efforts to prepare for future pandemics and improve the prevention and treatment of influenza.", "The word \"influenza\" comes from the Italian word \"influenza\", from medieval Latin \"influentia\", originally meaning \"visitation\" or \"influence\".", "Terms such as \"influenza di freddo\", meaning \"influence of the cold\", and \"influenza di stelle\", meaning \"influence of the stars\" are attested from the 14th century.", "The latter referred to the disease's cause, which at the time was ascribed by some to unfavorable astrological conditions.", "As early as 1504, \"influenza\" began to mean a \"visitation\" or \"outbreak\" of any disease affecting many people in a single place at once.", "During an outbreak of influenza in 1743 that started in Italy and spread throughout Europe, the word reached the English language and was anglicized in pronunciation.", "Since the mid-1800s, \"influenza\" has also been used to refer to severe colds.", "The shortened form of the word, \"(the) flu\", is first attested in 1839 as \"flue\" with the spelling \"flu\" first attested in 1893.", "Other names that have been used for influenza include \"epidemic catarrh\", \"la grippe\" from French, \"sweating sickness\", and, especially when referring to the 1918 pandemic strain, \"Spanish fever\".", "Influenza research is wide-ranging and includes efforts to understand how influenza viruses enter hosts, the relationship between influenza viruses and bacteria, how influenza symptoms progress, and what make some influenza viruses deadlier than others.", "Non-structural proteins encoded by influenza viruses are periodically discovered and their functions are continually under research.", "Past pandemics, and especially the 1918 pandemic, are the subject of much research to understand flu pandemics.", "As part of pandemic preparedness, the Global Influenza Surveillance and Response System is a global network of laboratories that monitors influenza transmission and epidemiology.", "Additional areas of research include ways to improve the diagnosis, treatment, and prevention of influenza.", "Existing diagnostic methods have a variety of limitations coupled with their advantages.", "For example, NATs have high sensitivity and specificity but are impractical in under-resourced regions due to their high cost, complexity, maintenance, and training required.", "Low-cost, portable RIDTs can rapidly diagnose influenza but have highly variable sensitivity and are unable to subtype IAV.", "As a result of these limitations and others, research into new diagnostic methods revolves around producing new methods that are cost-effective, less labor-intensive, and less complex than existing methods while also being able to differentiate influenza species and IAV subtypes.", "One approach in development are lab-on-a-chips, which are diagnostic devices that make use of a variety of diagnostic tests, such as RT-PCR and serological assays, in microchip form.", "These chips have many potential advantages, including high reaction efficiency, low energy consumption, and low waste generation.", "New antiviral drugs are also in development due to the elimination of adamantines as viable drugs and concerns over oseltamivir resistance.", "These include: NA inhibitors that can be injected intravenously, such as intravenous formulations of zanamivir; favipiravir, which is a polymerase inhibitor used against several RNA viruses; pimodivir, which prevents cap-binding required during viral transcription; and nitazoxanide, which inhibits HA maturation.", "Reducing excess inflammation in the respiratory tract is also subject to much research since this is one of the primary mechanisms of influenza pathology.", "Other forms of therapy in development include monoclonal and polyclonal antibodies that target viral proteins, convalescent plasma, different approaches to modify the host antiviral response, and stem cell-based therapies to repair lung damage.", "Much research on LAIVs focuses on identifying genome sequences that can be deleted to create harmless influenza viruses in vaccines that still confer immunity.", "The high variability and rapid evolution of influenza virus antigens, however, is a major obstacle in developing effective vaccines.", "Furthermore, it is hard to predict which strains will be in circulation during the next flu season, manufacturing a sufficient quantity of flu vaccines for the next season is difficult, LAIVs have limited efficacy, and repeated annual vaccination potentially has diminished efficacy.", "For these reasons, \"broadly-reactive\" or \"universal\" flu vaccines are being researched that can provide protection against many or all influenza viruses.", "Approaches to develop such a vaccine include HA stalk-based methods such as chimeras that have the same stalk but different heads, HA head-based methods such as computationally optimized broadly neutralizing antigens, anti-idiotypic antibodies, and vaccines to elicit immune responses to highly conserved viral proteins.", "mRNA vaccines to provide protection against influenza are also under research.", "Aquatic birds such as ducks, geese, shorebirds, and gulls are the primary reservoir of IAVs.", "In birds, AIVs may be either low pathogenic avian influenza (LPAI) viruses that produce little to no symptoms or highly pathogenic avian influenza (HPAI) viruses that cause severe illness.", "Symptoms of HPAI infection include lack of energy and appetite, decreased egg production, soft-shelled or misshapen eggs, swelling of the head, comb, wattles, and hocks, purple discoloration of wattles, combs, and legs, nasal discharge, coughing, sneezing, incoordination, and diarrhea.", "Birds infected with an HPAI virus may also die suddenly without any signs of infection.", "The distinction between LPAI and HPAI can generally be made based on how lethal an AIV is to chickens.", "At the genetic level, an AIV can be usually be identified as an HPAI virus if it has a multibasic cleavage site in the HA protein, which contains additional residues in the HA gene.", "Most AIVs are LPAI.", "Notable HPAI viruses include HPAI H5N1 and HPAI H7N9.", "HPAI viruses have been a major disease burden in the 21st century, resulting in the death of large numbers of birds.", "In H7N9's case, some circulating strains were originally LPAI but became HPAI by acquiring the HA multibasic cleavage site.", "Avian H9N2 is also of concern because although it is LPAI, it is a common donor of genes to H5N1 and H7N9 during reassortment.", "Migratory birds can spread influenza across long distances.", "An example of this was when an H5N1 strain in 2005 infected birds at Qinghai Lake, China, which is a stopover and breeding site for many migratory birds, subsequently spreading the virus to more than 20 countries across Asia, Europe, and the Middle East.", "AIVs can be transmitted from wild birds to domestic free-range ducks and in turn to poultry through contaminated water, aerosols, and fomites.", "Ducks therefore act as key intermediates between wild and domestic birds.", "Transmission to poultry typically occurs in backyard farming and live animal markets where multiple species interact with each other.", "From there, AIVs can spread to poultry farms in the absence of adequate biosecurity.", "Among poultry, HPAI transmission occurs through aerosols and contaminated feces, cages, feed, and dead animals.", "Back-transmission of HPAI viruses from poultry to wild birds has occurred and is implicated in mass die-offs and intercontinental spread.", "AIVs have occasionally infected humans through aerosols, fomites, and contaminated water.", "Direction transmission from wild birds is rare.", "Instead, most transmission involves domestic poultry, mainly chickens, ducks, and geese but also a variety of other birds such as guinea fowl, partridge, pheasants, and quails.", "The primary risk factor for infection with AIVs is exposure to birds in farms and live poultry markets.", "Typically, infection with an AIV has an incubation period of 3–5 days but can be up to 9 days.", "H5N1 and H7N9 cause severe lower respiratory tract illness, whereas other AIVs such as H9N2 cause a more mild upper respiratory tract illness, commonly with conjunctivitis.", "Limited transmission of avian H2, H5-7, H9, and H10 subtypes from one person to another through respiratory droplets, aerosols, and fomites has occurred, but sustained human-to-human transmission of AIVs has not occurred.", "Before 2013, H5N1 was the most common AIV to infect humans.", "Since then, H7N9 has been responsible for most human cases.", "Influenza in pigs is a respiratory disease similar to influenza in humans and is found worldwide.", "Asymptomatic infections are common.", "Symptoms typically appear 1–3 days after infection and include fever, lethargy, anorexia, weight loss, labored breathing, coughing, sneezing, and nasal discharge.", "In sows, pregnancy may be aborted.", "Complications include secondary infections and potentially fatal bronchopneumonia.", "Pigs become contagious within a day of infection and typically spread the virus for 7–10 days, which can spread rapidly within a herd.", "Pigs usually recover from infection within 3–7 days after symptoms appear.", "Prevention and control measures include inactivated vaccines and culling infected herds.", "The influenza viruses usually responsible for swine flu are IAV subtypes H1N1, H1N2, and H3N2.", "Some IAVs can be transmitted via aerosols from pigs to humans and vice versa.", "Furthermore, pigs, along with bats and quails, are recognized as a mixing vessel of influenza viruses because they have both α-2,3 and α-2,6 sialic acid receptors in their respiratory tract.", "Because of that, both avian and mammalian influenza viruses can infect pigs.", "If co-infection occurs, then reassortment is possible.", "A notable example of this was the reassortment of a swine, avian, and human influenza virus in 2009, resulting in a novel H1N1 strain that caused the 2009 flu pandemic.", "Spillover events from humans to pigs, however, appear to be more common than from pigs to humans.", "Influenza viruses have been found in many other animals, including cattle, horses, dogs, cats, and marine mammals.", "Nearly all IAVs are apparently descended from ancestral viruses in birds.", "The exception are bat influenza-like viruses, which have an uncertain origin.", "These bat viruses have HA and NA subtypes H17, H18, N10, and N11.", "H17N10 and H18N11 are unable to reassort with other IAVs, but they are still able to replicate in other mammals.", "AIVs sometimes crossover into mammals.", "For example, in late 2016 to early 2017, an avian H7N2 strain was found to be infecting cats in New York.", "Equine IAVs include H7N7 and two lineages of H3N8.", "H7N7, however, has not been detected in horses since the late 1970s, so it may have become extinct in horses.", "H3N8 in equines spreads via aerosols and causes respiratory illness.", "Equine H3N8 perferentially binds to α-2,3 sialic acids, so horses are usually considered dead-end hosts, but transmission to dogs and camels has occurred, raising concerns that horses may be mixing vessels for reassortment.", "In canines, the only IAVs in circulation are equine-derived H3N8 and avian-derived H3N2.", "Canine H3N8 has not been observed to reassort with other subtypes.", "H3N2 has a much broader host range and can reassort with H1N1 and H5N1.", "An isolated case of H6N1 likely from a chicken was found infecting a dog, so other AIVs may emerge in canines.", "Other mammals to be infected by IAVs include H7N7 and H4N5 in seals, H1N3 in whales, and H10N4 and H3N2 in minks.", "Various mutations have been identified that are associated with AIVs adapting to mammals.", "Since HA proteins vary in which sialic acids they bind to, mutations in the HA receptor binding site can allow AIVs to infect mammals.", "Other mutations include mutations affecting which sialic acids NA proteins cleave and a mutation in the PB2 polymerase subunit that improves tolerance of lower temperatures in mammalian respiratory tracts and enhances RNP assembly by stabilizing NP and PB2 binding.", "IBV is mainly found in humans but has also been detected in pigs, dogs, horses, and seals.", "Likewise, ICV primarily infects humans but has been observed in pigs, dogs, cattle, and dromedary camels.", "IDV causes an influenza-like illness in pigs but its impact in its natural reservoir, cattle, is relatively unknown.", "It may cause respiratory disease resembling human influenza on its own, or it may be part of a bovine respiratory disease (BRD) complex with other pathogens during co-infection.", "BRD is a concern for the cattle industry, so IDV's possible involvement in BRD has led to research on vaccines for cattle that can provide protection against IDV.", "Two antigenic lineages are in circulation: D/swine/Oklahoma/1334/2011 (D/OK) and D/bovine/Oklahoma/660/2013 (D/660)." ]

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[ "\"Influenza B virus\" (IBV) and \"Influenza C virus\" (ICV) primarily infect humans, and \"Influenza D virus\" (IDV) is found in cattle and pigs.", "IAV and IBV circulate in humans and cause seasonal epidemics, and ICV causes a mild infection, primarily in children.", "IDV can infect humans but is not known to cause illness.", "Vaccines currently in use provide protection against IAV subtypes H1N1 and H3N2 and one or two IBV subtypes." ]

[ "The time between exposure to the virus and development of symptoms, called the incubation period, is 1–4 days, most commonly 1–2 days.", "Many infections, however, are asymptomatic.", "The onset of symptoms is sudden, and initial symptoms are predominately non-specific, including fever, chills, headaches, muscle pain or aching, a feeling of discomfort, loss of appetite, lack of energy/fatigue, and confusion.", "These symptoms are usually accompanied by respiratory symptoms such as a dry cough, sore or dry throat, hoarse voice, and a stuffy or runny nose.", "Coughing is the most common symptom.", "Gastrointestinal symptoms may also occur, including nausea, vomiting, diarrhea, and gastroenteritis, especially in children.", "The standard influenza symptoms typically last for 2–8 days.", "A 2021 study suggests influenza can cause long lasting symptoms in a similar way to long COVID.\nSymptomatic infections are usually mild and limited to the upper respiratory tract, but progression to pneumonia is relatively common.", "Pneumonia may be caused by the primary viral infection or by a secondary bacterial infection.", "Primary pneumonia is characterized by rapid progression of fever, cough, labored breathing, and low oxygen levels that cause bluish skin.", "It is especially common among those who have an underlying cardiovascular disease such as rheumatic heart disease.", "Secondary pneumonia typically has a period of improvement in symptoms for 1–3 weeks followed by recurrent fever, sputum production, and fluid buildup in the lungs, but can also occur just a few days after influenza symptoms appear.", "About a third of primary pneumonia cases are followed by secondary pneumonia, which is most frequently caused by the bacteria \"Streptococcus pneumoniae\" and \"Staphylococcus aureus\".", "Influenza viruses comprise four species.", "Each of the four species is the sole member of its own genus, and the four influenza genera comprise four of the seven genera in the family \"Orthomyxoviridae\".", "They are:\n\n\nIAV is responsible for most cases of severe illness as well as seasonal epidemics and occasional pandemics.", "It infects people of all ages but tends to disproportionately cause severe illness in the elderly, the very young, and those who have chronic health issues.", "Birds are the primary reservoir of IAV, especially aquatic birds such as ducks, geese, shorebirds, and gulls, but the virus also circulates among mammals, including pigs, horses, and marine mammals.", "IAV is classified into subtypes based on the viral proteins haemagglutinin (H) and neuraminidase (N).", "As of 2019, 18 H subtypes and 11 N subtypes have been identified.", "Most potential combinations have been reported in birds, but H17-18 and N10-11 have only been found in bats.", "Only H subtypes H1-3 and N subtypes N1-2 are known to have circulated in humans, the current IAV subtypes in circulation being H1N1 and H3N2.", "IAVs can be classified more specifically to also include natural host species, geographical origin, year of isolation, and strain number, such as H1N1/A/duck/Alberta/35/76.", "IBV mainly infects humans but has been identified in seals, horses, dogs, and pigs.", "IBV does not have subtypes like IAV but has two antigenically distinct lineages, termed the B/Victoria/2/1987-like and B/Yamagata/16/1988-like lineages, or simply (B/)Victoria(-like) and (B/)Yamagata(-like).", "Both lineages are in circulation in humans, disproportionately affecting children.", "IBVs contribute to seasonal epidemics alongside IAVs but have never been associated with a pandemic.", "ICV, like IBV, is primarily found in humans, though it also has been detected in pigs, feral dogs, dromedary camels, cattle, and dogs.", "ICV infection primarily affects children and is usually asymptomatic or has mild cold-like symptoms, though more severe symptoms such as gastroenteritis and pneumonia can occur.", "Unlike IAV and IBV, ICV has not been a major focus of research pertaining to antiviral drugs, vaccines, and other measures against influenza.", "ICV is subclassified into six genetic/antigenic lineages.", "IDV has been isolated from pigs and cattle, the latter being the natural reservoir.", "Infection has also been observed in humans, horses, dromedary camels, and small ruminants such as goats and sheep.", "IDV is distantly related to ICV.", "While cattle workers have occasionally tested positive to prior IDV infection, it is not known to cause disease in humans.", "ICV and IDV experience a slower rate of antigenic evolution than IAV and IBV.", "Because of this antigenic stability, relatively few novel lineages emerge.", "Influenza viruses have a negative-sense, single-stranded RNA genome that is segmented.", "The negative sense of the genome means it can be used as a template to synthesize messenger RNA (mRNA).", "IAV and IBV have eight genome segments that encode 10 major proteins.", "ICV and IDV have seven genome segments that encode nine major proteins.", "Three segments encode three subunits of an RNA-dependent RNA polymerase (RdRp) complex: PB1, a transcriptase, PB2, which recognizes 5' caps, and PA (P3 for ICV and IDV), an endonuclease.", "The matrix protein (M1) and membrane protein (M2) share a segment, as do the non-structural protein (NS1) and the nuclear export protein (NEP).", "For IAV and IBV, hemagglutinin (HA) and neuraminidase (NA) are encoded on one segment each, whereas ICV and IDV encode a hemagglutinin-esterase fusion (HEF) protein on one segment that merges the functions of HA and NA.", "The final genome segment encodes the viral nucleoprotein (NP).", "Influenza viruses also encode various accessory proteins, such as PB1-F2 and PA-X, that are expressed through alternative open reading frames and which are important in host defense suppression, virulence, and pathogenicity.", "The virus particle, called a virion, is pleomorphic and varies between being filamentous, bacilliform, or spherical in shape.", "Clinical isolates tend to be pleomorphic, whereas strains adapted to laboratory growth typically produce spherical virions.", "Filamentous virions are about 250 nanometers (nm) by 80 nm, bacilliform 120–250 by 95 nm, and spherical 120 nm in diameter.", "The virion consists of each segment of the genome bound to nucleoproteins in separate ribonucleoprotein (RNP) complexes for each segment, all of which are surrounded by a lipid bilayer membrane called the viral envelope.", "There is a copy of the RdRp, all subunits included, bound to each RNP.", "The envelope is reinforced structurally by matrix proteins on the interior that enclose the RNPs, and the envelope contains HA and NA (or HEF) proteins extending outward from the exterior surface of the envelope.", "HA and HEF proteins have a distinct \"head\" and \"stalk\" structure.", "M2 proteins form proton ion channels through the viral envelope that are required for viral entry and exit.", "IBVs contain a surface protein named NB that is anchored in the envelope, but its function is unknown.", "The viral life cycle begins by binding to a target cell.", "Binding is mediated by the viral HA proteins on the surface of the evelope, which bind to cells that contain sialic acid receptors on the surface of the cell membrane.", "For N1 subtypes with the \"G147R\" mutation and N2 subtypes, the NA protein can initiate entry.", "Prior to binding, NA proteins promote access to target cells by degrading mucous, which helps to remove extracellular decoy receptors that would impede access to target cells.", "After binding, the virus is internalized into the cell by an endosome that contains the virion inside it.", "The endosome is acidified by cellular vATPase to have lower pH, which triggers a conformational change in HA that allows fusion of the viral envelope with the endosomal membrane.", "At the same time, hydrogen ions diffuse into the virion through M2 ion channels, disrupting internal protein-protein interactions to release RNPs into the host cell's cytosol.", "The M1 protein shell surrounding RNPs is degraded, fully uncoating RNPs in the cytosol.", "RNPs are then imported into the nucleus with the help of viral localization signals.", "There, the viral RNA polymerase transcribes mRNA using the genomic negative-sense strand as a template.", "The polymerase snatches 5' caps for viral mRNA from cellular RNA to prime mRNA synthesis and the 3'-end of mRNA is polyadenylated at the end of transcription.", "Once viral mRNA is transcribed, it is exported out of the nucleus and translated by host ribosomes in a cap-dependent manner to synthesize viral proteins.", "RdRp also synthesizes complementary positive-sense strands of the viral genome in a complementary RNP complex which are then used as templates by viral polymerases to synthesize copies of the negative-sense genome.", "During these processes, RdRps of avian influenza viruses (AIVs) function optimally at a higher temperature than mammalian influenza viruses.", "Newly synthesized viral polymerase subunits and NP proteins are imported to the nucleus to further increase the rate of viral replication and form RNPs.", "HA, NA, and M2 proteins are trafficked with the aid of M1 and NEP proteins to the cell membrane through the Golgi apparatus and inserted into the cell's membrane.", "Viral non-structural proteins including NS1, PB1-F2, and PA-X regulate host cellular processes to disable antiviral responses.", "PB1-F2 aso interacts with PB1 to keep polymerases in the nucleus longer.", "M1 and NEP proteins localize to the nucleus during the later stages of infection, bind to viral RNPs and mediate their export to the cytoplasm where they migrate to the cell membrane with the aid of recycled endosomes and are bundled into the segments of the genome.", "Progenic viruses leave the cell by budding from the cell membrane, which is initiated by the accumulation of M1 proteins at the cytoplasmic side of the membrane.", "The viral genome is incorporated inside a viral envelope derived from portions of the cell membrane that have HA, NA, and M2 proteins.", "At the end of budding, HA proteins remain attached to cellular sialic acid until they are cleaved by the sialidase activity of NA proteins.", "The virion is then released from the cell.", "The sialidase activity of NA also cleaves any sialic acid residues from the viral surface, which helps prevent newly assembled viruses from aggregating near the cell surface and improving infectivity.", "Similar to other aspects of influenza replication, optimal NA activity is temperature- and pH-dependent.", "Ultimately, presence of large quantities of viral RNA in the cell triggers apoptosis, i.e. programmed cell death, which is initiated by cellular factors to restrict viral replication.", "Two key processes that influenza viruses evolve through are antigenic drift and antigenic shift.", "Antigenic drift is when an influenza virus's antigens change due to the gradual accumulation of mutations in the antigen's (HA or NA) gene.", "This can occur in response to evolutionary pressure exerted by the host immune response.", "Antigenic drift is especially common for the HA protein, in which just a few amino acid changes in the head region can constitute antigenic drift.", "The result is the production of novel strains that can evade pre-existing antibody-mediated immunity.", "Antigenic drift occurs in all influenza species but is slower in B than A and slowest in C and D. Antigenic drift is a major cause of seasonal influenza, and requires that flu vaccines be updated annually.", "HA is the main component of inactivated vaccines, so surveillance monitors antigenic drift of this antigen among circulating strains.", "Antigenic evolution of influenza viruses of humans appears to be faster than influenza viruses in swine and equines.", "In wild birds, within-subtype antigenic variation appears to be limited but has been observed in poultry.", "Antigenic shift is a sudden, drastic change in an influenza virus's antigen, usually HA.", "During antigenic shift, antigenically different strains that infect the same cell can reassort genome segments with each other, producing hybrid progeny.", "Since all influenza viruses have segmented genomes, all are capable of reassortment.", "Antigenic shift, however, only occurs among influenza viruses of the same genus and most commonly occurs among IAVs.", "In particular, reassortment is very common in AIVs, creating a large diversity of influenza viruses in birds, but is uncommon in human, equine, and canine lineages.", "Pigs, bats, and quails have receptors for both mammalian and avian IAVs, so they are potential \"mixing vessels\" for reassortment.", "If an animal strain reassorts with a human strain, then a novel strain can emerge that is capable of human-to-human transmission.", "This has caused pandemics, but only a limited number have occurred, so it is difficult to predict when the next will happen.", "People who are infected can transmit influenza viruses through breathing, talking, coughing, and sneezing, which spread respiratory droplets and aerosols that contain virus particles into the air.", "A person susceptible to infection can then contract influenza by coming into contact with these particles.", "Respiratory droplets are relatively large and travel less than two meters before falling onto nearby surfaces.", "Aerosols are smaller and remain suspended in the air longer, so they take longer to settle and can travel further than respiratory droplets.", "Inhalation of aerosols can lead to infection, but most transmission is in the area about two meters around an infected person via respiratory droplets that come into contact with mucosa of the upper respiratory tract.", "Transmission through contact with a person, bodily fluids, or intermediate objects (fomites) can also occur, such as through contaminated hands and surfaces since influenza viruses can survive for hours on non-porous surfaces.", "If one's hands are contaminated, then touching one's face can cause infection.", "Influenza is usually transmissible from one day before the onset of symptoms to 5–7 days after.", "In healthy adults, the virus is shed for up to 3–5 days.", "In children and the immunocompromised, the virus may be transmissible for several weeks.", "Children ages 2–17 are considered to be the primary and most efficient spreaders of influenza.", "Children who have not had multiple prior exposures to influenza viruses shed the virus at greater quantities and for a longer duration than other children.", "People who are at risk of exposure to influenza include health care workers, social care workers, and those who live with or care for people vulnerable to influenza.", "In long-term care facilities, the flu can spread rapidly after it is introduced.", "A variety of factors likely encourage influenza transmission, including lower temperature, lower absolute and relative humidity, less ultraviolet radiation from the Sun, and crowding.", "Influenza viruses that infect the upper respiratory tract like H1N1 tend to be more mild but more transmissible, whereas those that infect the lower respiratory tract like H5N1 tend to cause more severe illness but are less contagious.", "In humans, influenza viruses first cause infection by infecting epithelial cells in the respiratory tract.", "Illness during infection is primarily the result of lung inflammation and compromise caused by epithelial cell infection and death, combined with inflammation caused by the immune system's response to infection.", "Non-respiratory organs can become involved, but the mechanisms by which influenza is involved in these cases are unknown.", "Severe respiratory illness can be caused by multiple, non-exclusive mechanisms, including obstruction of the airways, loss of alveolar structure, loss of lung epithelial integrity due to epithelial cell infection and death, and degradation of the extracellular matrix that maintains lung structure.", "In particular, alveolar cell infection appears to drive severe symptoms since this results in impaired gas exchange and enables viruses to infect endothelial cells, which produce large quantities of pro-inflammatory cytokines.", "Pneumonia caused by influenza viruses is characterized by high levels of viral replication in the lower respiratory tract, accompanied by a strong pro-inflammatory response called a cytokine storm.", "Infection with H5N1 or H7N9 especially produces high levels of pro-inflammatory cytokines.", "In bacterial infections, early depletion of macrophages during influenza creates a favorable environment in the lungs for bacterial growth since these white blood cells are important in responding to bacterial infection.", "Host mechanisms to encourage tissue repair may inadvertently allow bacterial infection.", "Infection also induces production of systemic glucocorticoids that can reduce inflammation to preserve tissue integrity but allow increased bacterial growth.", "The pathophysiology of influenza is significantly influenced by which receptors influenza viruses bind to during entry into cells.", "Mammalian influenza viruses preferentially bind to sialic acids connected to the rest of the oligosaccharide by an α-2,6 link, most commonly found in various respiratory cells, such as respiratory and retinal epithelial cells.", "AIVs prefer sialic acids with an α-2,3 linkage, which are most common in birds in gastrointestinal epithelial cells and in humans in the lower respiratory tract.", "Furthermore, cleavage of the HA protein into HA, the binding subunit, and HA, the fusion subunit, is performed by different proteases, affecting which cells can be infected.", "For mammalian influenza viruses and low pathogenic AIVs, cleavage is extracellular, which limits infection to cells that have the appropriate proteases, whereas for highly pathogenic AIVs, cleavage is intracellular and performed by ubiquitous proteases, which allows for infection of a greater variety of cells, thereby contributing to more severe disease.", "Cells possess sensors to detect viral RNA, which can then induce interferon production.", "Interferons mediate expression of antiviral proteins and proteins that recruit immune cells to the infection site, and they also notify nearby uninfected cells of infection.", "Some infected cells release pro-inflammatory cytokines that recruit immune cells to the site of infection.", "Immune cells control viral infection by killing infected cells and phagocytizing viral particles and apoptotic cells.", "An exacerbated immune response, however, can harm the host organism through a cytokine storm.", "To counter the immune response, influenza viruses encode various non-structural proteins, including NS1, NEP, PB1-F2, and PA-X, that are involved in curtailing the host immune response by suppressing interferon production and host gene expression.", "B cells, a type of white blood cell, produce antibodies that bind to influenza antigens HA and NA (or HEF) and other proteins to a lesser degree.", "Once bound to these proteins, antibodies block virions from binding to cellular receptors, neutralizing the virus.", "In humans, a sizeable antibody response occurs ~1 week after viral exposure.", "This antibody response is typically robust and long-lasting, especially for ICV and IDV.", "In other words, people exposed to a certain strain in childhood still possess antibodies to that strain at a reasonable level later in life, which can provide some protection to related strains.", "There is, however, an \"original antigenic sin\", in which the first HA subtype a person is exposed to influences the antibody-based immune response to future infections and vaccines.", "Annual vaccination is the primary and most effective way to prevent influenza and influenza-associated complications, especially for high-risk groups.", "Vaccines against the flu are trivalent or quadrivalent, providing protection against an H1N1 strain, an H3N2 strain, and one or two IBV strains corresponding to the two IBV lineages.", "Two types of vaccines are in use: inactivated vaccines that contain \"killed\" (i.e. inactivated) viruses and live attenuated influenza vaccines (LAIVs) that contain weakened viruses.", "There are three types of inactivated vaccines: whole virus, split virus, in which the virus is disrupted by a detergent, and subunit, which only contains the viral antigens HA and NA.", "Most flu vaccines are inactivated and administered via intramuscular injection.", "LAIVs are sprayed into the nasal cavity.", "Vaccination recommendations vary by country.", "Some recommend vaccination for all people above a certain age, such as 6 months, whereas other countries recommendation is limited for high at risk groups, such as pregnant women, young children (excluding newborns), the elderly, people with chronic medical conditions, health care workers, people who come into contact with high-risk people, and people who transmit the virus easily.", "Young infants cannot receive flu vaccines for safety reasons, but they can inherit passive immunity from their mother if inactivated vaccines are administered to the mother during pregnancy.", "Influenza vaccination also helps to reduce the probability of reassortment.", "In general, influenza vaccines are only effective if there is an antigenic match between vaccine strains and circulating strains.", "Additionally, most commercially available flu vaccines are manufactured by propagation of influenza viruses in embryonated chicken eggs, taking 6–8 months.", "Flu seasons are different in the northern and southern hemisphere, so the WHO meets twice a year, one for each hemisphere, to discuss which strains should be included in flu vaccines based on observation from HA inhibition assays.", "Other manufacturing methods include an MDCK cell culture-based inactivated vaccine and a recombinant subunit vaccine manufactured from baculovirus overexpression in insect cells.", "Influenza can be prevented or reduced in severity by post-exposure prophylaxis with the antiviral drugs oseltamivir, which can be taken orally by those at least three months old, and zanamivir, which can be inhaled by those above seven years of age.", "Chemoprophylaxis is most useful for individuals at high-risk of developing complications and those who cannot receive the flu vaccine due to contraindications or lack of effectiveness.", "Post-exposure chemoprophylaxis is only recommended if oseltamivir is taken within 48 hours of contact with a confirmed or suspected influenza case and zanamivir within 36 hours.", "It is recommended that it be offered to people who have yet to receive a vaccine for the current flu season, who have been vaccinated less than two week since contact, if there is a significant mismatch between vaccine and circulating strains, or during an outbreak in a closed setting regardless of vaccination history.", "Hand hygiene is important in reducing the spread of influenza.", "This includes frequent hand washing with soap and water, using alcohol-based hand sanitizers, and not touching one's eyes, nose, and mouth with one's hands.", "Covering one's nose and mouth when coughing or sneezing is important.", "Other methods to limit influenza transmission include staying home when sick, avoiding contact with others until one day after symptoms end, and disinfecting surfaces likely to be contaminated by the virus, such as doorknobs.", "Health education through media and posters is often used to remind people of the aforementioned etiquette and hygiene.", "There is uncertainty about the use of masks since research thus far has not shown a significant reduction in seasonal influenza with mask usage.", "Likewise, the effectiveness of screening at points of entry into countries is not well researched.", "Social distancing measures such as school closures, avoiding contact with infected people via isolation or quarantine, and limiting mass gatherings may reduce transmission, but these measures are often expensive, unpopular, and difficult to implement.", "Consequently, the commonly recommended methods of infection control are respiratory etiquette, hand hygiene, and mask wearing, which are inexpensive and easy to perform.", "Pharmaceutical measures are effective but may not be available in the early stages of an outbreak.", "In health care settings, infected individuals may be cohorted or assigned to individual rooms.", "Protective clothing such as masks, gloves, and gowns is recommended when coming into contact with infected individuals if there is a risk of exposure to infected bodily fluids.", "Keeping patients in negative pressure rooms and avoiding aerosol-producing activities may help, but special air handling and ventilation systems are not considered necessary to prevent the spread of influenza in the air.", "In residential homes, new admissions may need to be closed until the spread of influenza is controlled.", "When discharging patients to care homes, it is important to take care if there is a known influenza outbreak.", "Since influenza viruses circulate in animals such as birds and pigs, prevention of transmission from these animals is important.", "Water treatment, indoor raising of animals, quarantining sick animals, vaccination, and biosecurity are the primary measures used.", "Placing poultry houses and piggeries on high ground away from high-density farms, backyard farms, live poultry markets, and bodies of water helps to minimize contact with wild birds.", "Closure of live poultry markets appears to the most effective measure and has shown to be effective at controlling the spread of H5N1, H7N9, and H9N2.", "Other biosecurity measures include cleaning and disinfecting facilities and vehicles, banning visits to poultry farms, not bringing birds intended for slaughter back to farms, changing clothes, disinfecting foot baths, and treating food and water.", "If live poultry markets are not closed, then \"clean days\" when unsold poultry is removed and facilities are disinfected and \"no carry-over\" policies to eliminate infectious material before new poultry arrive can be used to reduce the spread of influenza viruses.", "If a novel influenza viruses has breached the aforementioned biosecurity measures, then rapid detection to stamp it out via quarantining, decontamination, and culling may be necessary to prevent the virus from becoming endemic.", "Vaccines exist for avian H5, H7, and H9 subtypes that are used in some countries.", "In China, for example, vaccination of domestic birds against H7N9 successfully limited its spread, indicating that vaccination may be an effective strategy if used in combination with other measures to limit transmission.", "In pigs and horses, management of influenza is dependent on vaccination with biosecurity.", "Diagnosis based on symptoms is fairly accurate in otherwise healthy people during seasonal epidemics and should be suspected in cases of pneumonia, acute respiratory distress syndrome (ARDS), sepsis, or if encephalitis, myocarditis, or breaking down of muscle tissue occur.", "Because influenza is similar to other viral respiratory tract illnesses, laboratory diagnosis is necessary for confirmation.", "Common ways of collecting samples for testing include nasal and throat swabs.", "Samples may be taken from the lower respiratory tract if infection has cleared the upper but not lower respiratory tract.", "Influenza testing is recommended for anyone hospitalized with symptoms resembling influenza during flu season or who is connected to an influenza case.", "For severe cases, earlier diagnosis improves patient outcome.", "Diagnostic methods that can identify influenza include viral cultures, antibody- and antigen-detecting tests, and nucleic acid-based tests.", "Viruses can be grown in a culture of mammalian cells or embryonated eggs for 3–10 days to monitor cytopathic effect.", "Final confirmation can then be done via antibody staining, hemadsorption using red blood cells, or immunofluorescence microscopy.", "Shell vial cultures, which can identify infection via immunostaining before a cytopathic effect appears, are more sensitive than traditional cultures with results in 1–3 days.", "Cultures can be used to characterize novel viruses, observe sensitivity to antiviral drugs, and monitor antigenic drift, but they are relatively slow and require specialized skills and equipment.", "Serological assays can be used to detect an antibody response to influenza after natural infection or vaccination.", "Common serological assays include hemagglutination inhibition assays that detect HA-specific antibodies, virus neutralization assays that check whether antibodies have neutralized the virus, and enzyme-linked immunoabsorbant assays.", "These methods tend to be relatively inexpensive and fast but are less reliable than nucleic-acid based tests.", "Direct fluorescent or immunofluorescent antibody (DFA/IFA) tests involve staining respiratory epithelial cells in samples with fluorescently-labeled influenza-specific antibodies, followed by examination under a fluorescent microscope.", "They can differentiate between IAV and IBV but can't subtype IAV.", "Rapid influenza diagnostic tests (RIDTs) are a simple way of obtaining assay results, are low cost, and produce results quickly, at less than 30 minutes, so they are commonly used, but they can't distinguish between IAV and IBV or between IAV subtypes and are not as sensitive as nucleic-acid based tests.", "Nucleic acid-based tests (NATs) amplify and detect viral nucleic acid.", "Most of these tests take a few hours, but rapid molecular assays are as fast as RIDTs.", "Among NATs, reverse transcription polymerase chain reaction (RT-PCR) is the most traditional and considered the gold standard for diagnosing influenza because it is fast and can subtype IAV, but it is relatively expensive and more prone to false-positives than cultures.", "Other NATs that have been used include loop-mediated isothermal amplification-based assays, simple amplification-based assays, and nucleic acid sequence-based amplification.", "Nucleic acid sequencing methods can identify infection by obtaining the nucleic acid sequence of viral samples to identify the virus and antiviral drug resistance.", "The traditional method is Sanger sequencing, but it has been largely replaced by next-generation methods that have greater sequencing speed and throughput.", "Treatment of influenza in cases of mild or moderate illness is supportive and includes anti-fever medications such as acetaminophen and ibuprofen, adequate fluid intake to avoid dehydration, and resting at home.", "Cough drops and throat sprays may be beneficial for sore throat.", "It is recommended to avoid alcohol and tobacco use while sick with the flu.", "Aspirin is not recommended to treat influenza in children due to an elevated risk of developing Reye syndrome.", "Corticosteroids likewise are not recommended except when treating septic shock or an underlying medical condition, such as chronic obstructive pulmonary disease or asthma exacerbation, since they are associated with increased mortality.", "If a secondary bacterial infection occurs, then treatment with antibiotics may be necessary.", "Antiviral drugs are primarily used to treat severely ill patients, especially those with compromised immune systems.", "Antivirals are most effective when started in the first 48 hours after symptoms appear.", "Later administration may still be beneficial for those who have underlying immune defects, those with more severe symptoms, or those who have a higher risk of developing complications if these individuals are still shedding the virus.", "Antiviral treatment is also recommended if a person is hospitalized with suspected influenza instead of waiting for test results to return and if symptoms are worsening.", "Most antiviral drugs against influenza fall into two categories: neuraminidase (NA) inhibitors and M2 inhibitors.", "Baloxavir marboxil is a notable exception, which targets the endonuclease activity of the viral RNA polymerase and can be used as an alternative to NA and M2 inhibitors for IAV and IBV.", "NA inhibitors target the enzymatic activity of NA receptors, mimicking the binding of sialic acid in the active site of NA on IAV and IBV virions so that viral release from infected cells and the rate of viral replication are impaired.", "NA inhibitors include oseltamivir, which is consumed orally in a prodrug form and converted to its active form in the liver, and zanamivir, which is a powder that is inhaled nasally.", "Oseltamivir and zanamivir are effective for prophylaxis and post-exposure prophylaxis, and research overall indicates that NA inhibitors are effective at reducing rates of complications, hospitalization, and mortality and the duration of illness.", "Additionally, the earlier NA inhibitors are provided, the better the outcome, though late administration can still be beneficial in severe cases.", "Other NA inhibitors include laninamivir and peramivir, the latter of which can be used as an alternative to oseltamivir for people who cannot tolerate or absorb it.", "The adamantanes amantadine and rimantadine are orally administered drugs that block the influenza virus's M2 ion channel, preventing viral uncoating.", "These drugs are only functional against IAV but are no longer recommended for use because of widespread resistance to them among IAVs.", "Adamantane resistance first emerged in H3N2 in 2003, becoming worldwide by 2008.", "Oseltamivir resistance is no longer widespread because the 2009 pandemic H1N1 strain (H1N1 pdm09), which is resistant to adamantanes, seemingly replaced resistant strains in circulation.", "Since the 2009 pandemic, oseltamivir resistance has mainly been observed in patients undergoing therapy, especially the immunocompromised and young children.", "Oseltamivir resistance is usually reported in H1N1, but has been reported in H3N2 and IBVs less commonly.", "Because of this, oseltamivir is recommended as the first drug of choice for immunocompetent people, whereas for the immunocompromised, oseltamivir is recommended against H3N2 and IBV and zanamivir against H1N1 pdm09.", "Zanamivir resistance is observed less frequently, and resistance to peramivir and baloxavir marboxil is possible.", "In healthy individuals, influenza infection is usually self-limiting and rarely fatal.", "Symptoms usually last for 2–8 days.", "Influenza can cause people to miss work or school, and it is associated with decreased job performance and, in older adults, reduced independence.", "Fatigue and malaise may last for several weeks after recovery, and healthy adults may experience pulmonary abnormalities that can take several weeks to resolve.", "Complications and mortality primarily occur in high-risk populations and those who are hospitalized.", "Severe disease and mortality are usually attributable to pneumonia from the primary viral infection or a secondary bacterial infection, which can progress to ARDS.", "Other respiratory complications that may occur include sinusitis, bronchitis, bronchiolitis, excess fluid buildup in the lungs, and exacerbation of chronic bronchitis and asthma.", "Middle ear infection and croup may occur, most commonly in children.", "Secondary \"S. aureus\" infection has been observed, primarily in children, to cause toxic shock syndrome after influenza, with hypotension, fever, and reddening and peeling of the skin.", "Complications affecting the cardiovascular system are rare and include pericarditis, fulminant myocarditis with a fast, slow, or irregular heartbeat, and exacerbation of pre-existing cardiovascular disease.", "Inflammation or swelling of muscles accompanied by muscle tissue breaking down occurs rarely, usually in children, which presents as extreme tenderness and muscle pain in the legs and a reluctance to walk for 2–3 days.", "Influenza can affect pregnancy, including causing smaller neonatal size, increased risk of premature birth, and an increased risk of child death shortly before or after birth.", "Neurological complications have been associated with influenza on rare occasions, including aseptic meningitis, encephalitis, disseminated encephalomyelitis, transverse myelitis, and Guillain–Barré syndrome.", "Additionally, febrile seizures and Reye syndrome can occur, most commonly in children.", "Influenza-associated encephalopathy can occur directly from central nervous system infection from the presence of the virus in blood and presents as suddent onset of fever with convulsions, followed by rapid progression to coma.", "An atypical form of encephalitis called encephalitis lethargica, characterized by headache, drowsiness, and coma, may rarely occur sometime after infection.", "In survivors of influenza-associated encephalopathy, neurological defects may occur.", "Primarily in children, in severe cases the immune system may rarely dramatically overproduce white blood cells that release cytokines, causing severe inflammation.", "People who are at least 65 years of age, due to a weakened immune system from aging or a chronic illness, are a high-risk group for developing complications, as are children less than one year of age and children who have not been previously exposed to influenza viruses multiple times.", "Pregnant women are at an elevated risk, which increases by trimester and lasts up to two weeks after childbirth.", "Obesity, in particular a body mass index greater than 35–40, is associated with greater amounts of viral replication, increased severity of secondary bacterial infection, and reduced vaccination efficacy.", "People who have underlying health conditions are also considered at-risk, including those who have congenital or chronic heart problems or lung (e.g. asthma), kidney, liver, blood, neurological, or metabolic (e.g. diabetes) disorders, as are people who are immunocompromised from chemotherapy, asplenia, prolonged steroid treatment, splenic dysfunction, or HIV infection.", "Current or past tobacco use also places a person at risk.", "The role of genetics in influenza is not well researched, but it may be a factor in influenza mortality.", "Influenza is typically characterized by seasonal epidemics and sporadic pandemics.", "Most of the burden of influenza is a result of flu seasons caused by IAV and IBV.", "Among IAV subtypes, H1N1 and H3N2 currently circulate in humans and are responsible for seasonal influenza.", "Cases disproportionately occur in children, but most severe causes are among the elderly, the very young, and the immunocompromised.", "In a typical year, influenza viruses infect 5–15% of the global population, causing 3–5 million cases of severe illness annually and accounting for 290,000–650,000 deaths each year due to respiratory illness.", "5–10% of adults and 20–30% of children contract influenza each year.", "The reported number of influenza cases is usually much lower than the actual number of cases.", "During seasonal epidemics, it is estimated that about 80% of otherwise healthy people who have a cough or sore throat have the flu.", "Approximately 30–40% of people hospitalized for influenza develop pneumonia, and about 5% of all severe pneumonia cases in hospitals are due to influenza, which is also the most common cause of ARDS in adults.", "In children, influenza is one of the two most common causes of ARDS, the other being the respiratory syncytial virus.", "About 3–5% of children each year develop otitis media due to influenza.", "Adults who develop organ failure from influenza and children who have PIM scores and acute renal failure have higher rates of mortality.", "During seasonal influenza, mortality is concentrated in the very young and the elderly, whereas during flu pandemics, young adults are often affected at a high rate.", "In temperate regions, the number of influenza cases varies from season to season.", "Lower vitamin D levels, presumably due to less sunlight, lower humidity, lower temperature, and minor changes in virus proteins caused by antigenic drift contribute to annual epidemics that peak during the winter season.", "In the northern hemisphere, this is from October to May (more narrowly December to April), and in the southern hemisphere, this is from May to October (more narrowly June to September).", "There are therefore two distinct influenza seasons every year in temperate regions, one in the northern hemisphere and one in the southern hemisphere.", "In tropical and subtropical regions, seasonality is more complex and appears to be affected by various climatic factors such as minimum temperature, hours of sunshine, maximum rainfall, and high humidity.", "Influenza may therefore occur year-round in these regions.", "Influenza epidemics in modern times have the tendency to start in the eastern or southern hemisphere, with Asia being a key reservoir of influenza viruses.", "IAV and IBV co-circulate, so the two have the same patterns of transmission.", "The seasonality of ICV, however, is poorly understood.", "ICV infection is most common in children under the age of 2, and by adulthood most people have been exposed to it.", "ICV-associated hospitalization most commonly occurs in children under the age of 3 and is frequently accompanied by co-infection with another virus or a bacterium, which may increase the severity of disease.", "When considering all hospitalizations for respiratory illness among young children, ICV appears to account for only a small percentage of such cases.", "Large outbreaks of ICV infection can occur, so incidence varies significantly.", "Outbreaks of influenza caused by novel influenza viruses are common.", "Depending on the level of pre-existing immunity in the population, novel influenza viruses can spread rapidly and cause pandemics with millions of deaths.", "These pandemics, in contrast to seasonal influenza, are caused by antigenic shifts involving animal influenza viruses.", "To date, all known flu pandemics have been caused by IAVs, and they follow the same pattern of spreading from an origin point to the rest of the world over the course of multiple waves in a year.", "Pandemic strains tend to be associated with higher rates of pneumonia in otherwise healthy individuals.", "Generally after each influenza pandemic, the pandemic strain continues to circulate as the cause of seasonal influenza, replacing prior strains.", "From 1700 to 1889, influenza pandemics occurred about once every 50–60 years.", "Since then, pandemics have occurred about once every 10–50 years, so they may be getting more frequent over time.", "It is impossible to know when an influenza virus first infected humans or when the first influenza pandemic occurred.", "Possibly the first influenza epidemic occurred around 6,000 BC in China, and possible descriptions of influenza exist in Greek writings from the 5th century BC.", "In both 1173–1174 AD and 1387 AD, epidemics occurred across Europe that were named \"influenza\".", "Whether these epidemics and others were caused by influenza is unclear since there was no consistent naming pattern for epidemic respiratory diseases at that time, and \"influenza\" didn't become completely attached to respiratory disease until centuries later.", "Influenza may have been brought to the Americas as early as 1493, when an epidemic disease resembling influenza killed most of the population of the Antilles.", "The first convincing record of an influenza pandemic was chronicled in 1510; it began in East Asia before spreading to North Africa and then Europe.", "Following the pandemic, seasonal influenza occurred, with subsequent pandemics in 1557 and 1580.", "The flu pandemic in 1557 was potentially the first time influenza was connected to miscarriage and death of pregnant women.", "The 1580 flu pandemic originated in Asia during summer, spread to Africa, then Europe, and finally America.", "By the end of the 16th century, influenza was likely beginning to become understood as a specific, recognizable disease with epidemic and endemic forms.", "In 1648, it was discovered that horses also experience influenza.", "Influenza data after 1700 is more informative, so it is easier to identify flu pandemics after this point, each of which incrementally increased understanding of influenza.", "The first flu pandemic of the 18th century started in 1729 in Russia in spring, spreading worldwide over the course of three years with distinct waves, the later ones being more lethal.", "The second flu pandemic of the 18th century was in 1781–1782, starting in China in autumn.", "From this pandemic, influenza became associated with sudden outbreaks of febrile illness.", "The next flu pandemic was from 1830 to 1833, beginning in China in winter.", "This pandemic had a high attack rate, but the mortality rate was low.", "A minor influenza pandemic occurred from 1847 to 1851 at the same time as the third cholera pandemic and was the first flu pandemic to occur with vital statistics being recorded, so influenza mortality was clearly recorded for the first time.", "Highly pathogenic avian influenza was recognized in 1878 and was soon linked to transmission to humans.", "By the time of the 1889 pandemic, which may have been caused by an H2N2 strain, the flu had become an easily recognizable disease.", "Initially, the microbial agent responsible for influenza was incorrently identified in 1892 by R. F. J. Pfeiffer as the bacteria species \"Haemophilus influenzae\", which retains \"influenza\" in its name.", "In the following years, the field of virology began to form as viruses were identified as the cause of many diseases.", "From 1901 to 1903, Italian and Austrian researchers were able to show that avian influenza, then called \"fowl plague\", was caused by a microscopic agent smaller than bacteria by using filters with pores too small for bacteria to pass through.", "The fundamental differences between viruses and bacteria, however, were not yet fully understood.", "From 1918 to 1920, the Spanish flu pandemic became the most devastating influenza pandemic and one of the deadliest pandemics in history.", "The pandemic, probably caused by H1N1, likely began in the USA before spreading worldwide by soldiers during and after the First World War.", "The initial wave in the first half of 1918 was relatively minor and resembled past flu pandemics, but the second wave later that year had a much higher mortality rate, accounting for most deaths.", "A third wave with lower mortality occurred in many places a few months after the second.", "By the end of 1920, it is estimated that about a third to half of all people in the world had been infected, with tens of millions of deaths, disproportionately young adults.", "During the 1918 pandemic, the respiratory route of transmission was clearly identified and influenza was shown to be caused by a \"filter passer\", not a bacterium, but there remained a lack of agreement about influenza's cause for another decade and research on influenza declined.", "After the pandemic, H1N1 circulated in humans in seasonal form up until the next pandemic.", "In 1931, Richard Shope published three papers identifying a virus as the cause of swine influenza, a then newly recognized disease among pigs that was first characterized during the second wave of the 1918 pandemic.", "Shope's research reinvigorated research on human influenza, and many advances in virology, serology, immunology, experimental animal models, vaccinology, and immunotherapy have since arisen from influenza research.", "Just two years after influenza viruses were discovered, in 1933, IAV was identified as the agent responsible for human influenza.", "Subtypes of IAV were discovered throughout the 1930s, and IBV was discovered in 1940.", "During the Second World War, the US government worked on developing inactivated vaccines for influenza, resulting in the first influenza vaccine being licensed in 1945 in the United States.", "ICV was discovered two years later in 1947.", "In 1955, avian influenza was confirmed to be caused by IAV.", "Four influenza pandemics have occurred since WWII, each less severe than the 1918 pandemic.", "The first of these was the Asian flu from 1957 to 1958, caused by an H2N2 strain and beginning in China's Yunnan province.", "The number of deaths probably exceeded one million, mostly among the very young and very old.", "Notably, the 1957 pandemic was the first flu pandemic to occur in the presence of a global surveillance system and laboratories able to study the novel influenza virus.", "After the pandemic, H2N2 was the IAV subtype responsible for seasonal influenza.", "The first antiviral drug against influenza, amantadine, was approved for use in 1966, with additional antiviral drugs being used since the 1990s.", "In 1968, H3N2 was introduced into humans as a result of a reassortment between an avian H3N2 strain and an H2N2 strain that was circulating in humans.", "The novel H3N2 strain first emerged in Hong Kong and spread worldwide, causing the Hong Kong flu pandemic, which resulted in 500,000–2,000,000 deaths.", "This was the first pandemic to spread significantly by air travel.", "H2N2 and H3N2 co-circulated after the pandemic until 1971 when H2N2 waned in prevalence and was completely replaced by H3N2.", "In 1977, H1N1 reemerged in humans, possibly after it was released from a freezer in a laboratory accident, and caused a pseudo-pandemic.", "Whether the 1977 \"pandemic\" deserves to be included in the natural history of flu pandemics is debatable.", "This H1N1 strain was antigenically similar to the H1N1 strains that circulated prior to 1957.", "Since 1977, both H1N1 and H3N2 have circulated in humans as part of seasonal influenza.", "In 1980, the current classification system used to subtype influenza viruses was introduced.", "At some point, IBV diverged into two lineages, named the B/Victoria-like and B/Yamagata-like lineages, both of which have been circulating in humans since 1983.", "In 1996, HPAI H5N1 was detected in Guangdong, China and a year later emerged in poultry in Hong Kong, gradually spreading worldwide from there.", "A small H5N1 outbreak in humans in Hong Kong occurred then, and sporadic human cases have occurred since 1997, carrying a high case fatality rate.", "The most recent flu pandemic was the 2009 swine flu pandemic, which originated in Mexico and resulted in hundreds of thousands of deaths.", "It was caused by a novel H1N1 strain that was a reassortment of human, swine, and avian influenza viruses.", "The 2009 pandemic had the effect of replacing prior H1N1 strains in circulation with the novel strain but not any other influenza viruses.", "Consequently, H1N1, H3N2, and both IBV lineages have been in circulation in seasonal form since the 2009 pandemic.", "In 2011, IDV was discovered in pigs in Oklahoma, USA, and cattle were later identified as the primary reservoir of IDV.", "In the same year, avian H7N9 was detected in China and began to cause human infections in 2013, starting in Shanghai and Anhui and remaining mostly in China.", "HPAI H7N9 emerged sometime in 2016 and has occasionally infected humans incidentally.", "Other AIVs have less commonly infected humans since the 1990s, including H5N6, H6N1, H7N2-4, H7N7, and H10N7-8, and HPAI H subtypes such as H5N1-3, H5N5-6, and H5N8 have begun to spread throughout much of the world since the 2010s.", "Future flu pandemics, which may be caused by an influenza virus of avian origin, are viewed as almost inevitable, and increased globalization has made it easier for novel viruses to spread, so there are continual efforts to prepare for future pandemics and improve the prevention and treatment of influenza.", "The word \"influenza\" comes from the Italian word \"influenza\", from medieval Latin \"influentia\", originally meaning \"visitation\" or \"influence\".", "Terms such as \"influenza di freddo\", meaning \"influence of the cold\", and \"influenza di stelle\", meaning \"influence of the stars\" are attested from the 14th century.", "The latter referred to the disease's cause, which at the time was ascribed by some to unfavorable astrological conditions.", "As early as 1504, \"influenza\" began to mean a \"visitation\" or \"outbreak\" of any disease affecting many people in a single place at once.", "During an outbreak of influenza in 1743 that started in Italy and spread throughout Europe, the word reached the English language and was anglicized in pronunciation.", "Since the mid-1800s, \"influenza\" has also been used to refer to severe colds.", "The shortened form of the word, \"(the) flu\", is first attested in 1839 as \"flue\" with the spelling \"flu\" first attested in 1893.", "Other names that have been used for influenza include \"epidemic catarrh\", \"la grippe\" from French, \"sweating sickness\", and, especially when referring to the 1918 pandemic strain, \"Spanish fever\".", "Influenza research is wide-ranging and includes efforts to understand how influenza viruses enter hosts, the relationship between influenza viruses and bacteria, how influenza symptoms progress, and what make some influenza viruses deadlier than others.", "Non-structural proteins encoded by influenza viruses are periodically discovered and their functions are continually under research.", "Past pandemics, and especially the 1918 pandemic, are the subject of much research to understand flu pandemics.", "As part of pandemic preparedness, the Global Influenza Surveillance and Response System is a global network of laboratories that monitors influenza transmission and epidemiology.", "Additional areas of research include ways to improve the diagnosis, treatment, and prevention of influenza.", "Existing diagnostic methods have a variety of limitations coupled with their advantages.", "For example, NATs have high sensitivity and specificity but are impractical in under-resourced regions due to their high cost, complexity, maintenance, and training required.", "Low-cost, portable RIDTs can rapidly diagnose influenza but have highly variable sensitivity and are unable to subtype IAV.", "As a result of these limitations and others, research into new diagnostic methods revolves around producing new methods that are cost-effective, less labor-intensive, and less complex than existing methods while also being able to differentiate influenza species and IAV subtypes.", "One approach in development are lab-on-a-chips, which are diagnostic devices that make use of a variety of diagnostic tests, such as RT-PCR and serological assays, in microchip form.", "These chips have many potential advantages, including high reaction efficiency, low energy consumption, and low waste generation.", "New antiviral drugs are also in development due to the elimination of adamantines as viable drugs and concerns over oseltamivir resistance.", "These include: NA inhibitors that can be injected intravenously, such as intravenous formulations of zanamivir; favipiravir, which is a polymerase inhibitor used against several RNA viruses; pimodivir, which prevents cap-binding required during viral transcription; and nitazoxanide, which inhibits HA maturation.", "Reducing excess inflammation in the respiratory tract is also subject to much research since this is one of the primary mechanisms of influenza pathology.", "Other forms of therapy in development include monoclonal and polyclonal antibodies that target viral proteins, convalescent plasma, different approaches to modify the host antiviral response, and stem cell-based therapies to repair lung damage.", "Much research on LAIVs focuses on identifying genome sequences that can be deleted to create harmless influenza viruses in vaccines that still confer immunity.", "The high variability and rapid evolution of influenza virus antigens, however, is a major obstacle in developing effective vaccines.", "Furthermore, it is hard to predict which strains will be in circulation during the next flu season, manufacturing a sufficient quantity of flu vaccines for the next season is difficult, LAIVs have limited efficacy, and repeated annual vaccination potentially has diminished efficacy.", "For these reasons, \"broadly-reactive\" or \"universal\" flu vaccines are being researched that can provide protection against many or all influenza viruses.", "Approaches to develop such a vaccine include HA stalk-based methods such as chimeras that have the same stalk but different heads, HA head-based methods such as computationally optimized broadly neutralizing antigens, anti-idiotypic antibodies, and vaccines to elicit immune responses to highly conserved viral proteins.", "mRNA vaccines to provide protection against influenza are also under research.", "Aquatic birds such as ducks, geese, shorebirds, and gulls are the primary reservoir of IAVs.", "In birds, AIVs may be either low pathogenic avian influenza (LPAI) viruses that produce little to no symptoms or highly pathogenic avian influenza (HPAI) viruses that cause severe illness.", "Symptoms of HPAI infection include lack of energy and appetite, decreased egg production, soft-shelled or misshapen eggs, swelling of the head, comb, wattles, and hocks, purple discoloration of wattles, combs, and legs, nasal discharge, coughing, sneezing, incoordination, and diarrhea.", "Birds infected with an HPAI virus may also die suddenly without any signs of infection.", "The distinction between LPAI and HPAI can generally be made based on how lethal an AIV is to chickens.", "At the genetic level, an AIV can be usually be identified as an HPAI virus if it has a multibasic cleavage site in the HA protein, which contains additional residues in the HA gene.", "Most AIVs are LPAI.", "Notable HPAI viruses include HPAI H5N1 and HPAI H7N9.", "HPAI viruses have been a major disease burden in the 21st century, resulting in the death of large numbers of birds.", "In H7N9's case, some circulating strains were originally LPAI but became HPAI by acquiring the HA multibasic cleavage site.", "Avian H9N2 is also of concern because although it is LPAI, it is a common donor of genes to H5N1 and H7N9 during reassortment.", "Migratory birds can spread influenza across long distances.", "An example of this was when an H5N1 strain in 2005 infected birds at Qinghai Lake, China, which is a stopover and breeding site for many migratory birds, subsequently spreading the virus to more than 20 countries across Asia, Europe, and the Middle East.", "AIVs can be transmitted from wild birds to domestic free-range ducks and in turn to poultry through contaminated water, aerosols, and fomites.", "Ducks therefore act as key intermediates between wild and domestic birds.", "Transmission to poultry typically occurs in backyard farming and live animal markets where multiple species interact with each other.", "From there, AIVs can spread to poultry farms in the absence of adequate biosecurity.", "Among poultry, HPAI transmission occurs through aerosols and contaminated feces, cages, feed, and dead animals.", "Back-transmission of HPAI viruses from poultry to wild birds has occurred and is implicated in mass die-offs and intercontinental spread.", "AIVs have occasionally infected humans through aerosols, fomites, and contaminated water.", "Direction transmission from wild birds is rare.", "Instead, most transmission involves domestic poultry, mainly chickens, ducks, and geese but also a variety of other birds such as guinea fowl, partridge, pheasants, and quails.", "The primary risk factor for infection with AIVs is exposure to birds in farms and live poultry markets.", "Typically, infection with an AIV has an incubation period of 3–5 days but can be up to 9 days.", "H5N1 and H7N9 cause severe lower respiratory tract illness, whereas other AIVs such as H9N2 cause a more mild upper respiratory tract illness, commonly with conjunctivitis.", "Limited transmission of avian H2, H5-7, H9, and H10 subtypes from one person to another through respiratory droplets, aerosols, and fomites has occurred, but sustained human-to-human transmission of AIVs has not occurred.", "Before 2013, H5N1 was the most common AIV to infect humans.", "Since then, H7N9 has been responsible for most human cases.", "Influenza in pigs is a respiratory disease similar to influenza in humans and is found worldwide.", "Asymptomatic infections are common.", "Symptoms typically appear 1–3 days after infection and include fever, lethargy, anorexia, weight loss, labored breathing, coughing, sneezing, and nasal discharge.", "In sows, pregnancy may be aborted.", "Complications include secondary infections and potentially fatal bronchopneumonia.", "Pigs become contagious within a day of infection and typically spread the virus for 7–10 days, which can spread rapidly within a herd.", "Pigs usually recover from infection within 3–7 days after symptoms appear.", "Prevention and control measures include inactivated vaccines and culling infected herds.", "The influenza viruses usually responsible for swine flu are IAV subtypes H1N1, H1N2, and H3N2.", "Some IAVs can be transmitted via aerosols from pigs to humans and vice versa.", "Furthermore, pigs, along with bats and quails, are recognized as a mixing vessel of influenza viruses because they have both α-2,3 and α-2,6 sialic acid receptors in their respiratory tract.", "Because of that, both avian and mammalian influenza viruses can infect pigs.", "If co-infection occurs, then reassortment is possible.", "A notable example of this was the reassortment of a swine, avian, and human influenza virus in 2009, resulting in a novel H1N1 strain that caused the 2009 flu pandemic.", "Spillover events from humans to pigs, however, appear to be more common than from pigs to humans.", "Influenza viruses have been found in many other animals, including cattle, horses, dogs, cats, and marine mammals.", "Nearly all IAVs are apparently descended from ancestral viruses in birds.", "The exception are bat influenza-like viruses, which have an uncertain origin.", "These bat viruses have HA and NA subtypes H17, H18, N10, and N11.", "H17N10 and H18N11 are unable to reassort with other IAVs, but they are still able to replicate in other mammals.", "AIVs sometimes crossover into mammals.", "For example, in late 2016 to early 2017, an avian H7N2 strain was found to be infecting cats in New York.", "Equine IAVs include H7N7 and two lineages of H3N8.", "H7N7, however, has not been detected in horses since the late 1970s, so it may have become extinct in horses.", "H3N8 in equines spreads via aerosols and causes respiratory illness.", "Equine H3N8 perferentially binds to α-2,3 sialic acids, so horses are usually considered dead-end hosts, but transmission to dogs and camels has occurred, raising concerns that horses may be mixing vessels for reassortment.", "In canines, the only IAVs in circulation are equine-derived H3N8 and avian-derived H3N2.", "Canine H3N8 has not been observed to reassort with other subtypes.", "H3N2 has a much broader host range and can reassort with H1N1 and H5N1.", "An isolated case of H6N1 likely from a chicken was found infecting a dog, so other AIVs may emerge in canines.", "Other mammals to be infected by IAVs include H7N7 and H4N5 in seals, H1N3 in whales, and H10N4 and H3N2 in minks.", "Various mutations have been identified that are associated with AIVs adapting to mammals.", "Since HA proteins vary in which sialic acids they bind to, mutations in the HA receptor binding site can allow AIVs to infect mammals.", "Other mutations include mutations affecting which sialic acids NA proteins cleave and a mutation in the PB2 polymerase subunit that improves tolerance of lower temperatures in mammalian respiratory tracts and enhances RNP assembly by stabilizing NP and PB2 binding.", "IBV is mainly found in humans but has also been detected in pigs, dogs, horses, and seals.", "Likewise, ICV primarily infects humans but has been observed in pigs, dogs, cattle, and dromedary camels.", "IDV causes an influenza-like illness in pigs but its impact in its natural reservoir, cattle, is relatively unknown.", "It may cause respiratory disease resembling human influenza on its own, or it may be part of a bovine respiratory disease (BRD) complex with other pathogens during co-infection.", "BRD is a concern for the cattle industry, so IDV's possible involvement in BRD has led to research on vaccines for cattle that can provide protection against IDV.", "Two antigenic lineages are in circulation: D/swine/Oklahoma/1334/2011 (D/OK) and D/bovine/Oklahoma/660/2013 (D/660)." ]

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[ "Annual vaccination can help to provide protection against influenza.", "Influenza viruses, particularly IAV, evolve quickly, so flu vaccines are updated regularly to match which influenza strains are in circulation." ]

[ "The time between exposure to the virus and development of symptoms, called the incubation period, is 1–4 days, most commonly 1–2 days.", "Many infections, however, are asymptomatic.", "The onset of symptoms is sudden, and initial symptoms are predominately non-specific, including fever, chills, headaches, muscle pain or aching, a feeling of discomfort, loss of appetite, lack of energy/fatigue, and confusion.", "These symptoms are usually accompanied by respiratory symptoms such as a dry cough, sore or dry throat, hoarse voice, and a stuffy or runny nose.", "Coughing is the most common symptom.", "Gastrointestinal symptoms may also occur, including nausea, vomiting, diarrhea, and gastroenteritis, especially in children.", "The standard influenza symptoms typically last for 2–8 days.", "A 2021 study suggests influenza can cause long lasting symptoms in a similar way to long COVID.\nSymptomatic infections are usually mild and limited to the upper respiratory tract, but progression to pneumonia is relatively common.", "Pneumonia may be caused by the primary viral infection or by a secondary bacterial infection.", "Primary pneumonia is characterized by rapid progression of fever, cough, labored breathing, and low oxygen levels that cause bluish skin.", "It is especially common among those who have an underlying cardiovascular disease such as rheumatic heart disease.", "Secondary pneumonia typically has a period of improvement in symptoms for 1–3 weeks followed by recurrent fever, sputum production, and fluid buildup in the lungs, but can also occur just a few days after influenza symptoms appear.", "About a third of primary pneumonia cases are followed by secondary pneumonia, which is most frequently caused by the bacteria \"Streptococcus pneumoniae\" and \"Staphylococcus aureus\".", "Influenza viruses comprise four species.", "Each of the four species is the sole member of its own genus, and the four influenza genera comprise four of the seven genera in the family \"Orthomyxoviridae\".", "They are:\n\n\nIAV is responsible for most cases of severe illness as well as seasonal epidemics and occasional pandemics.", "It infects people of all ages but tends to disproportionately cause severe illness in the elderly, the very young, and those who have chronic health issues.", "Birds are the primary reservoir of IAV, especially aquatic birds such as ducks, geese, shorebirds, and gulls, but the virus also circulates among mammals, including pigs, horses, and marine mammals.", "IAV is classified into subtypes based on the viral proteins haemagglutinin (H) and neuraminidase (N).", "As of 2019, 18 H subtypes and 11 N subtypes have been identified.", "Most potential combinations have been reported in birds, but H17-18 and N10-11 have only been found in bats.", "Only H subtypes H1-3 and N subtypes N1-2 are known to have circulated in humans, the current IAV subtypes in circulation being H1N1 and H3N2.", "IAVs can be classified more specifically to also include natural host species, geographical origin, year of isolation, and strain number, such as H1N1/A/duck/Alberta/35/76.", "IBV mainly infects humans but has been identified in seals, horses, dogs, and pigs.", "IBV does not have subtypes like IAV but has two antigenically distinct lineages, termed the B/Victoria/2/1987-like and B/Yamagata/16/1988-like lineages, or simply (B/)Victoria(-like) and (B/)Yamagata(-like).", "Both lineages are in circulation in humans, disproportionately affecting children.", "IBVs contribute to seasonal epidemics alongside IAVs but have never been associated with a pandemic.", "ICV, like IBV, is primarily found in humans, though it also has been detected in pigs, feral dogs, dromedary camels, cattle, and dogs.", "ICV infection primarily affects children and is usually asymptomatic or has mild cold-like symptoms, though more severe symptoms such as gastroenteritis and pneumonia can occur.", "Unlike IAV and IBV, ICV has not been a major focus of research pertaining to antiviral drugs, vaccines, and other measures against influenza.", "ICV is subclassified into six genetic/antigenic lineages.", "IDV has been isolated from pigs and cattle, the latter being the natural reservoir.", "Infection has also been observed in humans, horses, dromedary camels, and small ruminants such as goats and sheep.", "IDV is distantly related to ICV.", "While cattle workers have occasionally tested positive to prior IDV infection, it is not known to cause disease in humans.", "ICV and IDV experience a slower rate of antigenic evolution than IAV and IBV.", "Because of this antigenic stability, relatively few novel lineages emerge.", "Influenza viruses have a negative-sense, single-stranded RNA genome that is segmented.", "The negative sense of the genome means it can be used as a template to synthesize messenger RNA (mRNA).", "IAV and IBV have eight genome segments that encode 10 major proteins.", "ICV and IDV have seven genome segments that encode nine major proteins.", "Three segments encode three subunits of an RNA-dependent RNA polymerase (RdRp) complex: PB1, a transcriptase, PB2, which recognizes 5' caps, and PA (P3 for ICV and IDV), an endonuclease.", "The matrix protein (M1) and membrane protein (M2) share a segment, as do the non-structural protein (NS1) and the nuclear export protein (NEP).", "For IAV and IBV, hemagglutinin (HA) and neuraminidase (NA) are encoded on one segment each, whereas ICV and IDV encode a hemagglutinin-esterase fusion (HEF) protein on one segment that merges the functions of HA and NA.", "The final genome segment encodes the viral nucleoprotein (NP).", "Influenza viruses also encode various accessory proteins, such as PB1-F2 and PA-X, that are expressed through alternative open reading frames and which are important in host defense suppression, virulence, and pathogenicity.", "The virus particle, called a virion, is pleomorphic and varies between being filamentous, bacilliform, or spherical in shape.", "Clinical isolates tend to be pleomorphic, whereas strains adapted to laboratory growth typically produce spherical virions.", "Filamentous virions are about 250 nanometers (nm) by 80 nm, bacilliform 120–250 by 95 nm, and spherical 120 nm in diameter.", "The virion consists of each segment of the genome bound to nucleoproteins in separate ribonucleoprotein (RNP) complexes for each segment, all of which are surrounded by a lipid bilayer membrane called the viral envelope.", "There is a copy of the RdRp, all subunits included, bound to each RNP.", "The envelope is reinforced structurally by matrix proteins on the interior that enclose the RNPs, and the envelope contains HA and NA (or HEF) proteins extending outward from the exterior surface of the envelope.", "HA and HEF proteins have a distinct \"head\" and \"stalk\" structure.", "M2 proteins form proton ion channels through the viral envelope that are required for viral entry and exit.", "IBVs contain a surface protein named NB that is anchored in the envelope, but its function is unknown.", "The viral life cycle begins by binding to a target cell.", "Binding is mediated by the viral HA proteins on the surface of the evelope, which bind to cells that contain sialic acid receptors on the surface of the cell membrane.", "For N1 subtypes with the \"G147R\" mutation and N2 subtypes, the NA protein can initiate entry.", "Prior to binding, NA proteins promote access to target cells by degrading mucous, which helps to remove extracellular decoy receptors that would impede access to target cells.", "After binding, the virus is internalized into the cell by an endosome that contains the virion inside it.", "The endosome is acidified by cellular vATPase to have lower pH, which triggers a conformational change in HA that allows fusion of the viral envelope with the endosomal membrane.", "At the same time, hydrogen ions diffuse into the virion through M2 ion channels, disrupting internal protein-protein interactions to release RNPs into the host cell's cytosol.", "The M1 protein shell surrounding RNPs is degraded, fully uncoating RNPs in the cytosol.", "RNPs are then imported into the nucleus with the help of viral localization signals.", "There, the viral RNA polymerase transcribes mRNA using the genomic negative-sense strand as a template.", "The polymerase snatches 5' caps for viral mRNA from cellular RNA to prime mRNA synthesis and the 3'-end of mRNA is polyadenylated at the end of transcription.", "Once viral mRNA is transcribed, it is exported out of the nucleus and translated by host ribosomes in a cap-dependent manner to synthesize viral proteins.", "RdRp also synthesizes complementary positive-sense strands of the viral genome in a complementary RNP complex which are then used as templates by viral polymerases to synthesize copies of the negative-sense genome.", "During these processes, RdRps of avian influenza viruses (AIVs) function optimally at a higher temperature than mammalian influenza viruses.", "Newly synthesized viral polymerase subunits and NP proteins are imported to the nucleus to further increase the rate of viral replication and form RNPs.", "HA, NA, and M2 proteins are trafficked with the aid of M1 and NEP proteins to the cell membrane through the Golgi apparatus and inserted into the cell's membrane.", "Viral non-structural proteins including NS1, PB1-F2, and PA-X regulate host cellular processes to disable antiviral responses.", "PB1-F2 aso interacts with PB1 to keep polymerases in the nucleus longer.", "M1 and NEP proteins localize to the nucleus during the later stages of infection, bind to viral RNPs and mediate their export to the cytoplasm where they migrate to the cell membrane with the aid of recycled endosomes and are bundled into the segments of the genome.", "Progenic viruses leave the cell by budding from the cell membrane, which is initiated by the accumulation of M1 proteins at the cytoplasmic side of the membrane.", "The viral genome is incorporated inside a viral envelope derived from portions of the cell membrane that have HA, NA, and M2 proteins.", "At the end of budding, HA proteins remain attached to cellular sialic acid until they are cleaved by the sialidase activity of NA proteins.", "The virion is then released from the cell.", "The sialidase activity of NA also cleaves any sialic acid residues from the viral surface, which helps prevent newly assembled viruses from aggregating near the cell surface and improving infectivity.", "Similar to other aspects of influenza replication, optimal NA activity is temperature- and pH-dependent.", "Ultimately, presence of large quantities of viral RNA in the cell triggers apoptosis, i.e. programmed cell death, which is initiated by cellular factors to restrict viral replication.", "Two key processes that influenza viruses evolve through are antigenic drift and antigenic shift.", "Antigenic drift is when an influenza virus's antigens change due to the gradual accumulation of mutations in the antigen's (HA or NA) gene.", "This can occur in response to evolutionary pressure exerted by the host immune response.", "Antigenic drift is especially common for the HA protein, in which just a few amino acid changes in the head region can constitute antigenic drift.", "The result is the production of novel strains that can evade pre-existing antibody-mediated immunity.", "Antigenic drift occurs in all influenza species but is slower in B than A and slowest in C and D. Antigenic drift is a major cause of seasonal influenza, and requires that flu vaccines be updated annually.", "HA is the main component of inactivated vaccines, so surveillance monitors antigenic drift of this antigen among circulating strains.", "Antigenic evolution of influenza viruses of humans appears to be faster than influenza viruses in swine and equines.", "In wild birds, within-subtype antigenic variation appears to be limited but has been observed in poultry.", "Antigenic shift is a sudden, drastic change in an influenza virus's antigen, usually HA.", "During antigenic shift, antigenically different strains that infect the same cell can reassort genome segments with each other, producing hybrid progeny.", "Since all influenza viruses have segmented genomes, all are capable of reassortment.", "Antigenic shift, however, only occurs among influenza viruses of the same genus and most commonly occurs among IAVs.", "In particular, reassortment is very common in AIVs, creating a large diversity of influenza viruses in birds, but is uncommon in human, equine, and canine lineages.", "Pigs, bats, and quails have receptors for both mammalian and avian IAVs, so they are potential \"mixing vessels\" for reassortment.", "If an animal strain reassorts with a human strain, then a novel strain can emerge that is capable of human-to-human transmission.", "This has caused pandemics, but only a limited number have occurred, so it is difficult to predict when the next will happen.", "People who are infected can transmit influenza viruses through breathing, talking, coughing, and sneezing, which spread respiratory droplets and aerosols that contain virus particles into the air.", "A person susceptible to infection can then contract influenza by coming into contact with these particles.", "Respiratory droplets are relatively large and travel less than two meters before falling onto nearby surfaces.", "Aerosols are smaller and remain suspended in the air longer, so they take longer to settle and can travel further than respiratory droplets.", "Inhalation of aerosols can lead to infection, but most transmission is in the area about two meters around an infected person via respiratory droplets that come into contact with mucosa of the upper respiratory tract.", "Transmission through contact with a person, bodily fluids, or intermediate objects (fomites) can also occur, such as through contaminated hands and surfaces since influenza viruses can survive for hours on non-porous surfaces.", "If one's hands are contaminated, then touching one's face can cause infection.", "Influenza is usually transmissible from one day before the onset of symptoms to 5–7 days after.", "In healthy adults, the virus is shed for up to 3–5 days.", "In children and the immunocompromised, the virus may be transmissible for several weeks.", "Children ages 2–17 are considered to be the primary and most efficient spreaders of influenza.", "Children who have not had multiple prior exposures to influenza viruses shed the virus at greater quantities and for a longer duration than other children.", "People who are at risk of exposure to influenza include health care workers, social care workers, and those who live with or care for people vulnerable to influenza.", "In long-term care facilities, the flu can spread rapidly after it is introduced.", "A variety of factors likely encourage influenza transmission, including lower temperature, lower absolute and relative humidity, less ultraviolet radiation from the Sun, and crowding.", "Influenza viruses that infect the upper respiratory tract like H1N1 tend to be more mild but more transmissible, whereas those that infect the lower respiratory tract like H5N1 tend to cause more severe illness but are less contagious.", "In humans, influenza viruses first cause infection by infecting epithelial cells in the respiratory tract.", "Illness during infection is primarily the result of lung inflammation and compromise caused by epithelial cell infection and death, combined with inflammation caused by the immune system's response to infection.", "Non-respiratory organs can become involved, but the mechanisms by which influenza is involved in these cases are unknown.", "Severe respiratory illness can be caused by multiple, non-exclusive mechanisms, including obstruction of the airways, loss of alveolar structure, loss of lung epithelial integrity due to epithelial cell infection and death, and degradation of the extracellular matrix that maintains lung structure.", "In particular, alveolar cell infection appears to drive severe symptoms since this results in impaired gas exchange and enables viruses to infect endothelial cells, which produce large quantities of pro-inflammatory cytokines.", "Pneumonia caused by influenza viruses is characterized by high levels of viral replication in the lower respiratory tract, accompanied by a strong pro-inflammatory response called a cytokine storm.", "Infection with H5N1 or H7N9 especially produces high levels of pro-inflammatory cytokines.", "In bacterial infections, early depletion of macrophages during influenza creates a favorable environment in the lungs for bacterial growth since these white blood cells are important in responding to bacterial infection.", "Host mechanisms to encourage tissue repair may inadvertently allow bacterial infection.", "Infection also induces production of systemic glucocorticoids that can reduce inflammation to preserve tissue integrity but allow increased bacterial growth.", "The pathophysiology of influenza is significantly influenced by which receptors influenza viruses bind to during entry into cells.", "Mammalian influenza viruses preferentially bind to sialic acids connected to the rest of the oligosaccharide by an α-2,6 link, most commonly found in various respiratory cells, such as respiratory and retinal epithelial cells.", "AIVs prefer sialic acids with an α-2,3 linkage, which are most common in birds in gastrointestinal epithelial cells and in humans in the lower respiratory tract.", "Furthermore, cleavage of the HA protein into HA, the binding subunit, and HA, the fusion subunit, is performed by different proteases, affecting which cells can be infected.", "For mammalian influenza viruses and low pathogenic AIVs, cleavage is extracellular, which limits infection to cells that have the appropriate proteases, whereas for highly pathogenic AIVs, cleavage is intracellular and performed by ubiquitous proteases, which allows for infection of a greater variety of cells, thereby contributing to more severe disease.", "Cells possess sensors to detect viral RNA, which can then induce interferon production.", "Interferons mediate expression of antiviral proteins and proteins that recruit immune cells to the infection site, and they also notify nearby uninfected cells of infection.", "Some infected cells release pro-inflammatory cytokines that recruit immune cells to the site of infection.", "Immune cells control viral infection by killing infected cells and phagocytizing viral particles and apoptotic cells.", "An exacerbated immune response, however, can harm the host organism through a cytokine storm.", "To counter the immune response, influenza viruses encode various non-structural proteins, including NS1, NEP, PB1-F2, and PA-X, that are involved in curtailing the host immune response by suppressing interferon production and host gene expression.", "B cells, a type of white blood cell, produce antibodies that bind to influenza antigens HA and NA (or HEF) and other proteins to a lesser degree.", "Once bound to these proteins, antibodies block virions from binding to cellular receptors, neutralizing the virus.", "In humans, a sizeable antibody response occurs ~1 week after viral exposure.", "This antibody response is typically robust and long-lasting, especially for ICV and IDV.", "In other words, people exposed to a certain strain in childhood still possess antibodies to that strain at a reasonable level later in life, which can provide some protection to related strains.", "There is, however, an \"original antigenic sin\", in which the first HA subtype a person is exposed to influences the antibody-based immune response to future infections and vaccines.", "Annual vaccination is the primary and most effective way to prevent influenza and influenza-associated complications, especially for high-risk groups.", "Vaccines against the flu are trivalent or quadrivalent, providing protection against an H1N1 strain, an H3N2 strain, and one or two IBV strains corresponding to the two IBV lineages.", "Two types of vaccines are in use: inactivated vaccines that contain \"killed\" (i.e. inactivated) viruses and live attenuated influenza vaccines (LAIVs) that contain weakened viruses.", "There are three types of inactivated vaccines: whole virus, split virus, in which the virus is disrupted by a detergent, and subunit, which only contains the viral antigens HA and NA.", "Most flu vaccines are inactivated and administered via intramuscular injection.", "LAIVs are sprayed into the nasal cavity.", "Vaccination recommendations vary by country.", "Some recommend vaccination for all people above a certain age, such as 6 months, whereas other countries recommendation is limited for high at risk groups, such as pregnant women, young children (excluding newborns), the elderly, people with chronic medical conditions, health care workers, people who come into contact with high-risk people, and people who transmit the virus easily.", "Young infants cannot receive flu vaccines for safety reasons, but they can inherit passive immunity from their mother if inactivated vaccines are administered to the mother during pregnancy.", "Influenza vaccination also helps to reduce the probability of reassortment.", "In general, influenza vaccines are only effective if there is an antigenic match between vaccine strains and circulating strains.", "Additionally, most commercially available flu vaccines are manufactured by propagation of influenza viruses in embryonated chicken eggs, taking 6–8 months.", "Flu seasons are different in the northern and southern hemisphere, so the WHO meets twice a year, one for each hemisphere, to discuss which strains should be included in flu vaccines based on observation from HA inhibition assays.", "Other manufacturing methods include an MDCK cell culture-based inactivated vaccine and a recombinant subunit vaccine manufactured from baculovirus overexpression in insect cells.", "Influenza can be prevented or reduced in severity by post-exposure prophylaxis with the antiviral drugs oseltamivir, which can be taken orally by those at least three months old, and zanamivir, which can be inhaled by those above seven years of age.", "Chemoprophylaxis is most useful for individuals at high-risk of developing complications and those who cannot receive the flu vaccine due to contraindications or lack of effectiveness.", "Post-exposure chemoprophylaxis is only recommended if oseltamivir is taken within 48 hours of contact with a confirmed or suspected influenza case and zanamivir within 36 hours.", "It is recommended that it be offered to people who have yet to receive a vaccine for the current flu season, who have been vaccinated less than two week since contact, if there is a significant mismatch between vaccine and circulating strains, or during an outbreak in a closed setting regardless of vaccination history.", "Hand hygiene is important in reducing the spread of influenza.", "This includes frequent hand washing with soap and water, using alcohol-based hand sanitizers, and not touching one's eyes, nose, and mouth with one's hands.", "Covering one's nose and mouth when coughing or sneezing is important.", "Other methods to limit influenza transmission include staying home when sick, avoiding contact with others until one day after symptoms end, and disinfecting surfaces likely to be contaminated by the virus, such as doorknobs.", "Health education through media and posters is often used to remind people of the aforementioned etiquette and hygiene.", "There is uncertainty about the use of masks since research thus far has not shown a significant reduction in seasonal influenza with mask usage.", "Likewise, the effectiveness of screening at points of entry into countries is not well researched.", "Social distancing measures such as school closures, avoiding contact with infected people via isolation or quarantine, and limiting mass gatherings may reduce transmission, but these measures are often expensive, unpopular, and difficult to implement.", "Consequently, the commonly recommended methods of infection control are respiratory etiquette, hand hygiene, and mask wearing, which are inexpensive and easy to perform.", "Pharmaceutical measures are effective but may not be available in the early stages of an outbreak.", "In health care settings, infected individuals may be cohorted or assigned to individual rooms.", "Protective clothing such as masks, gloves, and gowns is recommended when coming into contact with infected individuals if there is a risk of exposure to infected bodily fluids.", "Keeping patients in negative pressure rooms and avoiding aerosol-producing activities may help, but special air handling and ventilation systems are not considered necessary to prevent the spread of influenza in the air.", "In residential homes, new admissions may need to be closed until the spread of influenza is controlled.", "When discharging patients to care homes, it is important to take care if there is a known influenza outbreak.", "Since influenza viruses circulate in animals such as birds and pigs, prevention of transmission from these animals is important.", "Water treatment, indoor raising of animals, quarantining sick animals, vaccination, and biosecurity are the primary measures used.", "Placing poultry houses and piggeries on high ground away from high-density farms, backyard farms, live poultry markets, and bodies of water helps to minimize contact with wild birds.", "Closure of live poultry markets appears to the most effective measure and has shown to be effective at controlling the spread of H5N1, H7N9, and H9N2.", "Other biosecurity measures include cleaning and disinfecting facilities and vehicles, banning visits to poultry farms, not bringing birds intended for slaughter back to farms, changing clothes, disinfecting foot baths, and treating food and water.", "If live poultry markets are not closed, then \"clean days\" when unsold poultry is removed and facilities are disinfected and \"no carry-over\" policies to eliminate infectious material before new poultry arrive can be used to reduce the spread of influenza viruses.", "If a novel influenza viruses has breached the aforementioned biosecurity measures, then rapid detection to stamp it out via quarantining, decontamination, and culling may be necessary to prevent the virus from becoming endemic.", "Vaccines exist for avian H5, H7, and H9 subtypes that are used in some countries.", "In China, for example, vaccination of domestic birds against H7N9 successfully limited its spread, indicating that vaccination may be an effective strategy if used in combination with other measures to limit transmission.", "In pigs and horses, management of influenza is dependent on vaccination with biosecurity.", "Diagnosis based on symptoms is fairly accurate in otherwise healthy people during seasonal epidemics and should be suspected in cases of pneumonia, acute respiratory distress syndrome (ARDS), sepsis, or if encephalitis, myocarditis, or breaking down of muscle tissue occur.", "Because influenza is similar to other viral respiratory tract illnesses, laboratory diagnosis is necessary for confirmation.", "Common ways of collecting samples for testing include nasal and throat swabs.", "Samples may be taken from the lower respiratory tract if infection has cleared the upper but not lower respiratory tract.", "Influenza testing is recommended for anyone hospitalized with symptoms resembling influenza during flu season or who is connected to an influenza case.", "For severe cases, earlier diagnosis improves patient outcome.", "Diagnostic methods that can identify influenza include viral cultures, antibody- and antigen-detecting tests, and nucleic acid-based tests.", "Viruses can be grown in a culture of mammalian cells or embryonated eggs for 3–10 days to monitor cytopathic effect.", "Final confirmation can then be done via antibody staining, hemadsorption using red blood cells, or immunofluorescence microscopy.", "Shell vial cultures, which can identify infection via immunostaining before a cytopathic effect appears, are more sensitive than traditional cultures with results in 1–3 days.", "Cultures can be used to characterize novel viruses, observe sensitivity to antiviral drugs, and monitor antigenic drift, but they are relatively slow and require specialized skills and equipment.", "Serological assays can be used to detect an antibody response to influenza after natural infection or vaccination.", "Common serological assays include hemagglutination inhibition assays that detect HA-specific antibodies, virus neutralization assays that check whether antibodies have neutralized the virus, and enzyme-linked immunoabsorbant assays.", "These methods tend to be relatively inexpensive and fast but are less reliable than nucleic-acid based tests.", "Direct fluorescent or immunofluorescent antibody (DFA/IFA) tests involve staining respiratory epithelial cells in samples with fluorescently-labeled influenza-specific antibodies, followed by examination under a fluorescent microscope.", "They can differentiate between IAV and IBV but can't subtype IAV.", "Rapid influenza diagnostic tests (RIDTs) are a simple way of obtaining assay results, are low cost, and produce results quickly, at less than 30 minutes, so they are commonly used, but they can't distinguish between IAV and IBV or between IAV subtypes and are not as sensitive as nucleic-acid based tests.", "Nucleic acid-based tests (NATs) amplify and detect viral nucleic acid.", "Most of these tests take a few hours, but rapid molecular assays are as fast as RIDTs.", "Among NATs, reverse transcription polymerase chain reaction (RT-PCR) is the most traditional and considered the gold standard for diagnosing influenza because it is fast and can subtype IAV, but it is relatively expensive and more prone to false-positives than cultures.", "Other NATs that have been used include loop-mediated isothermal amplification-based assays, simple amplification-based assays, and nucleic acid sequence-based amplification.", "Nucleic acid sequencing methods can identify infection by obtaining the nucleic acid sequence of viral samples to identify the virus and antiviral drug resistance.", "The traditional method is Sanger sequencing, but it has been largely replaced by next-generation methods that have greater sequencing speed and throughput.", "Treatment of influenza in cases of mild or moderate illness is supportive and includes anti-fever medications such as acetaminophen and ibuprofen, adequate fluid intake to avoid dehydration, and resting at home.", "Cough drops and throat sprays may be beneficial for sore throat.", "It is recommended to avoid alcohol and tobacco use while sick with the flu.", "Aspirin is not recommended to treat influenza in children due to an elevated risk of developing Reye syndrome.", "Corticosteroids likewise are not recommended except when treating septic shock or an underlying medical condition, such as chronic obstructive pulmonary disease or asthma exacerbation, since they are associated with increased mortality.", "If a secondary bacterial infection occurs, then treatment with antibiotics may be necessary.", "Antiviral drugs are primarily used to treat severely ill patients, especially those with compromised immune systems.", "Antivirals are most effective when started in the first 48 hours after symptoms appear.", "Later administration may still be beneficial for those who have underlying immune defects, those with more severe symptoms, or those who have a higher risk of developing complications if these individuals are still shedding the virus.", "Antiviral treatment is also recommended if a person is hospitalized with suspected influenza instead of waiting for test results to return and if symptoms are worsening.", "Most antiviral drugs against influenza fall into two categories: neuraminidase (NA) inhibitors and M2 inhibitors.", "Baloxavir marboxil is a notable exception, which targets the endonuclease activity of the viral RNA polymerase and can be used as an alternative to NA and M2 inhibitors for IAV and IBV.", "NA inhibitors target the enzymatic activity of NA receptors, mimicking the binding of sialic acid in the active site of NA on IAV and IBV virions so that viral release from infected cells and the rate of viral replication are impaired.", "NA inhibitors include oseltamivir, which is consumed orally in a prodrug form and converted to its active form in the liver, and zanamivir, which is a powder that is inhaled nasally.", "Oseltamivir and zanamivir are effective for prophylaxis and post-exposure prophylaxis, and research overall indicates that NA inhibitors are effective at reducing rates of complications, hospitalization, and mortality and the duration of illness.", "Additionally, the earlier NA inhibitors are provided, the better the outcome, though late administration can still be beneficial in severe cases.", "Other NA inhibitors include laninamivir and peramivir, the latter of which can be used as an alternative to oseltamivir for people who cannot tolerate or absorb it.", "The adamantanes amantadine and rimantadine are orally administered drugs that block the influenza virus's M2 ion channel, preventing viral uncoating.", "These drugs are only functional against IAV but are no longer recommended for use because of widespread resistance to them among IAVs.", "Adamantane resistance first emerged in H3N2 in 2003, becoming worldwide by 2008.", "Oseltamivir resistance is no longer widespread because the 2009 pandemic H1N1 strain (H1N1 pdm09), which is resistant to adamantanes, seemingly replaced resistant strains in circulation.", "Since the 2009 pandemic, oseltamivir resistance has mainly been observed in patients undergoing therapy, especially the immunocompromised and young children.", "Oseltamivir resistance is usually reported in H1N1, but has been reported in H3N2 and IBVs less commonly.", "Because of this, oseltamivir is recommended as the first drug of choice for immunocompetent people, whereas for the immunocompromised, oseltamivir is recommended against H3N2 and IBV and zanamivir against H1N1 pdm09.", "Zanamivir resistance is observed less frequently, and resistance to peramivir and baloxavir marboxil is possible.", "In healthy individuals, influenza infection is usually self-limiting and rarely fatal.", "Symptoms usually last for 2–8 days.", "Influenza can cause people to miss work or school, and it is associated with decreased job performance and, in older adults, reduced independence.", "Fatigue and malaise may last for several weeks after recovery, and healthy adults may experience pulmonary abnormalities that can take several weeks to resolve.", "Complications and mortality primarily occur in high-risk populations and those who are hospitalized.", "Severe disease and mortality are usually attributable to pneumonia from the primary viral infection or a secondary bacterial infection, which can progress to ARDS.", "Other respiratory complications that may occur include sinusitis, bronchitis, bronchiolitis, excess fluid buildup in the lungs, and exacerbation of chronic bronchitis and asthma.", "Middle ear infection and croup may occur, most commonly in children.", "Secondary \"S. aureus\" infection has been observed, primarily in children, to cause toxic shock syndrome after influenza, with hypotension, fever, and reddening and peeling of the skin.", "Complications affecting the cardiovascular system are rare and include pericarditis, fulminant myocarditis with a fast, slow, or irregular heartbeat, and exacerbation of pre-existing cardiovascular disease.", "Inflammation or swelling of muscles accompanied by muscle tissue breaking down occurs rarely, usually in children, which presents as extreme tenderness and muscle pain in the legs and a reluctance to walk for 2–3 days.", "Influenza can affect pregnancy, including causing smaller neonatal size, increased risk of premature birth, and an increased risk of child death shortly before or after birth.", "Neurological complications have been associated with influenza on rare occasions, including aseptic meningitis, encephalitis, disseminated encephalomyelitis, transverse myelitis, and Guillain–Barré syndrome.", "Additionally, febrile seizures and Reye syndrome can occur, most commonly in children.", "Influenza-associated encephalopathy can occur directly from central nervous system infection from the presence of the virus in blood and presents as suddent onset of fever with convulsions, followed by rapid progression to coma.", "An atypical form of encephalitis called encephalitis lethargica, characterized by headache, drowsiness, and coma, may rarely occur sometime after infection.", "In survivors of influenza-associated encephalopathy, neurological defects may occur.", "Primarily in children, in severe cases the immune system may rarely dramatically overproduce white blood cells that release cytokines, causing severe inflammation.", "People who are at least 65 years of age, due to a weakened immune system from aging or a chronic illness, are a high-risk group for developing complications, as are children less than one year of age and children who have not been previously exposed to influenza viruses multiple times.", "Pregnant women are at an elevated risk, which increases by trimester and lasts up to two weeks after childbirth.", "Obesity, in particular a body mass index greater than 35–40, is associated with greater amounts of viral replication, increased severity of secondary bacterial infection, and reduced vaccination efficacy.", "People who have underlying health conditions are also considered at-risk, including those who have congenital or chronic heart problems or lung (e.g. asthma), kidney, liver, blood, neurological, or metabolic (e.g. diabetes) disorders, as are people who are immunocompromised from chemotherapy, asplenia, prolonged steroid treatment, splenic dysfunction, or HIV infection.", "Current or past tobacco use also places a person at risk.", "The role of genetics in influenza is not well researched, but it may be a factor in influenza mortality.", "Influenza is typically characterized by seasonal epidemics and sporadic pandemics.", "Most of the burden of influenza is a result of flu seasons caused by IAV and IBV.", "Among IAV subtypes, H1N1 and H3N2 currently circulate in humans and are responsible for seasonal influenza.", "Cases disproportionately occur in children, but most severe causes are among the elderly, the very young, and the immunocompromised.", "In a typical year, influenza viruses infect 5–15% of the global population, causing 3–5 million cases of severe illness annually and accounting for 290,000–650,000 deaths each year due to respiratory illness.", "5–10% of adults and 20–30% of children contract influenza each year.", "The reported number of influenza cases is usually much lower than the actual number of cases.", "During seasonal epidemics, it is estimated that about 80% of otherwise healthy people who have a cough or sore throat have the flu.", "Approximately 30–40% of people hospitalized for influenza develop pneumonia, and about 5% of all severe pneumonia cases in hospitals are due to influenza, which is also the most common cause of ARDS in adults.", "In children, influenza is one of the two most common causes of ARDS, the other being the respiratory syncytial virus.", "About 3–5% of children each year develop otitis media due to influenza.", "Adults who develop organ failure from influenza and children who have PIM scores and acute renal failure have higher rates of mortality.", "During seasonal influenza, mortality is concentrated in the very young and the elderly, whereas during flu pandemics, young adults are often affected at a high rate.", "In temperate regions, the number of influenza cases varies from season to season.", "Lower vitamin D levels, presumably due to less sunlight, lower humidity, lower temperature, and minor changes in virus proteins caused by antigenic drift contribute to annual epidemics that peak during the winter season.", "In the northern hemisphere, this is from October to May (more narrowly December to April), and in the southern hemisphere, this is from May to October (more narrowly June to September).", "There are therefore two distinct influenza seasons every year in temperate regions, one in the northern hemisphere and one in the southern hemisphere.", "In tropical and subtropical regions, seasonality is more complex and appears to be affected by various climatic factors such as minimum temperature, hours of sunshine, maximum rainfall, and high humidity.", "Influenza may therefore occur year-round in these regions.", "Influenza epidemics in modern times have the tendency to start in the eastern or southern hemisphere, with Asia being a key reservoir of influenza viruses.", "IAV and IBV co-circulate, so the two have the same patterns of transmission.", "The seasonality of ICV, however, is poorly understood.", "ICV infection is most common in children under the age of 2, and by adulthood most people have been exposed to it.", "ICV-associated hospitalization most commonly occurs in children under the age of 3 and is frequently accompanied by co-infection with another virus or a bacterium, which may increase the severity of disease.", "When considering all hospitalizations for respiratory illness among young children, ICV appears to account for only a small percentage of such cases.", "Large outbreaks of ICV infection can occur, so incidence varies significantly.", "Outbreaks of influenza caused by novel influenza viruses are common.", "Depending on the level of pre-existing immunity in the population, novel influenza viruses can spread rapidly and cause pandemics with millions of deaths.", "These pandemics, in contrast to seasonal influenza, are caused by antigenic shifts involving animal influenza viruses.", "To date, all known flu pandemics have been caused by IAVs, and they follow the same pattern of spreading from an origin point to the rest of the world over the course of multiple waves in a year.", "Pandemic strains tend to be associated with higher rates of pneumonia in otherwise healthy individuals.", "Generally after each influenza pandemic, the pandemic strain continues to circulate as the cause of seasonal influenza, replacing prior strains.", "From 1700 to 1889, influenza pandemics occurred about once every 50–60 years.", "Since then, pandemics have occurred about once every 10–50 years, so they may be getting more frequent over time.", "It is impossible to know when an influenza virus first infected humans or when the first influenza pandemic occurred.", "Possibly the first influenza epidemic occurred around 6,000 BC in China, and possible descriptions of influenza exist in Greek writings from the 5th century BC.", "In both 1173–1174 AD and 1387 AD, epidemics occurred across Europe that were named \"influenza\".", "Whether these epidemics and others were caused by influenza is unclear since there was no consistent naming pattern for epidemic respiratory diseases at that time, and \"influenza\" didn't become completely attached to respiratory disease until centuries later.", "Influenza may have been brought to the Americas as early as 1493, when an epidemic disease resembling influenza killed most of the population of the Antilles.", "The first convincing record of an influenza pandemic was chronicled in 1510; it began in East Asia before spreading to North Africa and then Europe.", "Following the pandemic, seasonal influenza occurred, with subsequent pandemics in 1557 and 1580.", "The flu pandemic in 1557 was potentially the first time influenza was connected to miscarriage and death of pregnant women.", "The 1580 flu pandemic originated in Asia during summer, spread to Africa, then Europe, and finally America.", "By the end of the 16th century, influenza was likely beginning to become understood as a specific, recognizable disease with epidemic and endemic forms.", "In 1648, it was discovered that horses also experience influenza.", "Influenza data after 1700 is more informative, so it is easier to identify flu pandemics after this point, each of which incrementally increased understanding of influenza.", "The first flu pandemic of the 18th century started in 1729 in Russia in spring, spreading worldwide over the course of three years with distinct waves, the later ones being more lethal.", "The second flu pandemic of the 18th century was in 1781–1782, starting in China in autumn.", "From this pandemic, influenza became associated with sudden outbreaks of febrile illness.", "The next flu pandemic was from 1830 to 1833, beginning in China in winter.", "This pandemic had a high attack rate, but the mortality rate was low.", "A minor influenza pandemic occurred from 1847 to 1851 at the same time as the third cholera pandemic and was the first flu pandemic to occur with vital statistics being recorded, so influenza mortality was clearly recorded for the first time.", "Highly pathogenic avian influenza was recognized in 1878 and was soon linked to transmission to humans.", "By the time of the 1889 pandemic, which may have been caused by an H2N2 strain, the flu had become an easily recognizable disease.", "Initially, the microbial agent responsible for influenza was incorrently identified in 1892 by R. F. J. Pfeiffer as the bacteria species \"Haemophilus influenzae\", which retains \"influenza\" in its name.", "In the following years, the field of virology began to form as viruses were identified as the cause of many diseases.", "From 1901 to 1903, Italian and Austrian researchers were able to show that avian influenza, then called \"fowl plague\", was caused by a microscopic agent smaller than bacteria by using filters with pores too small for bacteria to pass through.", "The fundamental differences between viruses and bacteria, however, were not yet fully understood.", "From 1918 to 1920, the Spanish flu pandemic became the most devastating influenza pandemic and one of the deadliest pandemics in history.", "The pandemic, probably caused by H1N1, likely began in the USA before spreading worldwide by soldiers during and after the First World War.", "The initial wave in the first half of 1918 was relatively minor and resembled past flu pandemics, but the second wave later that year had a much higher mortality rate, accounting for most deaths.", "A third wave with lower mortality occurred in many places a few months after the second.", "By the end of 1920, it is estimated that about a third to half of all people in the world had been infected, with tens of millions of deaths, disproportionately young adults.", "During the 1918 pandemic, the respiratory route of transmission was clearly identified and influenza was shown to be caused by a \"filter passer\", not a bacterium, but there remained a lack of agreement about influenza's cause for another decade and research on influenza declined.", "After the pandemic, H1N1 circulated in humans in seasonal form up until the next pandemic.", "In 1931, Richard Shope published three papers identifying a virus as the cause of swine influenza, a then newly recognized disease among pigs that was first characterized during the second wave of the 1918 pandemic.", "Shope's research reinvigorated research on human influenza, and many advances in virology, serology, immunology, experimental animal models, vaccinology, and immunotherapy have since arisen from influenza research.", "Just two years after influenza viruses were discovered, in 1933, IAV was identified as the agent responsible for human influenza.", "Subtypes of IAV were discovered throughout the 1930s, and IBV was discovered in 1940.", "During the Second World War, the US government worked on developing inactivated vaccines for influenza, resulting in the first influenza vaccine being licensed in 1945 in the United States.", "ICV was discovered two years later in 1947.", "In 1955, avian influenza was confirmed to be caused by IAV.", "Four influenza pandemics have occurred since WWII, each less severe than the 1918 pandemic.", "The first of these was the Asian flu from 1957 to 1958, caused by an H2N2 strain and beginning in China's Yunnan province.", "The number of deaths probably exceeded one million, mostly among the very young and very old.", "Notably, the 1957 pandemic was the first flu pandemic to occur in the presence of a global surveillance system and laboratories able to study the novel influenza virus.", "After the pandemic, H2N2 was the IAV subtype responsible for seasonal influenza.", "The first antiviral drug against influenza, amantadine, was approved for use in 1966, with additional antiviral drugs being used since the 1990s.", "In 1968, H3N2 was introduced into humans as a result of a reassortment between an avian H3N2 strain and an H2N2 strain that was circulating in humans.", "The novel H3N2 strain first emerged in Hong Kong and spread worldwide, causing the Hong Kong flu pandemic, which resulted in 500,000–2,000,000 deaths.", "This was the first pandemic to spread significantly by air travel.", "H2N2 and H3N2 co-circulated after the pandemic until 1971 when H2N2 waned in prevalence and was completely replaced by H3N2.", "In 1977, H1N1 reemerged in humans, possibly after it was released from a freezer in a laboratory accident, and caused a pseudo-pandemic.", "Whether the 1977 \"pandemic\" deserves to be included in the natural history of flu pandemics is debatable.", "This H1N1 strain was antigenically similar to the H1N1 strains that circulated prior to 1957.", "Since 1977, both H1N1 and H3N2 have circulated in humans as part of seasonal influenza.", "In 1980, the current classification system used to subtype influenza viruses was introduced.", "At some point, IBV diverged into two lineages, named the B/Victoria-like and B/Yamagata-like lineages, both of which have been circulating in humans since 1983.", "In 1996, HPAI H5N1 was detected in Guangdong, China and a year later emerged in poultry in Hong Kong, gradually spreading worldwide from there.", "A small H5N1 outbreak in humans in Hong Kong occurred then, and sporadic human cases have occurred since 1997, carrying a high case fatality rate.", "The most recent flu pandemic was the 2009 swine flu pandemic, which originated in Mexico and resulted in hundreds of thousands of deaths.", "It was caused by a novel H1N1 strain that was a reassortment of human, swine, and avian influenza viruses.", "The 2009 pandemic had the effect of replacing prior H1N1 strains in circulation with the novel strain but not any other influenza viruses.", "Consequently, H1N1, H3N2, and both IBV lineages have been in circulation in seasonal form since the 2009 pandemic.", "In 2011, IDV was discovered in pigs in Oklahoma, USA, and cattle were later identified as the primary reservoir of IDV.", "In the same year, avian H7N9 was detected in China and began to cause human infections in 2013, starting in Shanghai and Anhui and remaining mostly in China.", "HPAI H7N9 emerged sometime in 2016 and has occasionally infected humans incidentally.", "Other AIVs have less commonly infected humans since the 1990s, including H5N6, H6N1, H7N2-4, H7N7, and H10N7-8, and HPAI H subtypes such as H5N1-3, H5N5-6, and H5N8 have begun to spread throughout much of the world since the 2010s.", "Future flu pandemics, which may be caused by an influenza virus of avian origin, are viewed as almost inevitable, and increased globalization has made it easier for novel viruses to spread, so there are continual efforts to prepare for future pandemics and improve the prevention and treatment of influenza.", "The word \"influenza\" comes from the Italian word \"influenza\", from medieval Latin \"influentia\", originally meaning \"visitation\" or \"influence\".", "Terms such as \"influenza di freddo\", meaning \"influence of the cold\", and \"influenza di stelle\", meaning \"influence of the stars\" are attested from the 14th century.", "The latter referred to the disease's cause, which at the time was ascribed by some to unfavorable astrological conditions.", "As early as 1504, \"influenza\" began to mean a \"visitation\" or \"outbreak\" of any disease affecting many people in a single place at once.", "During an outbreak of influenza in 1743 that started in Italy and spread throughout Europe, the word reached the English language and was anglicized in pronunciation.", "Since the mid-1800s, \"influenza\" has also been used to refer to severe colds.", "The shortened form of the word, \"(the) flu\", is first attested in 1839 as \"flue\" with the spelling \"flu\" first attested in 1893.", "Other names that have been used for influenza include \"epidemic catarrh\", \"la grippe\" from French, \"sweating sickness\", and, especially when referring to the 1918 pandemic strain, \"Spanish fever\".", "Influenza research is wide-ranging and includes efforts to understand how influenza viruses enter hosts, the relationship between influenza viruses and bacteria, how influenza symptoms progress, and what make some influenza viruses deadlier than others.", "Non-structural proteins encoded by influenza viruses are periodically discovered and their functions are continually under research.", "Past pandemics, and especially the 1918 pandemic, are the subject of much research to understand flu pandemics.", "As part of pandemic preparedness, the Global Influenza Surveillance and Response System is a global network of laboratories that monitors influenza transmission and epidemiology.", "Additional areas of research include ways to improve the diagnosis, treatment, and prevention of influenza.", "Existing diagnostic methods have a variety of limitations coupled with their advantages.", "For example, NATs have high sensitivity and specificity but are impractical in under-resourced regions due to their high cost, complexity, maintenance, and training required.", "Low-cost, portable RIDTs can rapidly diagnose influenza but have highly variable sensitivity and are unable to subtype IAV.", "As a result of these limitations and others, research into new diagnostic methods revolves around producing new methods that are cost-effective, less labor-intensive, and less complex than existing methods while also being able to differentiate influenza species and IAV subtypes.", "One approach in development are lab-on-a-chips, which are diagnostic devices that make use of a variety of diagnostic tests, such as RT-PCR and serological assays, in microchip form.", "These chips have many potential advantages, including high reaction efficiency, low energy consumption, and low waste generation.", "New antiviral drugs are also in development due to the elimination of adamantines as viable drugs and concerns over oseltamivir resistance.", "These include: NA inhibitors that can be injected intravenously, such as intravenous formulations of zanamivir; favipiravir, which is a polymerase inhibitor used against several RNA viruses; pimodivir, which prevents cap-binding required during viral transcription; and nitazoxanide, which inhibits HA maturation.", "Reducing excess inflammation in the respiratory tract is also subject to much research since this is one of the primary mechanisms of influenza pathology.", "Other forms of therapy in development include monoclonal and polyclonal antibodies that target viral proteins, convalescent plasma, different approaches to modify the host antiviral response, and stem cell-based therapies to repair lung damage.", "Much research on LAIVs focuses on identifying genome sequences that can be deleted to create harmless influenza viruses in vaccines that still confer immunity.", "The high variability and rapid evolution of influenza virus antigens, however, is a major obstacle in developing effective vaccines.", "Furthermore, it is hard to predict which strains will be in circulation during the next flu season, manufacturing a sufficient quantity of flu vaccines for the next season is difficult, LAIVs have limited efficacy, and repeated annual vaccination potentially has diminished efficacy.", "For these reasons, \"broadly-reactive\" or \"universal\" flu vaccines are being researched that can provide protection against many or all influenza viruses.", "Approaches to develop such a vaccine include HA stalk-based methods such as chimeras that have the same stalk but different heads, HA head-based methods such as computationally optimized broadly neutralizing antigens, anti-idiotypic antibodies, and vaccines to elicit immune responses to highly conserved viral proteins.", "mRNA vaccines to provide protection against influenza are also under research.", "Aquatic birds such as ducks, geese, shorebirds, and gulls are the primary reservoir of IAVs.", "In birds, AIVs may be either low pathogenic avian influenza (LPAI) viruses that produce little to no symptoms or highly pathogenic avian influenza (HPAI) viruses that cause severe illness.", "Symptoms of HPAI infection include lack of energy and appetite, decreased egg production, soft-shelled or misshapen eggs, swelling of the head, comb, wattles, and hocks, purple discoloration of wattles, combs, and legs, nasal discharge, coughing, sneezing, incoordination, and diarrhea.", "Birds infected with an HPAI virus may also die suddenly without any signs of infection.", "The distinction between LPAI and HPAI can generally be made based on how lethal an AIV is to chickens.", "At the genetic level, an AIV can be usually be identified as an HPAI virus if it has a multibasic cleavage site in the HA protein, which contains additional residues in the HA gene.", "Most AIVs are LPAI.", "Notable HPAI viruses include HPAI H5N1 and HPAI H7N9.", "HPAI viruses have been a major disease burden in the 21st century, resulting in the death of large numbers of birds.", "In H7N9's case, some circulating strains were originally LPAI but became HPAI by acquiring the HA multibasic cleavage site.", "Avian H9N2 is also of concern because although it is LPAI, it is a common donor of genes to H5N1 and H7N9 during reassortment.", "Migratory birds can spread influenza across long distances.", "An example of this was when an H5N1 strain in 2005 infected birds at Qinghai Lake, China, which is a stopover and breeding site for many migratory birds, subsequently spreading the virus to more than 20 countries across Asia, Europe, and the Middle East.", "AIVs can be transmitted from wild birds to domestic free-range ducks and in turn to poultry through contaminated water, aerosols, and fomites.", "Ducks therefore act as key intermediates between wild and domestic birds.", "Transmission to poultry typically occurs in backyard farming and live animal markets where multiple species interact with each other.", "From there, AIVs can spread to poultry farms in the absence of adequate biosecurity.", "Among poultry, HPAI transmission occurs through aerosols and contaminated feces, cages, feed, and dead animals.", "Back-transmission of HPAI viruses from poultry to wild birds has occurred and is implicated in mass die-offs and intercontinental spread.", "AIVs have occasionally infected humans through aerosols, fomites, and contaminated water.", "Direction transmission from wild birds is rare.", "Instead, most transmission involves domestic poultry, mainly chickens, ducks, and geese but also a variety of other birds such as guinea fowl, partridge, pheasants, and quails.", "The primary risk factor for infection with AIVs is exposure to birds in farms and live poultry markets.", "Typically, infection with an AIV has an incubation period of 3–5 days but can be up to 9 days.", "H5N1 and H7N9 cause severe lower respiratory tract illness, whereas other AIVs such as H9N2 cause a more mild upper respiratory tract illness, commonly with conjunctivitis.", "Limited transmission of avian H2, H5-7, H9, and H10 subtypes from one person to another through respiratory droplets, aerosols, and fomites has occurred, but sustained human-to-human transmission of AIVs has not occurred.", "Before 2013, H5N1 was the most common AIV to infect humans.", "Since then, H7N9 has been responsible for most human cases.", "Influenza in pigs is a respiratory disease similar to influenza in humans and is found worldwide.", "Asymptomatic infections are common.", "Symptoms typically appear 1–3 days after infection and include fever, lethargy, anorexia, weight loss, labored breathing, coughing, sneezing, and nasal discharge.", "In sows, pregnancy may be aborted.", "Complications include secondary infections and potentially fatal bronchopneumonia.", "Pigs become contagious within a day of infection and typically spread the virus for 7–10 days, which can spread rapidly within a herd.", "Pigs usually recover from infection within 3–7 days after symptoms appear.", "Prevention and control measures include inactivated vaccines and culling infected herds.", "The influenza viruses usually responsible for swine flu are IAV subtypes H1N1, H1N2, and H3N2.", "Some IAVs can be transmitted via aerosols from pigs to humans and vice versa.", "Furthermore, pigs, along with bats and quails, are recognized as a mixing vessel of influenza viruses because they have both α-2,3 and α-2,6 sialic acid receptors in their respiratory tract.", "Because of that, both avian and mammalian influenza viruses can infect pigs.", "If co-infection occurs, then reassortment is possible.", "A notable example of this was the reassortment of a swine, avian, and human influenza virus in 2009, resulting in a novel H1N1 strain that caused the 2009 flu pandemic.", "Spillover events from humans to pigs, however, appear to be more common than from pigs to humans.", "Influenza viruses have been found in many other animals, including cattle, horses, dogs, cats, and marine mammals.", "Nearly all IAVs are apparently descended from ancestral viruses in birds.", "The exception are bat influenza-like viruses, which have an uncertain origin.", "These bat viruses have HA and NA subtypes H17, H18, N10, and N11.", "H17N10 and H18N11 are unable to reassort with other IAVs, but they are still able to replicate in other mammals.", "AIVs sometimes crossover into mammals.", "For example, in late 2016 to early 2017, an avian H7N2 strain was found to be infecting cats in New York.", "Equine IAVs include H7N7 and two lineages of H3N8.", "H7N7, however, has not been detected in horses since the late 1970s, so it may have become extinct in horses.", "H3N8 in equines spreads via aerosols and causes respiratory illness.", "Equine H3N8 perferentially binds to α-2,3 sialic acids, so horses are usually considered dead-end hosts, but transmission to dogs and camels has occurred, raising concerns that horses may be mixing vessels for reassortment.", "In canines, the only IAVs in circulation are equine-derived H3N8 and avian-derived H3N2.", "Canine H3N8 has not been observed to reassort with other subtypes.", "H3N2 has a much broader host range and can reassort with H1N1 and H5N1.", "An isolated case of H6N1 likely from a chicken was found infecting a dog, so other AIVs may emerge in canines.", "Other mammals to be infected by IAVs include H7N7 and H4N5 in seals, H1N3 in whales, and H10N4 and H3N2 in minks.", "Various mutations have been identified that are associated with AIVs adapting to mammals.", "Since HA proteins vary in which sialic acids they bind to, mutations in the HA receptor binding site can allow AIVs to infect mammals.", "Other mutations include mutations affecting which sialic acids NA proteins cleave and a mutation in the PB2 polymerase subunit that improves tolerance of lower temperatures in mammalian respiratory tracts and enhances RNP assembly by stabilizing NP and PB2 binding.", "IBV is mainly found in humans but has also been detected in pigs, dogs, horses, and seals.", "Likewise, ICV primarily infects humans but has been observed in pigs, dogs, cattle, and dromedary camels.", "IDV causes an influenza-like illness in pigs but its impact in its natural reservoir, cattle, is relatively unknown.", "It may cause respiratory disease resembling human influenza on its own, or it may be part of a bovine respiratory disease (BRD) complex with other pathogens during co-infection.", "BRD is a concern for the cattle industry, so IDV's possible involvement in BRD has led to research on vaccines for cattle that can provide protection against IDV.", "Two antigenic lineages are in circulation: D/swine/Oklahoma/1334/2011 (D/OK) and D/bovine/Oklahoma/660/2013 (D/660)." ]

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[ "In humans, influenza viruses are primarily transmitted through respiratory droplets produced from coughing and sneezing.", "Transmission through aerosols and intermediate objects and surfaces contaminated by the virus also occur." ]

[ "The time between exposure to the virus and development of symptoms, called the incubation period, is 1–4 days, most commonly 1–2 days.", "Many infections, however, are asymptomatic.", "The onset of symptoms is sudden, and initial symptoms are predominately non-specific, including fever, chills, headaches, muscle pain or aching, a feeling of discomfort, loss of appetite, lack of energy/fatigue, and confusion.", "These symptoms are usually accompanied by respiratory symptoms such as a dry cough, sore or dry throat, hoarse voice, and a stuffy or runny nose.", "Coughing is the most common symptom.", "Gastrointestinal symptoms may also occur, including nausea, vomiting, diarrhea, and gastroenteritis, especially in children.", "The standard influenza symptoms typically last for 2–8 days.", "A 2021 study suggests influenza can cause long lasting symptoms in a similar way to long COVID.\nSymptomatic infections are usually mild and limited to the upper respiratory tract, but progression to pneumonia is relatively common.", "Pneumonia may be caused by the primary viral infection or by a secondary bacterial infection.", "Primary pneumonia is characterized by rapid progression of fever, cough, labored breathing, and low oxygen levels that cause bluish skin.", "It is especially common among those who have an underlying cardiovascular disease such as rheumatic heart disease.", "Secondary pneumonia typically has a period of improvement in symptoms for 1–3 weeks followed by recurrent fever, sputum production, and fluid buildup in the lungs, but can also occur just a few days after influenza symptoms appear.", "About a third of primary pneumonia cases are followed by secondary pneumonia, which is most frequently caused by the bacteria \"Streptococcus pneumoniae\" and \"Staphylococcus aureus\".", "Influenza viruses comprise four species.", "Each of the four species is the sole member of its own genus, and the four influenza genera comprise four of the seven genera in the family \"Orthomyxoviridae\".", "They are:\n\n\nIAV is responsible for most cases of severe illness as well as seasonal epidemics and occasional pandemics.", "It infects people of all ages but tends to disproportionately cause severe illness in the elderly, the very young, and those who have chronic health issues.", "Birds are the primary reservoir of IAV, especially aquatic birds such as ducks, geese, shorebirds, and gulls, but the virus also circulates among mammals, including pigs, horses, and marine mammals.", "IAV is classified into subtypes based on the viral proteins haemagglutinin (H) and neuraminidase (N).", "As of 2019, 18 H subtypes and 11 N subtypes have been identified.", "Most potential combinations have been reported in birds, but H17-18 and N10-11 have only been found in bats.", "Only H subtypes H1-3 and N subtypes N1-2 are known to have circulated in humans, the current IAV subtypes in circulation being H1N1 and H3N2.", "IAVs can be classified more specifically to also include natural host species, geographical origin, year of isolation, and strain number, such as H1N1/A/duck/Alberta/35/76.", "IBV mainly infects humans but has been identified in seals, horses, dogs, and pigs.", "IBV does not have subtypes like IAV but has two antigenically distinct lineages, termed the B/Victoria/2/1987-like and B/Yamagata/16/1988-like lineages, or simply (B/)Victoria(-like) and (B/)Yamagata(-like).", "Both lineages are in circulation in humans, disproportionately affecting children.", "IBVs contribute to seasonal epidemics alongside IAVs but have never been associated with a pandemic.", "ICV, like IBV, is primarily found in humans, though it also has been detected in pigs, feral dogs, dromedary camels, cattle, and dogs.", "ICV infection primarily affects children and is usually asymptomatic or has mild cold-like symptoms, though more severe symptoms such as gastroenteritis and pneumonia can occur.", "Unlike IAV and IBV, ICV has not been a major focus of research pertaining to antiviral drugs, vaccines, and other measures against influenza.", "ICV is subclassified into six genetic/antigenic lineages.", "IDV has been isolated from pigs and cattle, the latter being the natural reservoir.", "Infection has also been observed in humans, horses, dromedary camels, and small ruminants such as goats and sheep.", "IDV is distantly related to ICV.", "While cattle workers have occasionally tested positive to prior IDV infection, it is not known to cause disease in humans.", "ICV and IDV experience a slower rate of antigenic evolution than IAV and IBV.", "Because of this antigenic stability, relatively few novel lineages emerge.", "Influenza viruses have a negative-sense, single-stranded RNA genome that is segmented.", "The negative sense of the genome means it can be used as a template to synthesize messenger RNA (mRNA).", "IAV and IBV have eight genome segments that encode 10 major proteins.", "ICV and IDV have seven genome segments that encode nine major proteins.", "Three segments encode three subunits of an RNA-dependent RNA polymerase (RdRp) complex: PB1, a transcriptase, PB2, which recognizes 5' caps, and PA (P3 for ICV and IDV), an endonuclease.", "The matrix protein (M1) and membrane protein (M2) share a segment, as do the non-structural protein (NS1) and the nuclear export protein (NEP).", "For IAV and IBV, hemagglutinin (HA) and neuraminidase (NA) are encoded on one segment each, whereas ICV and IDV encode a hemagglutinin-esterase fusion (HEF) protein on one segment that merges the functions of HA and NA.", "The final genome segment encodes the viral nucleoprotein (NP).", "Influenza viruses also encode various accessory proteins, such as PB1-F2 and PA-X, that are expressed through alternative open reading frames and which are important in host defense suppression, virulence, and pathogenicity.", "The virus particle, called a virion, is pleomorphic and varies between being filamentous, bacilliform, or spherical in shape.", "Clinical isolates tend to be pleomorphic, whereas strains adapted to laboratory growth typically produce spherical virions.", "Filamentous virions are about 250 nanometers (nm) by 80 nm, bacilliform 120–250 by 95 nm, and spherical 120 nm in diameter.", "The virion consists of each segment of the genome bound to nucleoproteins in separate ribonucleoprotein (RNP) complexes for each segment, all of which are surrounded by a lipid bilayer membrane called the viral envelope.", "There is a copy of the RdRp, all subunits included, bound to each RNP.", "The envelope is reinforced structurally by matrix proteins on the interior that enclose the RNPs, and the envelope contains HA and NA (or HEF) proteins extending outward from the exterior surface of the envelope.", "HA and HEF proteins have a distinct \"head\" and \"stalk\" structure.", "M2 proteins form proton ion channels through the viral envelope that are required for viral entry and exit.", "IBVs contain a surface protein named NB that is anchored in the envelope, but its function is unknown.", "The viral life cycle begins by binding to a target cell.", "Binding is mediated by the viral HA proteins on the surface of the evelope, which bind to cells that contain sialic acid receptors on the surface of the cell membrane.", "For N1 subtypes with the \"G147R\" mutation and N2 subtypes, the NA protein can initiate entry.", "Prior to binding, NA proteins promote access to target cells by degrading mucous, which helps to remove extracellular decoy receptors that would impede access to target cells.", "After binding, the virus is internalized into the cell by an endosome that contains the virion inside it.", "The endosome is acidified by cellular vATPase to have lower pH, which triggers a conformational change in HA that allows fusion of the viral envelope with the endosomal membrane.", "At the same time, hydrogen ions diffuse into the virion through M2 ion channels, disrupting internal protein-protein interactions to release RNPs into the host cell's cytosol.", "The M1 protein shell surrounding RNPs is degraded, fully uncoating RNPs in the cytosol.", "RNPs are then imported into the nucleus with the help of viral localization signals.", "There, the viral RNA polymerase transcribes mRNA using the genomic negative-sense strand as a template.", "The polymerase snatches 5' caps for viral mRNA from cellular RNA to prime mRNA synthesis and the 3'-end of mRNA is polyadenylated at the end of transcription.", "Once viral mRNA is transcribed, it is exported out of the nucleus and translated by host ribosomes in a cap-dependent manner to synthesize viral proteins.", "RdRp also synthesizes complementary positive-sense strands of the viral genome in a complementary RNP complex which are then used as templates by viral polymerases to synthesize copies of the negative-sense genome.", "During these processes, RdRps of avian influenza viruses (AIVs) function optimally at a higher temperature than mammalian influenza viruses.", "Newly synthesized viral polymerase subunits and NP proteins are imported to the nucleus to further increase the rate of viral replication and form RNPs.", "HA, NA, and M2 proteins are trafficked with the aid of M1 and NEP proteins to the cell membrane through the Golgi apparatus and inserted into the cell's membrane.", "Viral non-structural proteins including NS1, PB1-F2, and PA-X regulate host cellular processes to disable antiviral responses.", "PB1-F2 aso interacts with PB1 to keep polymerases in the nucleus longer.", "M1 and NEP proteins localize to the nucleus during the later stages of infection, bind to viral RNPs and mediate their export to the cytoplasm where they migrate to the cell membrane with the aid of recycled endosomes and are bundled into the segments of the genome.", "Progenic viruses leave the cell by budding from the cell membrane, which is initiated by the accumulation of M1 proteins at the cytoplasmic side of the membrane.", "The viral genome is incorporated inside a viral envelope derived from portions of the cell membrane that have HA, NA, and M2 proteins.", "At the end of budding, HA proteins remain attached to cellular sialic acid until they are cleaved by the sialidase activity of NA proteins.", "The virion is then released from the cell.", "The sialidase activity of NA also cleaves any sialic acid residues from the viral surface, which helps prevent newly assembled viruses from aggregating near the cell surface and improving infectivity.", "Similar to other aspects of influenza replication, optimal NA activity is temperature- and pH-dependent.", "Ultimately, presence of large quantities of viral RNA in the cell triggers apoptosis, i.e. programmed cell death, which is initiated by cellular factors to restrict viral replication.", "Two key processes that influenza viruses evolve through are antigenic drift and antigenic shift.", "Antigenic drift is when an influenza virus's antigens change due to the gradual accumulation of mutations in the antigen's (HA or NA) gene.", "This can occur in response to evolutionary pressure exerted by the host immune response.", "Antigenic drift is especially common for the HA protein, in which just a few amino acid changes in the head region can constitute antigenic drift.", "The result is the production of novel strains that can evade pre-existing antibody-mediated immunity.", "Antigenic drift occurs in all influenza species but is slower in B than A and slowest in C and D. Antigenic drift is a major cause of seasonal influenza, and requires that flu vaccines be updated annually.", "HA is the main component of inactivated vaccines, so surveillance monitors antigenic drift of this antigen among circulating strains.", "Antigenic evolution of influenza viruses of humans appears to be faster than influenza viruses in swine and equines.", "In wild birds, within-subtype antigenic variation appears to be limited but has been observed in poultry.", "Antigenic shift is a sudden, drastic change in an influenza virus's antigen, usually HA.", "During antigenic shift, antigenically different strains that infect the same cell can reassort genome segments with each other, producing hybrid progeny.", "Since all influenza viruses have segmented genomes, all are capable of reassortment.", "Antigenic shift, however, only occurs among influenza viruses of the same genus and most commonly occurs among IAVs.", "In particular, reassortment is very common in AIVs, creating a large diversity of influenza viruses in birds, but is uncommon in human, equine, and canine lineages.", "Pigs, bats, and quails have receptors for both mammalian and avian IAVs, so they are potential \"mixing vessels\" for reassortment.", "If an animal strain reassorts with a human strain, then a novel strain can emerge that is capable of human-to-human transmission.", "This has caused pandemics, but only a limited number have occurred, so it is difficult to predict when the next will happen.", "People who are infected can transmit influenza viruses through breathing, talking, coughing, and sneezing, which spread respiratory droplets and aerosols that contain virus particles into the air.", "A person susceptible to infection can then contract influenza by coming into contact with these particles.", "Respiratory droplets are relatively large and travel less than two meters before falling onto nearby surfaces.", "Aerosols are smaller and remain suspended in the air longer, so they take longer to settle and can travel further than respiratory droplets.", "Inhalation of aerosols can lead to infection, but most transmission is in the area about two meters around an infected person via respiratory droplets that come into contact with mucosa of the upper respiratory tract.", "Transmission through contact with a person, bodily fluids, or intermediate objects (fomites) can also occur, such as through contaminated hands and surfaces since influenza viruses can survive for hours on non-porous surfaces.", "If one's hands are contaminated, then touching one's face can cause infection.", "Influenza is usually transmissible from one day before the onset of symptoms to 5–7 days after.", "In healthy adults, the virus is shed for up to 3–5 days.", "In children and the immunocompromised, the virus may be transmissible for several weeks.", "Children ages 2–17 are considered to be the primary and most efficient spreaders of influenza.", "Children who have not had multiple prior exposures to influenza viruses shed the virus at greater quantities and for a longer duration than other children.", "People who are at risk of exposure to influenza include health care workers, social care workers, and those who live with or care for people vulnerable to influenza.", "In long-term care facilities, the flu can spread rapidly after it is introduced.", "A variety of factors likely encourage influenza transmission, including lower temperature, lower absolute and relative humidity, less ultraviolet radiation from the Sun, and crowding.", "Influenza viruses that infect the upper respiratory tract like H1N1 tend to be more mild but more transmissible, whereas those that infect the lower respiratory tract like H5N1 tend to cause more severe illness but are less contagious.", "In humans, influenza viruses first cause infection by infecting epithelial cells in the respiratory tract.", "Illness during infection is primarily the result of lung inflammation and compromise caused by epithelial cell infection and death, combined with inflammation caused by the immune system's response to infection.", "Non-respiratory organs can become involved, but the mechanisms by which influenza is involved in these cases are unknown.", "Severe respiratory illness can be caused by multiple, non-exclusive mechanisms, including obstruction of the airways, loss of alveolar structure, loss of lung epithelial integrity due to epithelial cell infection and death, and degradation of the extracellular matrix that maintains lung structure.", "In particular, alveolar cell infection appears to drive severe symptoms since this results in impaired gas exchange and enables viruses to infect endothelial cells, which produce large quantities of pro-inflammatory cytokines.", "Pneumonia caused by influenza viruses is characterized by high levels of viral replication in the lower respiratory tract, accompanied by a strong pro-inflammatory response called a cytokine storm.", "Infection with H5N1 or H7N9 especially produces high levels of pro-inflammatory cytokines.", "In bacterial infections, early depletion of macrophages during influenza creates a favorable environment in the lungs for bacterial growth since these white blood cells are important in responding to bacterial infection.", "Host mechanisms to encourage tissue repair may inadvertently allow bacterial infection.", "Infection also induces production of systemic glucocorticoids that can reduce inflammation to preserve tissue integrity but allow increased bacterial growth.", "The pathophysiology of influenza is significantly influenced by which receptors influenza viruses bind to during entry into cells.", "Mammalian influenza viruses preferentially bind to sialic acids connected to the rest of the oligosaccharide by an α-2,6 link, most commonly found in various respiratory cells, such as respiratory and retinal epithelial cells.", "AIVs prefer sialic acids with an α-2,3 linkage, which are most common in birds in gastrointestinal epithelial cells and in humans in the lower respiratory tract.", "Furthermore, cleavage of the HA protein into HA, the binding subunit, and HA, the fusion subunit, is performed by different proteases, affecting which cells can be infected.", "For mammalian influenza viruses and low pathogenic AIVs, cleavage is extracellular, which limits infection to cells that have the appropriate proteases, whereas for highly pathogenic AIVs, cleavage is intracellular and performed by ubiquitous proteases, which allows for infection of a greater variety of cells, thereby contributing to more severe disease.", "Cells possess sensors to detect viral RNA, which can then induce interferon production.", "Interferons mediate expression of antiviral proteins and proteins that recruit immune cells to the infection site, and they also notify nearby uninfected cells of infection.", "Some infected cells release pro-inflammatory cytokines that recruit immune cells to the site of infection.", "Immune cells control viral infection by killing infected cells and phagocytizing viral particles and apoptotic cells.", "An exacerbated immune response, however, can harm the host organism through a cytokine storm.", "To counter the immune response, influenza viruses encode various non-structural proteins, including NS1, NEP, PB1-F2, and PA-X, that are involved in curtailing the host immune response by suppressing interferon production and host gene expression.", "B cells, a type of white blood cell, produce antibodies that bind to influenza antigens HA and NA (or HEF) and other proteins to a lesser degree.", "Once bound to these proteins, antibodies block virions from binding to cellular receptors, neutralizing the virus.", "In humans, a sizeable antibody response occurs ~1 week after viral exposure.", "This antibody response is typically robust and long-lasting, especially for ICV and IDV.", "In other words, people exposed to a certain strain in childhood still possess antibodies to that strain at a reasonable level later in life, which can provide some protection to related strains.", "There is, however, an \"original antigenic sin\", in which the first HA subtype a person is exposed to influences the antibody-based immune response to future infections and vaccines.", "Annual vaccination is the primary and most effective way to prevent influenza and influenza-associated complications, especially for high-risk groups.", "Vaccines against the flu are trivalent or quadrivalent, providing protection against an H1N1 strain, an H3N2 strain, and one or two IBV strains corresponding to the two IBV lineages.", "Two types of vaccines are in use: inactivated vaccines that contain \"killed\" (i.e. inactivated) viruses and live attenuated influenza vaccines (LAIVs) that contain weakened viruses.", "There are three types of inactivated vaccines: whole virus, split virus, in which the virus is disrupted by a detergent, and subunit, which only contains the viral antigens HA and NA.", "Most flu vaccines are inactivated and administered via intramuscular injection.", "LAIVs are sprayed into the nasal cavity.", "Vaccination recommendations vary by country.", "Some recommend vaccination for all people above a certain age, such as 6 months, whereas other countries recommendation is limited for high at risk groups, such as pregnant women, young children (excluding newborns), the elderly, people with chronic medical conditions, health care workers, people who come into contact with high-risk people, and people who transmit the virus easily.", "Young infants cannot receive flu vaccines for safety reasons, but they can inherit passive immunity from their mother if inactivated vaccines are administered to the mother during pregnancy.", "Influenza vaccination also helps to reduce the probability of reassortment.", "In general, influenza vaccines are only effective if there is an antigenic match between vaccine strains and circulating strains.", "Additionally, most commercially available flu vaccines are manufactured by propagation of influenza viruses in embryonated chicken eggs, taking 6–8 months.", "Flu seasons are different in the northern and southern hemisphere, so the WHO meets twice a year, one for each hemisphere, to discuss which strains should be included in flu vaccines based on observation from HA inhibition assays.", "Other manufacturing methods include an MDCK cell culture-based inactivated vaccine and a recombinant subunit vaccine manufactured from baculovirus overexpression in insect cells.", "Influenza can be prevented or reduced in severity by post-exposure prophylaxis with the antiviral drugs oseltamivir, which can be taken orally by those at least three months old, and zanamivir, which can be inhaled by those above seven years of age.", "Chemoprophylaxis is most useful for individuals at high-risk of developing complications and those who cannot receive the flu vaccine due to contraindications or lack of effectiveness.", "Post-exposure chemoprophylaxis is only recommended if oseltamivir is taken within 48 hours of contact with a confirmed or suspected influenza case and zanamivir within 36 hours.", "It is recommended that it be offered to people who have yet to receive a vaccine for the current flu season, who have been vaccinated less than two week since contact, if there is a significant mismatch between vaccine and circulating strains, or during an outbreak in a closed setting regardless of vaccination history.", "Hand hygiene is important in reducing the spread of influenza.", "This includes frequent hand washing with soap and water, using alcohol-based hand sanitizers, and not touching one's eyes, nose, and mouth with one's hands.", "Covering one's nose and mouth when coughing or sneezing is important.", "Other methods to limit influenza transmission include staying home when sick, avoiding contact with others until one day after symptoms end, and disinfecting surfaces likely to be contaminated by the virus, such as doorknobs.", "Health education through media and posters is often used to remind people of the aforementioned etiquette and hygiene.", "There is uncertainty about the use of masks since research thus far has not shown a significant reduction in seasonal influenza with mask usage.", "Likewise, the effectiveness of screening at points of entry into countries is not well researched.", "Social distancing measures such as school closures, avoiding contact with infected people via isolation or quarantine, and limiting mass gatherings may reduce transmission, but these measures are often expensive, unpopular, and difficult to implement.", "Consequently, the commonly recommended methods of infection control are respiratory etiquette, hand hygiene, and mask wearing, which are inexpensive and easy to perform.", "Pharmaceutical measures are effective but may not be available in the early stages of an outbreak.", "In health care settings, infected individuals may be cohorted or assigned to individual rooms.", "Protective clothing such as masks, gloves, and gowns is recommended when coming into contact with infected individuals if there is a risk of exposure to infected bodily fluids.", "Keeping patients in negative pressure rooms and avoiding aerosol-producing activities may help, but special air handling and ventilation systems are not considered necessary to prevent the spread of influenza in the air.", "In residential homes, new admissions may need to be closed until the spread of influenza is controlled.", "When discharging patients to care homes, it is important to take care if there is a known influenza outbreak.", "Since influenza viruses circulate in animals such as birds and pigs, prevention of transmission from these animals is important.", "Water treatment, indoor raising of animals, quarantining sick animals, vaccination, and biosecurity are the primary measures used.", "Placing poultry houses and piggeries on high ground away from high-density farms, backyard farms, live poultry markets, and bodies of water helps to minimize contact with wild birds.", "Closure of live poultry markets appears to the most effective measure and has shown to be effective at controlling the spread of H5N1, H7N9, and H9N2.", "Other biosecurity measures include cleaning and disinfecting facilities and vehicles, banning visits to poultry farms, not bringing birds intended for slaughter back to farms, changing clothes, disinfecting foot baths, and treating food and water.", "If live poultry markets are not closed, then \"clean days\" when unsold poultry is removed and facilities are disinfected and \"no carry-over\" policies to eliminate infectious material before new poultry arrive can be used to reduce the spread of influenza viruses.", "If a novel influenza viruses has breached the aforementioned biosecurity measures, then rapid detection to stamp it out via quarantining, decontamination, and culling may be necessary to prevent the virus from becoming endemic.", "Vaccines exist for avian H5, H7, and H9 subtypes that are used in some countries.", "In China, for example, vaccination of domestic birds against H7N9 successfully limited its spread, indicating that vaccination may be an effective strategy if used in combination with other measures to limit transmission.", "In pigs and horses, management of influenza is dependent on vaccination with biosecurity.", "Diagnosis based on symptoms is fairly accurate in otherwise healthy people during seasonal epidemics and should be suspected in cases of pneumonia, acute respiratory distress syndrome (ARDS), sepsis, or if encephalitis, myocarditis, or breaking down of muscle tissue occur.", "Because influenza is similar to other viral respiratory tract illnesses, laboratory diagnosis is necessary for confirmation.", "Common ways of collecting samples for testing include nasal and throat swabs.", "Samples may be taken from the lower respiratory tract if infection has cleared the upper but not lower respiratory tract.", "Influenza testing is recommended for anyone hospitalized with symptoms resembling influenza during flu season or who is connected to an influenza case.", "For severe cases, earlier diagnosis improves patient outcome.", "Diagnostic methods that can identify influenza include viral cultures, antibody- and antigen-detecting tests, and nucleic acid-based tests.", "Viruses can be grown in a culture of mammalian cells or embryonated eggs for 3–10 days to monitor cytopathic effect.", "Final confirmation can then be done via antibody staining, hemadsorption using red blood cells, or immunofluorescence microscopy.", "Shell vial cultures, which can identify infection via immunostaining before a cytopathic effect appears, are more sensitive than traditional cultures with results in 1–3 days.", "Cultures can be used to characterize novel viruses, observe sensitivity to antiviral drugs, and monitor antigenic drift, but they are relatively slow and require specialized skills and equipment.", "Serological assays can be used to detect an antibody response to influenza after natural infection or vaccination.", "Common serological assays include hemagglutination inhibition assays that detect HA-specific antibodies, virus neutralization assays that check whether antibodies have neutralized the virus, and enzyme-linked immunoabsorbant assays.", "These methods tend to be relatively inexpensive and fast but are less reliable than nucleic-acid based tests.", "Direct fluorescent or immunofluorescent antibody (DFA/IFA) tests involve staining respiratory epithelial cells in samples with fluorescently-labeled influenza-specific antibodies, followed by examination under a fluorescent microscope.", "They can differentiate between IAV and IBV but can't subtype IAV.", "Rapid influenza diagnostic tests (RIDTs) are a simple way of obtaining assay results, are low cost, and produce results quickly, at less than 30 minutes, so they are commonly used, but they can't distinguish between IAV and IBV or between IAV subtypes and are not as sensitive as nucleic-acid based tests.", "Nucleic acid-based tests (NATs) amplify and detect viral nucleic acid.", "Most of these tests take a few hours, but rapid molecular assays are as fast as RIDTs.", "Among NATs, reverse transcription polymerase chain reaction (RT-PCR) is the most traditional and considered the gold standard for diagnosing influenza because it is fast and can subtype IAV, but it is relatively expensive and more prone to false-positives than cultures.", "Other NATs that have been used include loop-mediated isothermal amplification-based assays, simple amplification-based assays, and nucleic acid sequence-based amplification.", "Nucleic acid sequencing methods can identify infection by obtaining the nucleic acid sequence of viral samples to identify the virus and antiviral drug resistance.", "The traditional method is Sanger sequencing, but it has been largely replaced by next-generation methods that have greater sequencing speed and throughput.", "Treatment of influenza in cases of mild or moderate illness is supportive and includes anti-fever medications such as acetaminophen and ibuprofen, adequate fluid intake to avoid dehydration, and resting at home.", "Cough drops and throat sprays may be beneficial for sore throat.", "It is recommended to avoid alcohol and tobacco use while sick with the flu.", "Aspirin is not recommended to treat influenza in children due to an elevated risk of developing Reye syndrome.", "Corticosteroids likewise are not recommended except when treating septic shock or an underlying medical condition, such as chronic obstructive pulmonary disease or asthma exacerbation, since they are associated with increased mortality.", "If a secondary bacterial infection occurs, then treatment with antibiotics may be necessary.", "Antiviral drugs are primarily used to treat severely ill patients, especially those with compromised immune systems.", "Antivirals are most effective when started in the first 48 hours after symptoms appear.", "Later administration may still be beneficial for those who have underlying immune defects, those with more severe symptoms, or those who have a higher risk of developing complications if these individuals are still shedding the virus.", "Antiviral treatment is also recommended if a person is hospitalized with suspected influenza instead of waiting for test results to return and if symptoms are worsening.", "Most antiviral drugs against influenza fall into two categories: neuraminidase (NA) inhibitors and M2 inhibitors.", "Baloxavir marboxil is a notable exception, which targets the endonuclease activity of the viral RNA polymerase and can be used as an alternative to NA and M2 inhibitors for IAV and IBV.", "NA inhibitors target the enzymatic activity of NA receptors, mimicking the binding of sialic acid in the active site of NA on IAV and IBV virions so that viral release from infected cells and the rate of viral replication are impaired.", "NA inhibitors include oseltamivir, which is consumed orally in a prodrug form and converted to its active form in the liver, and zanamivir, which is a powder that is inhaled nasally.", "Oseltamivir and zanamivir are effective for prophylaxis and post-exposure prophylaxis, and research overall indicates that NA inhibitors are effective at reducing rates of complications, hospitalization, and mortality and the duration of illness.", "Additionally, the earlier NA inhibitors are provided, the better the outcome, though late administration can still be beneficial in severe cases.", "Other NA inhibitors include laninamivir and peramivir, the latter of which can be used as an alternative to oseltamivir for people who cannot tolerate or absorb it.", "The adamantanes amantadine and rimantadine are orally administered drugs that block the influenza virus's M2 ion channel, preventing viral uncoating.", "These drugs are only functional against IAV but are no longer recommended for use because of widespread resistance to them among IAVs.", "Adamantane resistance first emerged in H3N2 in 2003, becoming worldwide by 2008.", "Oseltamivir resistance is no longer widespread because the 2009 pandemic H1N1 strain (H1N1 pdm09), which is resistant to adamantanes, seemingly replaced resistant strains in circulation.", "Since the 2009 pandemic, oseltamivir resistance has mainly been observed in patients undergoing therapy, especially the immunocompromised and young children.", "Oseltamivir resistance is usually reported in H1N1, but has been reported in H3N2 and IBVs less commonly.", "Because of this, oseltamivir is recommended as the first drug of choice for immunocompetent people, whereas for the immunocompromised, oseltamivir is recommended against H3N2 and IBV and zanamivir against H1N1 pdm09.", "Zanamivir resistance is observed less frequently, and resistance to peramivir and baloxavir marboxil is possible.", "In healthy individuals, influenza infection is usually self-limiting and rarely fatal.", "Symptoms usually last for 2–8 days.", "Influenza can cause people to miss work or school, and it is associated with decreased job performance and, in older adults, reduced independence.", "Fatigue and malaise may last for several weeks after recovery, and healthy adults may experience pulmonary abnormalities that can take several weeks to resolve.", "Complications and mortality primarily occur in high-risk populations and those who are hospitalized.", "Severe disease and mortality are usually attributable to pneumonia from the primary viral infection or a secondary bacterial infection, which can progress to ARDS.", "Other respiratory complications that may occur include sinusitis, bronchitis, bronchiolitis, excess fluid buildup in the lungs, and exacerbation of chronic bronchitis and asthma.", "Middle ear infection and croup may occur, most commonly in children.", "Secondary \"S. aureus\" infection has been observed, primarily in children, to cause toxic shock syndrome after influenza, with hypotension, fever, and reddening and peeling of the skin.", "Complications affecting the cardiovascular system are rare and include pericarditis, fulminant myocarditis with a fast, slow, or irregular heartbeat, and exacerbation of pre-existing cardiovascular disease.", "Inflammation or swelling of muscles accompanied by muscle tissue breaking down occurs rarely, usually in children, which presents as extreme tenderness and muscle pain in the legs and a reluctance to walk for 2–3 days.", "Influenza can affect pregnancy, including causing smaller neonatal size, increased risk of premature birth, and an increased risk of child death shortly before or after birth.", "Neurological complications have been associated with influenza on rare occasions, including aseptic meningitis, encephalitis, disseminated encephalomyelitis, transverse myelitis, and Guillain–Barré syndrome.", "Additionally, febrile seizures and Reye syndrome can occur, most commonly in children.", "Influenza-associated encephalopathy can occur directly from central nervous system infection from the presence of the virus in blood and presents as suddent onset of fever with convulsions, followed by rapid progression to coma.", "An atypical form of encephalitis called encephalitis lethargica, characterized by headache, drowsiness, and coma, may rarely occur sometime after infection.", "In survivors of influenza-associated encephalopathy, neurological defects may occur.", "Primarily in children, in severe cases the immune system may rarely dramatically overproduce white blood cells that release cytokines, causing severe inflammation.", "People who are at least 65 years of age, due to a weakened immune system from aging or a chronic illness, are a high-risk group for developing complications, as are children less than one year of age and children who have not been previously exposed to influenza viruses multiple times.", "Pregnant women are at an elevated risk, which increases by trimester and lasts up to two weeks after childbirth.", "Obesity, in particular a body mass index greater than 35–40, is associated with greater amounts of viral replication, increased severity of secondary bacterial infection, and reduced vaccination efficacy.", "People who have underlying health conditions are also considered at-risk, including those who have congenital or chronic heart problems or lung (e.g. asthma), kidney, liver, blood, neurological, or metabolic (e.g. diabetes) disorders, as are people who are immunocompromised from chemotherapy, asplenia, prolonged steroid treatment, splenic dysfunction, or HIV infection.", "Current or past tobacco use also places a person at risk.", "The role of genetics in influenza is not well researched, but it may be a factor in influenza mortality.", "Influenza is typically characterized by seasonal epidemics and sporadic pandemics.", "Most of the burden of influenza is a result of flu seasons caused by IAV and IBV.", "Among IAV subtypes, H1N1 and H3N2 currently circulate in humans and are responsible for seasonal influenza.", "Cases disproportionately occur in children, but most severe causes are among the elderly, the very young, and the immunocompromised.", "In a typical year, influenza viruses infect 5–15% of the global population, causing 3–5 million cases of severe illness annually and accounting for 290,000–650,000 deaths each year due to respiratory illness.", "5–10% of adults and 20–30% of children contract influenza each year.", "The reported number of influenza cases is usually much lower than the actual number of cases.", "During seasonal epidemics, it is estimated that about 80% of otherwise healthy people who have a cough or sore throat have the flu.", "Approximately 30–40% of people hospitalized for influenza develop pneumonia, and about 5% of all severe pneumonia cases in hospitals are due to influenza, which is also the most common cause of ARDS in adults.", "In children, influenza is one of the two most common causes of ARDS, the other being the respiratory syncytial virus.", "About 3–5% of children each year develop otitis media due to influenza.", "Adults who develop organ failure from influenza and children who have PIM scores and acute renal failure have higher rates of mortality.", "During seasonal influenza, mortality is concentrated in the very young and the elderly, whereas during flu pandemics, young adults are often affected at a high rate.", "In temperate regions, the number of influenza cases varies from season to season.", "Lower vitamin D levels, presumably due to less sunlight, lower humidity, lower temperature, and minor changes in virus proteins caused by antigenic drift contribute to annual epidemics that peak during the winter season.", "In the northern hemisphere, this is from October to May (more narrowly December to April), and in the southern hemisphere, this is from May to October (more narrowly June to September).", "There are therefore two distinct influenza seasons every year in temperate regions, one in the northern hemisphere and one in the southern hemisphere.", "In tropical and subtropical regions, seasonality is more complex and appears to be affected by various climatic factors such as minimum temperature, hours of sunshine, maximum rainfall, and high humidity.", "Influenza may therefore occur year-round in these regions.", "Influenza epidemics in modern times have the tendency to start in the eastern or southern hemisphere, with Asia being a key reservoir of influenza viruses.", "IAV and IBV co-circulate, so the two have the same patterns of transmission.", "The seasonality of ICV, however, is poorly understood.", "ICV infection is most common in children under the age of 2, and by adulthood most people have been exposed to it.", "ICV-associated hospitalization most commonly occurs in children under the age of 3 and is frequently accompanied by co-infection with another virus or a bacterium, which may increase the severity of disease.", "When considering all hospitalizations for respiratory illness among young children, ICV appears to account for only a small percentage of such cases.", "Large outbreaks of ICV infection can occur, so incidence varies significantly.", "Outbreaks of influenza caused by novel influenza viruses are common.", "Depending on the level of pre-existing immunity in the population, novel influenza viruses can spread rapidly and cause pandemics with millions of deaths.", "These pandemics, in contrast to seasonal influenza, are caused by antigenic shifts involving animal influenza viruses.", "To date, all known flu pandemics have been caused by IAVs, and they follow the same pattern of spreading from an origin point to the rest of the world over the course of multiple waves in a year.", "Pandemic strains tend to be associated with higher rates of pneumonia in otherwise healthy individuals.", "Generally after each influenza pandemic, the pandemic strain continues to circulate as the cause of seasonal influenza, replacing prior strains.", "From 1700 to 1889, influenza pandemics occurred about once every 50–60 years.", "Since then, pandemics have occurred about once every 10–50 years, so they may be getting more frequent over time.", "It is impossible to know when an influenza virus first infected humans or when the first influenza pandemic occurred.", "Possibly the first influenza epidemic occurred around 6,000 BC in China, and possible descriptions of influenza exist in Greek writings from the 5th century BC.", "In both 1173–1174 AD and 1387 AD, epidemics occurred across Europe that were named \"influenza\".", "Whether these epidemics and others were caused by influenza is unclear since there was no consistent naming pattern for epidemic respiratory diseases at that time, and \"influenza\" didn't become completely attached to respiratory disease until centuries later.", "Influenza may have been brought to the Americas as early as 1493, when an epidemic disease resembling influenza killed most of the population of the Antilles.", "The first convincing record of an influenza pandemic was chronicled in 1510; it began in East Asia before spreading to North Africa and then Europe.", "Following the pandemic, seasonal influenza occurred, with subsequent pandemics in 1557 and 1580.", "The flu pandemic in 1557 was potentially the first time influenza was connected to miscarriage and death of pregnant women.", "The 1580 flu pandemic originated in Asia during summer, spread to Africa, then Europe, and finally America.", "By the end of the 16th century, influenza was likely beginning to become understood as a specific, recognizable disease with epidemic and endemic forms.", "In 1648, it was discovered that horses also experience influenza.", "Influenza data after 1700 is more informative, so it is easier to identify flu pandemics after this point, each of which incrementally increased understanding of influenza.", "The first flu pandemic of the 18th century started in 1729 in Russia in spring, spreading worldwide over the course of three years with distinct waves, the later ones being more lethal.", "The second flu pandemic of the 18th century was in 1781–1782, starting in China in autumn.", "From this pandemic, influenza became associated with sudden outbreaks of febrile illness.", "The next flu pandemic was from 1830 to 1833, beginning in China in winter.", "This pandemic had a high attack rate, but the mortality rate was low.", "A minor influenza pandemic occurred from 1847 to 1851 at the same time as the third cholera pandemic and was the first flu pandemic to occur with vital statistics being recorded, so influenza mortality was clearly recorded for the first time.", "Highly pathogenic avian influenza was recognized in 1878 and was soon linked to transmission to humans.", "By the time of the 1889 pandemic, which may have been caused by an H2N2 strain, the flu had become an easily recognizable disease.", "Initially, the microbial agent responsible for influenza was incorrently identified in 1892 by R. F. J. Pfeiffer as the bacteria species \"Haemophilus influenzae\", which retains \"influenza\" in its name.", "In the following years, the field of virology began to form as viruses were identified as the cause of many diseases.", "From 1901 to 1903, Italian and Austrian researchers were able to show that avian influenza, then called \"fowl plague\", was caused by a microscopic agent smaller than bacteria by using filters with pores too small for bacteria to pass through.", "The fundamental differences between viruses and bacteria, however, were not yet fully understood.", "From 1918 to 1920, the Spanish flu pandemic became the most devastating influenza pandemic and one of the deadliest pandemics in history.", "The pandemic, probably caused by H1N1, likely began in the USA before spreading worldwide by soldiers during and after the First World War.", "The initial wave in the first half of 1918 was relatively minor and resembled past flu pandemics, but the second wave later that year had a much higher mortality rate, accounting for most deaths.", "A third wave with lower mortality occurred in many places a few months after the second.", "By the end of 1920, it is estimated that about a third to half of all people in the world had been infected, with tens of millions of deaths, disproportionately young adults.", "During the 1918 pandemic, the respiratory route of transmission was clearly identified and influenza was shown to be caused by a \"filter passer\", not a bacterium, but there remained a lack of agreement about influenza's cause for another decade and research on influenza declined.", "After the pandemic, H1N1 circulated in humans in seasonal form up until the next pandemic.", "In 1931, Richard Shope published three papers identifying a virus as the cause of swine influenza, a then newly recognized disease among pigs that was first characterized during the second wave of the 1918 pandemic.", "Shope's research reinvigorated research on human influenza, and many advances in virology, serology, immunology, experimental animal models, vaccinology, and immunotherapy have since arisen from influenza research.", "Just two years after influenza viruses were discovered, in 1933, IAV was identified as the agent responsible for human influenza.", "Subtypes of IAV were discovered throughout the 1930s, and IBV was discovered in 1940.", "During the Second World War, the US government worked on developing inactivated vaccines for influenza, resulting in the first influenza vaccine being licensed in 1945 in the United States.", "ICV was discovered two years later in 1947.", "In 1955, avian influenza was confirmed to be caused by IAV.", "Four influenza pandemics have occurred since WWII, each less severe than the 1918 pandemic.", "The first of these was the Asian flu from 1957 to 1958, caused by an H2N2 strain and beginning in China's Yunnan province.", "The number of deaths probably exceeded one million, mostly among the very young and very old.", "Notably, the 1957 pandemic was the first flu pandemic to occur in the presence of a global surveillance system and laboratories able to study the novel influenza virus.", "After the pandemic, H2N2 was the IAV subtype responsible for seasonal influenza.", "The first antiviral drug against influenza, amantadine, was approved for use in 1966, with additional antiviral drugs being used since the 1990s.", "In 1968, H3N2 was introduced into humans as a result of a reassortment between an avian H3N2 strain and an H2N2 strain that was circulating in humans.", "The novel H3N2 strain first emerged in Hong Kong and spread worldwide, causing the Hong Kong flu pandemic, which resulted in 500,000–2,000,000 deaths.", "This was the first pandemic to spread significantly by air travel.", "H2N2 and H3N2 co-circulated after the pandemic until 1971 when H2N2 waned in prevalence and was completely replaced by H3N2.", "In 1977, H1N1 reemerged in humans, possibly after it was released from a freezer in a laboratory accident, and caused a pseudo-pandemic.", "Whether the 1977 \"pandemic\" deserves to be included in the natural history of flu pandemics is debatable.", "This H1N1 strain was antigenically similar to the H1N1 strains that circulated prior to 1957.", "Since 1977, both H1N1 and H3N2 have circulated in humans as part of seasonal influenza.", "In 1980, the current classification system used to subtype influenza viruses was introduced.", "At some point, IBV diverged into two lineages, named the B/Victoria-like and B/Yamagata-like lineages, both of which have been circulating in humans since 1983.", "In 1996, HPAI H5N1 was detected in Guangdong, China and a year later emerged in poultry in Hong Kong, gradually spreading worldwide from there.", "A small H5N1 outbreak in humans in Hong Kong occurred then, and sporadic human cases have occurred since 1997, carrying a high case fatality rate.", "The most recent flu pandemic was the 2009 swine flu pandemic, which originated in Mexico and resulted in hundreds of thousands of deaths.", "It was caused by a novel H1N1 strain that was a reassortment of human, swine, and avian influenza viruses.", "The 2009 pandemic had the effect of replacing prior H1N1 strains in circulation with the novel strain but not any other influenza viruses.", "Consequently, H1N1, H3N2, and both IBV lineages have been in circulation in seasonal form since the 2009 pandemic.", "In 2011, IDV was discovered in pigs in Oklahoma, USA, and cattle were later identified as the primary reservoir of IDV.", "In the same year, avian H7N9 was detected in China and began to cause human infections in 2013, starting in Shanghai and Anhui and remaining mostly in China.", "HPAI H7N9 emerged sometime in 2016 and has occasionally infected humans incidentally.", "Other AIVs have less commonly infected humans since the 1990s, including H5N6, H6N1, H7N2-4, H7N7, and H10N7-8, and HPAI H subtypes such as H5N1-3, H5N5-6, and H5N8 have begun to spread throughout much of the world since the 2010s.", "Future flu pandemics, which may be caused by an influenza virus of avian origin, are viewed as almost inevitable, and increased globalization has made it easier for novel viruses to spread, so there are continual efforts to prepare for future pandemics and improve the prevention and treatment of influenza.", "The word \"influenza\" comes from the Italian word \"influenza\", from medieval Latin \"influentia\", originally meaning \"visitation\" or \"influence\".", "Terms such as \"influenza di freddo\", meaning \"influence of the cold\", and \"influenza di stelle\", meaning \"influence of the stars\" are attested from the 14th century.", "The latter referred to the disease's cause, which at the time was ascribed by some to unfavorable astrological conditions.", "As early as 1504, \"influenza\" began to mean a \"visitation\" or \"outbreak\" of any disease affecting many people in a single place at once.", "During an outbreak of influenza in 1743 that started in Italy and spread throughout Europe, the word reached the English language and was anglicized in pronunciation.", "Since the mid-1800s, \"influenza\" has also been used to refer to severe colds.", "The shortened form of the word, \"(the) flu\", is first attested in 1839 as \"flue\" with the spelling \"flu\" first attested in 1893.", "Other names that have been used for influenza include \"epidemic catarrh\", \"la grippe\" from French, \"sweating sickness\", and, especially when referring to the 1918 pandemic strain, \"Spanish fever\".", "Influenza research is wide-ranging and includes efforts to understand how influenza viruses enter hosts, the relationship between influenza viruses and bacteria, how influenza symptoms progress, and what make some influenza viruses deadlier than others.", "Non-structural proteins encoded by influenza viruses are periodically discovered and their functions are continually under research.", "Past pandemics, and especially the 1918 pandemic, are the subject of much research to understand flu pandemics.", "As part of pandemic preparedness, the Global Influenza Surveillance and Response System is a global network of laboratories that monitors influenza transmission and epidemiology.", "Additional areas of research include ways to improve the diagnosis, treatment, and prevention of influenza.", "Existing diagnostic methods have a variety of limitations coupled with their advantages.", "For example, NATs have high sensitivity and specificity but are impractical in under-resourced regions due to their high cost, complexity, maintenance, and training required.", "Low-cost, portable RIDTs can rapidly diagnose influenza but have highly variable sensitivity and are unable to subtype IAV.", "As a result of these limitations and others, research into new diagnostic methods revolves around producing new methods that are cost-effective, less labor-intensive, and less complex than existing methods while also being able to differentiate influenza species and IAV subtypes.", "One approach in development are lab-on-a-chips, which are diagnostic devices that make use of a variety of diagnostic tests, such as RT-PCR and serological assays, in microchip form.", "These chips have many potential advantages, including high reaction efficiency, low energy consumption, and low waste generation.", "New antiviral drugs are also in development due to the elimination of adamantines as viable drugs and concerns over oseltamivir resistance.", "These include: NA inhibitors that can be injected intravenously, such as intravenous formulations of zanamivir; favipiravir, which is a polymerase inhibitor used against several RNA viruses; pimodivir, which prevents cap-binding required during viral transcription; and nitazoxanide, which inhibits HA maturation.", "Reducing excess inflammation in the respiratory tract is also subject to much research since this is one of the primary mechanisms of influenza pathology.", "Other forms of therapy in development include monoclonal and polyclonal antibodies that target viral proteins, convalescent plasma, different approaches to modify the host antiviral response, and stem cell-based therapies to repair lung damage.", "Much research on LAIVs focuses on identifying genome sequences that can be deleted to create harmless influenza viruses in vaccines that still confer immunity.", "The high variability and rapid evolution of influenza virus antigens, however, is a major obstacle in developing effective vaccines.", "Furthermore, it is hard to predict which strains will be in circulation during the next flu season, manufacturing a sufficient quantity of flu vaccines for the next season is difficult, LAIVs have limited efficacy, and repeated annual vaccination potentially has diminished efficacy.", "For these reasons, \"broadly-reactive\" or \"universal\" flu vaccines are being researched that can provide protection against many or all influenza viruses.", "Approaches to develop such a vaccine include HA stalk-based methods such as chimeras that have the same stalk but different heads, HA head-based methods such as computationally optimized broadly neutralizing antigens, anti-idiotypic antibodies, and vaccines to elicit immune responses to highly conserved viral proteins.", "mRNA vaccines to provide protection against influenza are also under research.", "Aquatic birds such as ducks, geese, shorebirds, and gulls are the primary reservoir of IAVs.", "In birds, AIVs may be either low pathogenic avian influenza (LPAI) viruses that produce little to no symptoms or highly pathogenic avian influenza (HPAI) viruses that cause severe illness.", "Symptoms of HPAI infection include lack of energy and appetite, decreased egg production, soft-shelled or misshapen eggs, swelling of the head, comb, wattles, and hocks, purple discoloration of wattles, combs, and legs, nasal discharge, coughing, sneezing, incoordination, and diarrhea.", "Birds infected with an HPAI virus may also die suddenly without any signs of infection.", "The distinction between LPAI and HPAI can generally be made based on how lethal an AIV is to chickens.", "At the genetic level, an AIV can be usually be identified as an HPAI virus if it has a multibasic cleavage site in the HA protein, which contains additional residues in the HA gene.", "Most AIVs are LPAI.", "Notable HPAI viruses include HPAI H5N1 and HPAI H7N9.", "HPAI viruses have been a major disease burden in the 21st century, resulting in the death of large numbers of birds.", "In H7N9's case, some circulating strains were originally LPAI but became HPAI by acquiring the HA multibasic cleavage site.", "Avian H9N2 is also of concern because although it is LPAI, it is a common donor of genes to H5N1 and H7N9 during reassortment.", "Migratory birds can spread influenza across long distances.", "An example of this was when an H5N1 strain in 2005 infected birds at Qinghai Lake, China, which is a stopover and breeding site for many migratory birds, subsequently spreading the virus to more than 20 countries across Asia, Europe, and the Middle East.", "AIVs can be transmitted from wild birds to domestic free-range ducks and in turn to poultry through contaminated water, aerosols, and fomites.", "Ducks therefore act as key intermediates between wild and domestic birds.", "Transmission to poultry typically occurs in backyard farming and live animal markets where multiple species interact with each other.", "From there, AIVs can spread to poultry farms in the absence of adequate biosecurity.", "Among poultry, HPAI transmission occurs through aerosols and contaminated feces, cages, feed, and dead animals.", "Back-transmission of HPAI viruses from poultry to wild birds has occurred and is implicated in mass die-offs and intercontinental spread.", "AIVs have occasionally infected humans through aerosols, fomites, and contaminated water.", "Direction transmission from wild birds is rare.", "Instead, most transmission involves domestic poultry, mainly chickens, ducks, and geese but also a variety of other birds such as guinea fowl, partridge, pheasants, and quails.", "The primary risk factor for infection with AIVs is exposure to birds in farms and live poultry markets.", "Typically, infection with an AIV has an incubation period of 3–5 days but can be up to 9 days.", "H5N1 and H7N9 cause severe lower respiratory tract illness, whereas other AIVs such as H9N2 cause a more mild upper respiratory tract illness, commonly with conjunctivitis.", "Limited transmission of avian H2, H5-7, H9, and H10 subtypes from one person to another through respiratory droplets, aerosols, and fomites has occurred, but sustained human-to-human transmission of AIVs has not occurred.", "Before 2013, H5N1 was the most common AIV to infect humans.", "Since then, H7N9 has been responsible for most human cases.", "Influenza in pigs is a respiratory disease similar to influenza in humans and is found worldwide.", "Asymptomatic infections are common.", "Symptoms typically appear 1–3 days after infection and include fever, lethargy, anorexia, weight loss, labored breathing, coughing, sneezing, and nasal discharge.", "In sows, pregnancy may be aborted.", "Complications include secondary infections and potentially fatal bronchopneumonia.", "Pigs become contagious within a day of infection and typically spread the virus for 7–10 days, which can spread rapidly within a herd.", "Pigs usually recover from infection within 3–7 days after symptoms appear.", "Prevention and control measures include inactivated vaccines and culling infected herds.", "The influenza viruses usually responsible for swine flu are IAV subtypes H1N1, H1N2, and H3N2.", "Some IAVs can be transmitted via aerosols from pigs to humans and vice versa.", "Furthermore, pigs, along with bats and quails, are recognized as a mixing vessel of influenza viruses because they have both α-2,3 and α-2,6 sialic acid receptors in their respiratory tract.", "Because of that, both avian and mammalian influenza viruses can infect pigs.", "If co-infection occurs, then reassortment is possible.", "A notable example of this was the reassortment of a swine, avian, and human influenza virus in 2009, resulting in a novel H1N1 strain that caused the 2009 flu pandemic.", "Spillover events from humans to pigs, however, appear to be more common than from pigs to humans.", "Influenza viruses have been found in many other animals, including cattle, horses, dogs, cats, and marine mammals.", "Nearly all IAVs are apparently descended from ancestral viruses in birds.", "The exception are bat influenza-like viruses, which have an uncertain origin.", "These bat viruses have HA and NA subtypes H17, H18, N10, and N11.", "H17N10 and H18N11 are unable to reassort with other IAVs, but they are still able to replicate in other mammals.", "AIVs sometimes crossover into mammals.", "For example, in late 2016 to early 2017, an avian H7N2 strain was found to be infecting cats in New York.", "Equine IAVs include H7N7 and two lineages of H3N8.", "H7N7, however, has not been detected in horses since the late 1970s, so it may have become extinct in horses.", "H3N8 in equines spreads via aerosols and causes respiratory illness.", "Equine H3N8 perferentially binds to α-2,3 sialic acids, so horses are usually considered dead-end hosts, but transmission to dogs and camels has occurred, raising concerns that horses may be mixing vessels for reassortment.", "In canines, the only IAVs in circulation are equine-derived H3N8 and avian-derived H3N2.", "Canine H3N8 has not been observed to reassort with other subtypes.", "H3N2 has a much broader host range and can reassort with H1N1 and H5N1.", "An isolated case of H6N1 likely from a chicken was found infecting a dog, so other AIVs may emerge in canines.", "Other mammals to be infected by IAVs include H7N7 and H4N5 in seals, H1N3 in whales, and H10N4 and H3N2 in minks.", "Various mutations have been identified that are associated with AIVs adapting to mammals.", "Since HA proteins vary in which sialic acids they bind to, mutations in the HA receptor binding site can allow AIVs to infect mammals.", "Other mutations include mutations affecting which sialic acids NA proteins cleave and a mutation in the PB2 polymerase subunit that improves tolerance of lower temperatures in mammalian respiratory tracts and enhances RNP assembly by stabilizing NP and PB2 binding.", "IBV is mainly found in humans but has also been detected in pigs, dogs, horses, and seals.", "Likewise, ICV primarily infects humans but has been observed in pigs, dogs, cattle, and dromedary camels.", "IDV causes an influenza-like illness in pigs but its impact in its natural reservoir, cattle, is relatively unknown.", "It may cause respiratory disease resembling human influenza on its own, or it may be part of a bovine respiratory disease (BRD) complex with other pathogens during co-infection.", "BRD is a concern for the cattle industry, so IDV's possible involvement in BRD has led to research on vaccines for cattle that can provide protection against IDV.", "Two antigenic lineages are in circulation: D/swine/Oklahoma/1334/2011 (D/OK) and D/bovine/Oklahoma/660/2013 (D/660)." ]

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[ "In humans, influenza viruses are primarily transmitted through respiratory droplets produced from coughing and sneezing.", "Transmission through aerosols and intermediate objects and surfaces contaminated by the virus also occur." ]

[ "The time between exposure to the virus and development of symptoms, called the incubation period, is 1–4 days, most commonly 1–2 days.", "Many infections, however, are asymptomatic.", "The onset of symptoms is sudden, and initial symptoms are predominately non-specific, including fever, chills, headaches, muscle pain or aching, a feeling of discomfort, loss of appetite, lack of energy/fatigue, and confusion.", "These symptoms are usually accompanied by respiratory symptoms such as a dry cough, sore or dry throat, hoarse voice, and a stuffy or runny nose.", "Coughing is the most common symptom.", "Gastrointestinal symptoms may also occur, including nausea, vomiting, diarrhea, and gastroenteritis, especially in children.", "The standard influenza symptoms typically last for 2–8 days.", "A 2021 study suggests influenza can cause long lasting symptoms in a similar way to long COVID.\nSymptomatic infections are usually mild and limited to the upper respiratory tract, but progression to pneumonia is relatively common.", "Pneumonia may be caused by the primary viral infection or by a secondary bacterial infection.", "Primary pneumonia is characterized by rapid progression of fever, cough, labored breathing, and low oxygen levels that cause bluish skin.", "It is especially common among those who have an underlying cardiovascular disease such as rheumatic heart disease.", "Secondary pneumonia typically has a period of improvement in symptoms for 1–3 weeks followed by recurrent fever, sputum production, and fluid buildup in the lungs, but can also occur just a few days after influenza symptoms appear.", "About a third of primary pneumonia cases are followed by secondary pneumonia, which is most frequently caused by the bacteria \"Streptococcus pneumoniae\" and \"Staphylococcus aureus\".", "Influenza viruses comprise four species.", "Each of the four species is the sole member of its own genus, and the four influenza genera comprise four of the seven genera in the family \"Orthomyxoviridae\".", "They are:\n\n\nIAV is responsible for most cases of severe illness as well as seasonal epidemics and occasional pandemics.", "It infects people of all ages but tends to disproportionately cause severe illness in the elderly, the very young, and those who have chronic health issues.", "Birds are the primary reservoir of IAV, especially aquatic birds such as ducks, geese, shorebirds, and gulls, but the virus also circulates among mammals, including pigs, horses, and marine mammals.", "IAV is classified into subtypes based on the viral proteins haemagglutinin (H) and neuraminidase (N).", "As of 2019, 18 H subtypes and 11 N subtypes have been identified.", "Most potential combinations have been reported in birds, but H17-18 and N10-11 have only been found in bats.", "Only H subtypes H1-3 and N subtypes N1-2 are known to have circulated in humans, the current IAV subtypes in circulation being H1N1 and H3N2.", "IAVs can be classified more specifically to also include natural host species, geographical origin, year of isolation, and strain number, such as H1N1/A/duck/Alberta/35/76.", "IBV mainly infects humans but has been identified in seals, horses, dogs, and pigs.", "IBV does not have subtypes like IAV but has two antigenically distinct lineages, termed the B/Victoria/2/1987-like and B/Yamagata/16/1988-like lineages, or simply (B/)Victoria(-like) and (B/)Yamagata(-like).", "Both lineages are in circulation in humans, disproportionately affecting children.", "IBVs contribute to seasonal epidemics alongside IAVs but have never been associated with a pandemic.", "ICV, like IBV, is primarily found in humans, though it also has been detected in pigs, feral dogs, dromedary camels, cattle, and dogs.", "ICV infection primarily affects children and is usually asymptomatic or has mild cold-like symptoms, though more severe symptoms such as gastroenteritis and pneumonia can occur.", "Unlike IAV and IBV, ICV has not been a major focus of research pertaining to antiviral drugs, vaccines, and other measures against influenza.", "ICV is subclassified into six genetic/antigenic lineages.", "IDV has been isolated from pigs and cattle, the latter being the natural reservoir.", "Infection has also been observed in humans, horses, dromedary camels, and small ruminants such as goats and sheep.", "IDV is distantly related to ICV.", "While cattle workers have occasionally tested positive to prior IDV infection, it is not known to cause disease in humans.", "ICV and IDV experience a slower rate of antigenic evolution than IAV and IBV.", "Because of this antigenic stability, relatively few novel lineages emerge.", "Influenza viruses have a negative-sense, single-stranded RNA genome that is segmented.", "The negative sense of the genome means it can be used as a template to synthesize messenger RNA (mRNA).", "IAV and IBV have eight genome segments that encode 10 major proteins.", "ICV and IDV have seven genome segments that encode nine major proteins.", "Three segments encode three subunits of an RNA-dependent RNA polymerase (RdRp) complex: PB1, a transcriptase, PB2, which recognizes 5' caps, and PA (P3 for ICV and IDV), an endonuclease.", "The matrix protein (M1) and membrane protein (M2) share a segment, as do the non-structural protein (NS1) and the nuclear export protein (NEP).", "For IAV and IBV, hemagglutinin (HA) and neuraminidase (NA) are encoded on one segment each, whereas ICV and IDV encode a hemagglutinin-esterase fusion (HEF) protein on one segment that merges the functions of HA and NA.", "The final genome segment encodes the viral nucleoprotein (NP).", "Influenza viruses also encode various accessory proteins, such as PB1-F2 and PA-X, that are expressed through alternative open reading frames and which are important in host defense suppression, virulence, and pathogenicity.", "The virus particle, called a virion, is pleomorphic and varies between being filamentous, bacilliform, or spherical in shape.", "Clinical isolates tend to be pleomorphic, whereas strains adapted to laboratory growth typically produce spherical virions.", "Filamentous virions are about 250 nanometers (nm) by 80 nm, bacilliform 120–250 by 95 nm, and spherical 120 nm in diameter.", "The virion consists of each segment of the genome bound to nucleoproteins in separate ribonucleoprotein (RNP) complexes for each segment, all of which are surrounded by a lipid bilayer membrane called the viral envelope.", "There is a copy of the RdRp, all subunits included, bound to each RNP.", "The envelope is reinforced structurally by matrix proteins on the interior that enclose the RNPs, and the envelope contains HA and NA (or HEF) proteins extending outward from the exterior surface of the envelope.", "HA and HEF proteins have a distinct \"head\" and \"stalk\" structure.", "M2 proteins form proton ion channels through the viral envelope that are required for viral entry and exit.", "IBVs contain a surface protein named NB that is anchored in the envelope, but its function is unknown.", "The viral life cycle begins by binding to a target cell.", "Binding is mediated by the viral HA proteins on the surface of the evelope, which bind to cells that contain sialic acid receptors on the surface of the cell membrane.", "For N1 subtypes with the \"G147R\" mutation and N2 subtypes, the NA protein can initiate entry.", "Prior to binding, NA proteins promote access to target cells by degrading mucous, which helps to remove extracellular decoy receptors that would impede access to target cells.", "After binding, the virus is internalized into the cell by an endosome that contains the virion inside it.", "The endosome is acidified by cellular vATPase to have lower pH, which triggers a conformational change in HA that allows fusion of the viral envelope with the endosomal membrane.", "At the same time, hydrogen ions diffuse into the virion through M2 ion channels, disrupting internal protein-protein interactions to release RNPs into the host cell's cytosol.", "The M1 protein shell surrounding RNPs is degraded, fully uncoating RNPs in the cytosol.", "RNPs are then imported into the nucleus with the help of viral localization signals.", "There, the viral RNA polymerase transcribes mRNA using the genomic negative-sense strand as a template.", "The polymerase snatches 5' caps for viral mRNA from cellular RNA to prime mRNA synthesis and the 3'-end of mRNA is polyadenylated at the end of transcription.", "Once viral mRNA is transcribed, it is exported out of the nucleus and translated by host ribosomes in a cap-dependent manner to synthesize viral proteins.", "RdRp also synthesizes complementary positive-sense strands of the viral genome in a complementary RNP complex which are then used as templates by viral polymerases to synthesize copies of the negative-sense genome.", "During these processes, RdRps of avian influenza viruses (AIVs) function optimally at a higher temperature than mammalian influenza viruses.", "Newly synthesized viral polymerase subunits and NP proteins are imported to the nucleus to further increase the rate of viral replication and form RNPs.", "HA, NA, and M2 proteins are trafficked with the aid of M1 and NEP proteins to the cell membrane through the Golgi apparatus and inserted into the cell's membrane.", "Viral non-structural proteins including NS1, PB1-F2, and PA-X regulate host cellular processes to disable antiviral responses.", "PB1-F2 aso interacts with PB1 to keep polymerases in the nucleus longer.", "M1 and NEP proteins localize to the nucleus during the later stages of infection, bind to viral RNPs and mediate their export to the cytoplasm where they migrate to the cell membrane with the aid of recycled endosomes and are bundled into the segments of the genome.", "Progenic viruses leave the cell by budding from the cell membrane, which is initiated by the accumulation of M1 proteins at the cytoplasmic side of the membrane.", "The viral genome is incorporated inside a viral envelope derived from portions of the cell membrane that have HA, NA, and M2 proteins.", "At the end of budding, HA proteins remain attached to cellular sialic acid until they are cleaved by the sialidase activity of NA proteins.", "The virion is then released from the cell.", "The sialidase activity of NA also cleaves any sialic acid residues from the viral surface, which helps prevent newly assembled viruses from aggregating near the cell surface and improving infectivity.", "Similar to other aspects of influenza replication, optimal NA activity is temperature- and pH-dependent.", "Ultimately, presence of large quantities of viral RNA in the cell triggers apoptosis, i.e. programmed cell death, which is initiated by cellular factors to restrict viral replication.", "Two key processes that influenza viruses evolve through are antigenic drift and antigenic shift.", "Antigenic drift is when an influenza virus's antigens change due to the gradual accumulation of mutations in the antigen's (HA or NA) gene.", "This can occur in response to evolutionary pressure exerted by the host immune response.", "Antigenic drift is especially common for the HA protein, in which just a few amino acid changes in the head region can constitute antigenic drift.", "The result is the production of novel strains that can evade pre-existing antibody-mediated immunity.", "Antigenic drift occurs in all influenza species but is slower in B than A and slowest in C and D. Antigenic drift is a major cause of seasonal influenza, and requires that flu vaccines be updated annually.", "HA is the main component of inactivated vaccines, so surveillance monitors antigenic drift of this antigen among circulating strains.", "Antigenic evolution of influenza viruses of humans appears to be faster than influenza viruses in swine and equines.", "In wild birds, within-subtype antigenic variation appears to be limited but has been observed in poultry.", "Antigenic shift is a sudden, drastic change in an influenza virus's antigen, usually HA.", "During antigenic shift, antigenically different strains that infect the same cell can reassort genome segments with each other, producing hybrid progeny.", "Since all influenza viruses have segmented genomes, all are capable of reassortment.", "Antigenic shift, however, only occurs among influenza viruses of the same genus and most commonly occurs among IAVs.", "In particular, reassortment is very common in AIVs, creating a large diversity of influenza viruses in birds, but is uncommon in human, equine, and canine lineages.", "Pigs, bats, and quails have receptors for both mammalian and avian IAVs, so they are potential \"mixing vessels\" for reassortment.", "If an animal strain reassorts with a human strain, then a novel strain can emerge that is capable of human-to-human transmission.", "This has caused pandemics, but only a limited number have occurred, so it is difficult to predict when the next will happen.", "People who are infected can transmit influenza viruses through breathing, talking, coughing, and sneezing, which spread respiratory droplets and aerosols that contain virus particles into the air.", "A person susceptible to infection can then contract influenza by coming into contact with these particles.", "Respiratory droplets are relatively large and travel less than two meters before falling onto nearby surfaces.", "Aerosols are smaller and remain suspended in the air longer, so they take longer to settle and can travel further than respiratory droplets.", "Inhalation of aerosols can lead to infection, but most transmission is in the area about two meters around an infected person via respiratory droplets that come into contact with mucosa of the upper respiratory tract.", "Transmission through contact with a person, bodily fluids, or intermediate objects (fomites) can also occur, such as through contaminated hands and surfaces since influenza viruses can survive for hours on non-porous surfaces.", "If one's hands are contaminated, then touching one's face can cause infection.", "Influenza is usually transmissible from one day before the onset of symptoms to 5–7 days after.", "In healthy adults, the virus is shed for up to 3–5 days.", "In children and the immunocompromised, the virus may be transmissible for several weeks.", "Children ages 2–17 are considered to be the primary and most efficient spreaders of influenza.", "Children who have not had multiple prior exposures to influenza viruses shed the virus at greater quantities and for a longer duration than other children.", "People who are at risk of exposure to influenza include health care workers, social care workers, and those who live with or care for people vulnerable to influenza.", "In long-term care facilities, the flu can spread rapidly after it is introduced.", "A variety of factors likely encourage influenza transmission, including lower temperature, lower absolute and relative humidity, less ultraviolet radiation from the Sun, and crowding.", "Influenza viruses that infect the upper respiratory tract like H1N1 tend to be more mild but more transmissible, whereas those that infect the lower respiratory tract like H5N1 tend to cause more severe illness but are less contagious.", "In humans, influenza viruses first cause infection by infecting epithelial cells in the respiratory tract.", "Illness during infection is primarily the result of lung inflammation and compromise caused by epithelial cell infection and death, combined with inflammation caused by the immune system's response to infection.", "Non-respiratory organs can become involved, but the mechanisms by which influenza is involved in these cases are unknown.", "Severe respiratory illness can be caused by multiple, non-exclusive mechanisms, including obstruction of the airways, loss of alveolar structure, loss of lung epithelial integrity due to epithelial cell infection and death, and degradation of the extracellular matrix that maintains lung structure.", "In particular, alveolar cell infection appears to drive severe symptoms since this results in impaired gas exchange and enables viruses to infect endothelial cells, which produce large quantities of pro-inflammatory cytokines.", "Pneumonia caused by influenza viruses is characterized by high levels of viral replication in the lower respiratory tract, accompanied by a strong pro-inflammatory response called a cytokine storm.", "Infection with H5N1 or H7N9 especially produces high levels of pro-inflammatory cytokines.", "In bacterial infections, early depletion of macrophages during influenza creates a favorable environment in the lungs for bacterial growth since these white blood cells are important in responding to bacterial infection.", "Host mechanisms to encourage tissue repair may inadvertently allow bacterial infection.", "Infection also induces production of systemic glucocorticoids that can reduce inflammation to preserve tissue integrity but allow increased bacterial growth.", "The pathophysiology of influenza is significantly influenced by which receptors influenza viruses bind to during entry into cells.", "Mammalian influenza viruses preferentially bind to sialic acids connected to the rest of the oligosaccharide by an α-2,6 link, most commonly found in various respiratory cells, such as respiratory and retinal epithelial cells.", "AIVs prefer sialic acids with an α-2,3 linkage, which are most common in birds in gastrointestinal epithelial cells and in humans in the lower respiratory tract.", "Furthermore, cleavage of the HA protein into HA, the binding subunit, and HA, the fusion subunit, is performed by different proteases, affecting which cells can be infected.", "For mammalian influenza viruses and low pathogenic AIVs, cleavage is extracellular, which limits infection to cells that have the appropriate proteases, whereas for highly pathogenic AIVs, cleavage is intracellular and performed by ubiquitous proteases, which allows for infection of a greater variety of cells, thereby contributing to more severe disease.", "Cells possess sensors to detect viral RNA, which can then induce interferon production.", "Interferons mediate expression of antiviral proteins and proteins that recruit immune cells to the infection site, and they also notify nearby uninfected cells of infection.", "Some infected cells release pro-inflammatory cytokines that recruit immune cells to the site of infection.", "Immune cells control viral infection by killing infected cells and phagocytizing viral particles and apoptotic cells.", "An exacerbated immune response, however, can harm the host organism through a cytokine storm.", "To counter the immune response, influenza viruses encode various non-structural proteins, including NS1, NEP, PB1-F2, and PA-X, that are involved in curtailing the host immune response by suppressing interferon production and host gene expression.", "B cells, a type of white blood cell, produce antibodies that bind to influenza antigens HA and NA (or HEF) and other proteins to a lesser degree.", "Once bound to these proteins, antibodies block virions from binding to cellular receptors, neutralizing the virus.", "In humans, a sizeable antibody response occurs ~1 week after viral exposure.", "This antibody response is typically robust and long-lasting, especially for ICV and IDV.", "In other words, people exposed to a certain strain in childhood still possess antibodies to that strain at a reasonable level later in life, which can provide some protection to related strains.", "There is, however, an \"original antigenic sin\", in which the first HA subtype a person is exposed to influences the antibody-based immune response to future infections and vaccines.", "Annual vaccination is the primary and most effective way to prevent influenza and influenza-associated complications, especially for high-risk groups.", "Vaccines against the flu are trivalent or quadrivalent, providing protection against an H1N1 strain, an H3N2 strain, and one or two IBV strains corresponding to the two IBV lineages.", "Two types of vaccines are in use: inactivated vaccines that contain \"killed\" (i.e. inactivated) viruses and live attenuated influenza vaccines (LAIVs) that contain weakened viruses.", "There are three types of inactivated vaccines: whole virus, split virus, in which the virus is disrupted by a detergent, and subunit, which only contains the viral antigens HA and NA.", "Most flu vaccines are inactivated and administered via intramuscular injection.", "LAIVs are sprayed into the nasal cavity.", "Vaccination recommendations vary by country.", "Some recommend vaccination for all people above a certain age, such as 6 months, whereas other countries recommendation is limited for high at risk groups, such as pregnant women, young children (excluding newborns), the elderly, people with chronic medical conditions, health care workers, people who come into contact with high-risk people, and people who transmit the virus easily.", "Young infants cannot receive flu vaccines for safety reasons, but they can inherit passive immunity from their mother if inactivated vaccines are administered to the mother during pregnancy.", "Influenza vaccination also helps to reduce the probability of reassortment.", "In general, influenza vaccines are only effective if there is an antigenic match between vaccine strains and circulating strains.", "Additionally, most commercially available flu vaccines are manufactured by propagation of influenza viruses in embryonated chicken eggs, taking 6–8 months.", "Flu seasons are different in the northern and southern hemisphere, so the WHO meets twice a year, one for each hemisphere, to discuss which strains should be included in flu vaccines based on observation from HA inhibition assays.", "Other manufacturing methods include an MDCK cell culture-based inactivated vaccine and a recombinant subunit vaccine manufactured from baculovirus overexpression in insect cells.", "Influenza can be prevented or reduced in severity by post-exposure prophylaxis with the antiviral drugs oseltamivir, which can be taken orally by those at least three months old, and zanamivir, which can be inhaled by those above seven years of age.", "Chemoprophylaxis is most useful for individuals at high-risk of developing complications and those who cannot receive the flu vaccine due to contraindications or lack of effectiveness.", "Post-exposure chemoprophylaxis is only recommended if oseltamivir is taken within 48 hours of contact with a confirmed or suspected influenza case and zanamivir within 36 hours.", "It is recommended that it be offered to people who have yet to receive a vaccine for the current flu season, who have been vaccinated less than two week since contact, if there is a significant mismatch between vaccine and circulating strains, or during an outbreak in a closed setting regardless of vaccination history.", "Hand hygiene is important in reducing the spread of influenza.", "This includes frequent hand washing with soap and water, using alcohol-based hand sanitizers, and not touching one's eyes, nose, and mouth with one's hands.", "Covering one's nose and mouth when coughing or sneezing is important.", "Other methods to limit influenza transmission include staying home when sick, avoiding contact with others until one day after symptoms end, and disinfecting surfaces likely to be contaminated by the virus, such as doorknobs.", "Health education through media and posters is often used to remind people of the aforementioned etiquette and hygiene.", "There is uncertainty about the use of masks since research thus far has not shown a significant reduction in seasonal influenza with mask usage.", "Likewise, the effectiveness of screening at points of entry into countries is not well researched.", "Social distancing measures such as school closures, avoiding contact with infected people via isolation or quarantine, and limiting mass gatherings may reduce transmission, but these measures are often expensive, unpopular, and difficult to implement.", "Consequently, the commonly recommended methods of infection control are respiratory etiquette, hand hygiene, and mask wearing, which are inexpensive and easy to perform.", "Pharmaceutical measures are effective but may not be available in the early stages of an outbreak.", "In health care settings, infected individuals may be cohorted or assigned to individual rooms.", "Protective clothing such as masks, gloves, and gowns is recommended when coming into contact with infected individuals if there is a risk of exposure to infected bodily fluids.", "Keeping patients in negative pressure rooms and avoiding aerosol-producing activities may help, but special air handling and ventilation systems are not considered necessary to prevent the spread of influenza in the air.", "In residential homes, new admissions may need to be closed until the spread of influenza is controlled.", "When discharging patients to care homes, it is important to take care if there is a known influenza outbreak.", "Since influenza viruses circulate in animals such as birds and pigs, prevention of transmission from these animals is important.", "Water treatment, indoor raising of animals, quarantining sick animals, vaccination, and biosecurity are the primary measures used.", "Placing poultry houses and piggeries on high ground away from high-density farms, backyard farms, live poultry markets, and bodies of water helps to minimize contact with wild birds.", "Closure of live poultry markets appears to the most effective measure and has shown to be effective at controlling the spread of H5N1, H7N9, and H9N2.", "Other biosecurity measures include cleaning and disinfecting facilities and vehicles, banning visits to poultry farms, not bringing birds intended for slaughter back to farms, changing clothes, disinfecting foot baths, and treating food and water.", "If live poultry markets are not closed, then \"clean days\" when unsold poultry is removed and facilities are disinfected and \"no carry-over\" policies to eliminate infectious material before new poultry arrive can be used to reduce the spread of influenza viruses.", "If a novel influenza viruses has breached the aforementioned biosecurity measures, then rapid detection to stamp it out via quarantining, decontamination, and culling may be necessary to prevent the virus from becoming endemic.", "Vaccines exist for avian H5, H7, and H9 subtypes that are used in some countries.", "In China, for example, vaccination of domestic birds against H7N9 successfully limited its spread, indicating that vaccination may be an effective strategy if used in combination with other measures to limit transmission.", "In pigs and horses, management of influenza is dependent on vaccination with biosecurity.", "Diagnosis based on symptoms is fairly accurate in otherwise healthy people during seasonal epidemics and should be suspected in cases of pneumonia, acute respiratory distress syndrome (ARDS), sepsis, or if encephalitis, myocarditis, or breaking down of muscle tissue occur.", "Because influenza is similar to other viral respiratory tract illnesses, laboratory diagnosis is necessary for confirmation.", "Common ways of collecting samples for testing include nasal and throat swabs.", "Samples may be taken from the lower respiratory tract if infection has cleared the upper but not lower respiratory tract.", "Influenza testing is recommended for anyone hospitalized with symptoms resembling influenza during flu season or who is connected to an influenza case.", "For severe cases, earlier diagnosis improves patient outcome.", "Diagnostic methods that can identify influenza include viral cultures, antibody- and antigen-detecting tests, and nucleic acid-based tests.", "Viruses can be grown in a culture of mammalian cells or embryonated eggs for 3–10 days to monitor cytopathic effect.", "Final confirmation can then be done via antibody staining, hemadsorption using red blood cells, or immunofluorescence microscopy.", "Shell vial cultures, which can identify infection via immunostaining before a cytopathic effect appears, are more sensitive than traditional cultures with results in 1–3 days.", "Cultures can be used to characterize novel viruses, observe sensitivity to antiviral drugs, and monitor antigenic drift, but they are relatively slow and require specialized skills and equipment.", "Serological assays can be used to detect an antibody response to influenza after natural infection or vaccination.", "Common serological assays include hemagglutination inhibition assays that detect HA-specific antibodies, virus neutralization assays that check whether antibodies have neutralized the virus, and enzyme-linked immunoabsorbant assays.", "These methods tend to be relatively inexpensive and fast but are less reliable than nucleic-acid based tests.", "Direct fluorescent or immunofluorescent antibody (DFA/IFA) tests involve staining respiratory epithelial cells in samples with fluorescently-labeled influenza-specific antibodies, followed by examination under a fluorescent microscope.", "They can differentiate between IAV and IBV but can't subtype IAV.", "Rapid influenza diagnostic tests (RIDTs) are a simple way of obtaining assay results, are low cost, and produce results quickly, at less than 30 minutes, so they are commonly used, but they can't distinguish between IAV and IBV or between IAV subtypes and are not as sensitive as nucleic-acid based tests.", "Nucleic acid-based tests (NATs) amplify and detect viral nucleic acid.", "Most of these tests take a few hours, but rapid molecular assays are as fast as RIDTs.", "Among NATs, reverse transcription polymerase chain reaction (RT-PCR) is the most traditional and considered the gold standard for diagnosing influenza because it is fast and can subtype IAV, but it is relatively expensive and more prone to false-positives than cultures.", "Other NATs that have been used include loop-mediated isothermal amplification-based assays, simple amplification-based assays, and nucleic acid sequence-based amplification.", "Nucleic acid sequencing methods can identify infection by obtaining the nucleic acid sequence of viral samples to identify the virus and antiviral drug resistance.", "The traditional method is Sanger sequencing, but it has been largely replaced by next-generation methods that have greater sequencing speed and throughput.", "Treatment of influenza in cases of mild or moderate illness is supportive and includes anti-fever medications such as acetaminophen and ibuprofen, adequate fluid intake to avoid dehydration, and resting at home.", "Cough drops and throat sprays may be beneficial for sore throat.", "It is recommended to avoid alcohol and tobacco use while sick with the flu.", "Aspirin is not recommended to treat influenza in children due to an elevated risk of developing Reye syndrome.", "Corticosteroids likewise are not recommended except when treating septic shock or an underlying medical condition, such as chronic obstructive pulmonary disease or asthma exacerbation, since they are associated with increased mortality.", "If a secondary bacterial infection occurs, then treatment with antibiotics may be necessary.", "Antiviral drugs are primarily used to treat severely ill patients, especially those with compromised immune systems.", "Antivirals are most effective when started in the first 48 hours after symptoms appear.", "Later administration may still be beneficial for those who have underlying immune defects, those with more severe symptoms, or those who have a higher risk of developing complications if these individuals are still shedding the virus.", "Antiviral treatment is also recommended if a person is hospitalized with suspected influenza instead of waiting for test results to return and if symptoms are worsening.", "Most antiviral drugs against influenza fall into two categories: neuraminidase (NA) inhibitors and M2 inhibitors.", "Baloxavir marboxil is a notable exception, which targets the endonuclease activity of the viral RNA polymerase and can be used as an alternative to NA and M2 inhibitors for IAV and IBV.", "NA inhibitors target the enzymatic activity of NA receptors, mimicking the binding of sialic acid in the active site of NA on IAV and IBV virions so that viral release from infected cells and the rate of viral replication are impaired.", "NA inhibitors include oseltamivir, which is consumed orally in a prodrug form and converted to its active form in the liver, and zanamivir, which is a powder that is inhaled nasally.", "Oseltamivir and zanamivir are effective for prophylaxis and post-exposure prophylaxis, and research overall indicates that NA inhibitors are effective at reducing rates of complications, hospitalization, and mortality and the duration of illness.", "Additionally, the earlier NA inhibitors are provided, the better the outcome, though late administration can still be beneficial in severe cases.", "Other NA inhibitors include laninamivir and peramivir, the latter of which can be used as an alternative to oseltamivir for people who cannot tolerate or absorb it.", "The adamantanes amantadine and rimantadine are orally administered drugs that block the influenza virus's M2 ion channel, preventing viral uncoating.", "These drugs are only functional against IAV but are no longer recommended for use because of widespread resistance to them among IAVs.", "Adamantane resistance first emerged in H3N2 in 2003, becoming worldwide by 2008.", "Oseltamivir resistance is no longer widespread because the 2009 pandemic H1N1 strain (H1N1 pdm09), which is resistant to adamantanes, seemingly replaced resistant strains in circulation.", "Since the 2009 pandemic, oseltamivir resistance has mainly been observed in patients undergoing therapy, especially the immunocompromised and young children.", "Oseltamivir resistance is usually reported in H1N1, but has been reported in H3N2 and IBVs less commonly.", "Because of this, oseltamivir is recommended as the first drug of choice for immunocompetent people, whereas for the immunocompromised, oseltamivir is recommended against H3N2 and IBV and zanamivir against H1N1 pdm09.", "Zanamivir resistance is observed less frequently, and resistance to peramivir and baloxavir marboxil is possible.", "In healthy individuals, influenza infection is usually self-limiting and rarely fatal.", "Symptoms usually last for 2–8 days.", "Influenza can cause people to miss work or school, and it is associated with decreased job performance and, in older adults, reduced independence.", "Fatigue and malaise may last for several weeks after recovery, and healthy adults may experience pulmonary abnormalities that can take several weeks to resolve.", "Complications and mortality primarily occur in high-risk populations and those who are hospitalized.", "Severe disease and mortality are usually attributable to pneumonia from the primary viral infection or a secondary bacterial infection, which can progress to ARDS.", "Other respiratory complications that may occur include sinusitis, bronchitis, bronchiolitis, excess fluid buildup in the lungs, and exacerbation of chronic bronchitis and asthma.", "Middle ear infection and croup may occur, most commonly in children.", "Secondary \"S. aureus\" infection has been observed, primarily in children, to cause toxic shock syndrome after influenza, with hypotension, fever, and reddening and peeling of the skin.", "Complications affecting the cardiovascular system are rare and include pericarditis, fulminant myocarditis with a fast, slow, or irregular heartbeat, and exacerbation of pre-existing cardiovascular disease.", "Inflammation or swelling of muscles accompanied by muscle tissue breaking down occurs rarely, usually in children, which presents as extreme tenderness and muscle pain in the legs and a reluctance to walk for 2–3 days.", "Influenza can affect pregnancy, including causing smaller neonatal size, increased risk of premature birth, and an increased risk of child death shortly before or after birth.", "Neurological complications have been associated with influenza on rare occasions, including aseptic meningitis, encephalitis, disseminated encephalomyelitis, transverse myelitis, and Guillain–Barré syndrome.", "Additionally, febrile seizures and Reye syndrome can occur, most commonly in children.", "Influenza-associated encephalopathy can occur directly from central nervous system infection from the presence of the virus in blood and presents as suddent onset of fever with convulsions, followed by rapid progression to coma.", "An atypical form of encephalitis called encephalitis lethargica, characterized by headache, drowsiness, and coma, may rarely occur sometime after infection.", "In survivors of influenza-associated encephalopathy, neurological defects may occur.", "Primarily in children, in severe cases the immune system may rarely dramatically overproduce white blood cells that release cytokines, causing severe inflammation.", "People who are at least 65 years of age, due to a weakened immune system from aging or a chronic illness, are a high-risk group for developing complications, as are children less than one year of age and children who have not been previously exposed to influenza viruses multiple times.", "Pregnant women are at an elevated risk, which increases by trimester and lasts up to two weeks after childbirth.", "Obesity, in particular a body mass index greater than 35–40, is associated with greater amounts of viral replication, increased severity of secondary bacterial infection, and reduced vaccination efficacy.", "People who have underlying health conditions are also considered at-risk, including those who have congenital or chronic heart problems or lung (e.g. asthma), kidney, liver, blood, neurological, or metabolic (e.g. diabetes) disorders, as are people who are immunocompromised from chemotherapy, asplenia, prolonged steroid treatment, splenic dysfunction, or HIV infection.", "Current or past tobacco use also places a person at risk.", "The role of genetics in influenza is not well researched, but it may be a factor in influenza mortality.", "Influenza is typically characterized by seasonal epidemics and sporadic pandemics.", "Most of the burden of influenza is a result of flu seasons caused by IAV and IBV.", "Among IAV subtypes, H1N1 and H3N2 currently circulate in humans and are responsible for seasonal influenza.", "Cases disproportionately occur in children, but most severe causes are among the elderly, the very young, and the immunocompromised.", "In a typical year, influenza viruses infect 5–15% of the global population, causing 3–5 million cases of severe illness annually and accounting for 290,000–650,000 deaths each year due to respiratory illness.", "5–10% of adults and 20–30% of children contract influenza each year.", "The reported number of influenza cases is usually much lower than the actual number of cases.", "During seasonal epidemics, it is estimated that about 80% of otherwise healthy people who have a cough or sore throat have the flu.", "Approximately 30–40% of people hospitalized for influenza develop pneumonia, and about 5% of all severe pneumonia cases in hospitals are due to influenza, which is also the most common cause of ARDS in adults.", "In children, influenza is one of the two most common causes of ARDS, the other being the respiratory syncytial virus.", "About 3–5% of children each year develop otitis media due to influenza.", "Adults who develop organ failure from influenza and children who have PIM scores and acute renal failure have higher rates of mortality.", "During seasonal influenza, mortality is concentrated in the very young and the elderly, whereas during flu pandemics, young adults are often affected at a high rate.", "In temperate regions, the number of influenza cases varies from season to season.", "Lower vitamin D levels, presumably due to less sunlight, lower humidity, lower temperature, and minor changes in virus proteins caused by antigenic drift contribute to annual epidemics that peak during the winter season.", "In the northern hemisphere, this is from October to May (more narrowly December to April), and in the southern hemisphere, this is from May to October (more narrowly June to September).", "There are therefore two distinct influenza seasons every year in temperate regions, one in the northern hemisphere and one in the southern hemisphere.", "In tropical and subtropical regions, seasonality is more complex and appears to be affected by various climatic factors such as minimum temperature, hours of sunshine, maximum rainfall, and high humidity.", "Influenza may therefore occur year-round in these regions.", "Influenza epidemics in modern times have the tendency to start in the eastern or southern hemisphere, with Asia being a key reservoir of influenza viruses.", "IAV and IBV co-circulate, so the two have the same patterns of transmission.", "The seasonality of ICV, however, is poorly understood.", "ICV infection is most common in children under the age of 2, and by adulthood most people have been exposed to it.", "ICV-associated hospitalization most commonly occurs in children under the age of 3 and is frequently accompanied by co-infection with another virus or a bacterium, which may increase the severity of disease.", "When considering all hospitalizations for respiratory illness among young children, ICV appears to account for only a small percentage of such cases.", "Large outbreaks of ICV infection can occur, so incidence varies significantly.", "Outbreaks of influenza caused by novel influenza viruses are common.", "Depending on the level of pre-existing immunity in the population, novel influenza viruses can spread rapidly and cause pandemics with millions of deaths.", "These pandemics, in contrast to seasonal influenza, are caused by antigenic shifts involving animal influenza viruses.", "To date, all known flu pandemics have been caused by IAVs, and they follow the same pattern of spreading from an origin point to the rest of the world over the course of multiple waves in a year.", "Pandemic strains tend to be associated with higher rates of pneumonia in otherwise healthy individuals.", "Generally after each influenza pandemic, the pandemic strain continues to circulate as the cause of seasonal influenza, replacing prior strains.", "From 1700 to 1889, influenza pandemics occurred about once every 50–60 years.", "Since then, pandemics have occurred about once every 10–50 years, so they may be getting more frequent over time.", "It is impossible to know when an influenza virus first infected humans or when the first influenza pandemic occurred.", "Possibly the first influenza epidemic occurred around 6,000 BC in China, and possible descriptions of influenza exist in Greek writings from the 5th century BC.", "In both 1173–1174 AD and 1387 AD, epidemics occurred across Europe that were named \"influenza\".", "Whether these epidemics and others were caused by influenza is unclear since there was no consistent naming pattern for epidemic respiratory diseases at that time, and \"influenza\" didn't become completely attached to respiratory disease until centuries later.", "Influenza may have been brought to the Americas as early as 1493, when an epidemic disease resembling influenza killed most of the population of the Antilles.", "The first convincing record of an influenza pandemic was chronicled in 1510; it began in East Asia before spreading to North Africa and then Europe.", "Following the pandemic, seasonal influenza occurred, with subsequent pandemics in 1557 and 1580.", "The flu pandemic in 1557 was potentially the first time influenza was connected to miscarriage and death of pregnant women.", "The 1580 flu pandemic originated in Asia during summer, spread to Africa, then Europe, and finally America.", "By the end of the 16th century, influenza was likely beginning to become understood as a specific, recognizable disease with epidemic and endemic forms.", "In 1648, it was discovered that horses also experience influenza.", "Influenza data after 1700 is more informative, so it is easier to identify flu pandemics after this point, each of which incrementally increased understanding of influenza.", "The first flu pandemic of the 18th century started in 1729 in Russia in spring, spreading worldwide over the course of three years with distinct waves, the later ones being more lethal.", "The second flu pandemic of the 18th century was in 1781–1782, starting in China in autumn.", "From this pandemic, influenza became associated with sudden outbreaks of febrile illness.", "The next flu pandemic was from 1830 to 1833, beginning in China in winter.", "This pandemic had a high attack rate, but the mortality rate was low.", "A minor influenza pandemic occurred from 1847 to 1851 at the same time as the third cholera pandemic and was the first flu pandemic to occur with vital statistics being recorded, so influenza mortality was clearly recorded for the first time.", "Highly pathogenic avian influenza was recognized in 1878 and was soon linked to transmission to humans.", "By the time of the 1889 pandemic, which may have been caused by an H2N2 strain, the flu had become an easily recognizable disease.", "Initially, the microbial agent responsible for influenza was incorrently identified in 1892 by R. F. J. Pfeiffer as the bacteria species \"Haemophilus influenzae\", which retains \"influenza\" in its name.", "In the following years, the field of virology began to form as viruses were identified as the cause of many diseases.", "From 1901 to 1903, Italian and Austrian researchers were able to show that avian influenza, then called \"fowl plague\", was caused by a microscopic agent smaller than bacteria by using filters with pores too small for bacteria to pass through.", "The fundamental differences between viruses and bacteria, however, were not yet fully understood.", "From 1918 to 1920, the Spanish flu pandemic became the most devastating influenza pandemic and one of the deadliest pandemics in history.", "The pandemic, probably caused by H1N1, likely began in the USA before spreading worldwide by soldiers during and after the First World War.", "The initial wave in the first half of 1918 was relatively minor and resembled past flu pandemics, but the second wave later that year had a much higher mortality rate, accounting for most deaths.", "A third wave with lower mortality occurred in many places a few months after the second.", "By the end of 1920, it is estimated that about a third to half of all people in the world had been infected, with tens of millions of deaths, disproportionately young adults.", "During the 1918 pandemic, the respiratory route of transmission was clearly identified and influenza was shown to be caused by a \"filter passer\", not a bacterium, but there remained a lack of agreement about influenza's cause for another decade and research on influenza declined.", "After the pandemic, H1N1 circulated in humans in seasonal form up until the next pandemic.", "In 1931, Richard Shope published three papers identifying a virus as the cause of swine influenza, a then newly recognized disease among pigs that was first characterized during the second wave of the 1918 pandemic.", "Shope's research reinvigorated research on human influenza, and many advances in virology, serology, immunology, experimental animal models, vaccinology, and immunotherapy have since arisen from influenza research.", "Just two years after influenza viruses were discovered, in 1933, IAV was identified as the agent responsible for human influenza.", "Subtypes of IAV were discovered throughout the 1930s, and IBV was discovered in 1940.", "During the Second World War, the US government worked on developing inactivated vaccines for influenza, resulting in the first influenza vaccine being licensed in 1945 in the United States.", "ICV was discovered two years later in 1947.", "In 1955, avian influenza was confirmed to be caused by IAV.", "Four influenza pandemics have occurred since WWII, each less severe than the 1918 pandemic.", "The first of these was the Asian flu from 1957 to 1958, caused by an H2N2 strain and beginning in China's Yunnan province.", "The number of deaths probably exceeded one million, mostly among the very young and very old.", "Notably, the 1957 pandemic was the first flu pandemic to occur in the presence of a global surveillance system and laboratories able to study the novel influenza virus.", "After the pandemic, H2N2 was the IAV subtype responsible for seasonal influenza.", "The first antiviral drug against influenza, amantadine, was approved for use in 1966, with additional antiviral drugs being used since the 1990s.", "In 1968, H3N2 was introduced into humans as a result of a reassortment between an avian H3N2 strain and an H2N2 strain that was circulating in humans.", "The novel H3N2 strain first emerged in Hong Kong and spread worldwide, causing the Hong Kong flu pandemic, which resulted in 500,000–2,000,000 deaths.", "This was the first pandemic to spread significantly by air travel.", "H2N2 and H3N2 co-circulated after the pandemic until 1971 when H2N2 waned in prevalence and was completely replaced by H3N2.", "In 1977, H1N1 reemerged in humans, possibly after it was released from a freezer in a laboratory accident, and caused a pseudo-pandemic.", "Whether the 1977 \"pandemic\" deserves to be included in the natural history of flu pandemics is debatable.", "This H1N1 strain was antigenically similar to the H1N1 strains that circulated prior to 1957.", "Since 1977, both H1N1 and H3N2 have circulated in humans as part of seasonal influenza.", "In 1980, the current classification system used to subtype influenza viruses was introduced.", "At some point, IBV diverged into two lineages, named the B/Victoria-like and B/Yamagata-like lineages, both of which have been circulating in humans since 1983.", "In 1996, HPAI H5N1 was detected in Guangdong, China and a year later emerged in poultry in Hong Kong, gradually spreading worldwide from there.", "A small H5N1 outbreak in humans in Hong Kong occurred then, and sporadic human cases have occurred since 1997, carrying a high case fatality rate.", "The most recent flu pandemic was the 2009 swine flu pandemic, which originated in Mexico and resulted in hundreds of thousands of deaths.", "It was caused by a novel H1N1 strain that was a reassortment of human, swine, and avian influenza viruses.", "The 2009 pandemic had the effect of replacing prior H1N1 strains in circulation with the novel strain but not any other influenza viruses.", "Consequently, H1N1, H3N2, and both IBV lineages have been in circulation in seasonal form since the 2009 pandemic.", "In 2011, IDV was discovered in pigs in Oklahoma, USA, and cattle were later identified as the primary reservoir of IDV.", "In the same year, avian H7N9 was detected in China and began to cause human infections in 2013, starting in Shanghai and Anhui and remaining mostly in China.", "HPAI H7N9 emerged sometime in 2016 and has occasionally infected humans incidentally.", "Other AIVs have less commonly infected humans since the 1990s, including H5N6, H6N1, H7N2-4, H7N7, and H10N7-8, and HPAI H subtypes such as H5N1-3, H5N5-6, and H5N8 have begun to spread throughout much of the world since the 2010s.", "Future flu pandemics, which may be caused by an influenza virus of avian origin, are viewed as almost inevitable, and increased globalization has made it easier for novel viruses to spread, so there are continual efforts to prepare for future pandemics and improve the prevention and treatment of influenza.", "The word \"influenza\" comes from the Italian word \"influenza\", from medieval Latin \"influentia\", originally meaning \"visitation\" or \"influence\".", "Terms such as \"influenza di freddo\", meaning \"influence of the cold\", and \"influenza di stelle\", meaning \"influence of the stars\" are attested from the 14th century.", "The latter referred to the disease's cause, which at the time was ascribed by some to unfavorable astrological conditions.", "As early as 1504, \"influenza\" began to mean a \"visitation\" or \"outbreak\" of any disease affecting many people in a single place at once.", "During an outbreak of influenza in 1743 that started in Italy and spread throughout Europe, the word reached the English language and was anglicized in pronunciation.", "Since the mid-1800s, \"influenza\" has also been used to refer to severe colds.", "The shortened form of the word, \"(the) flu\", is first attested in 1839 as \"flue\" with the spelling \"flu\" first attested in 1893.", "Other names that have been used for influenza include \"epidemic catarrh\", \"la grippe\" from French, \"sweating sickness\", and, especially when referring to the 1918 pandemic strain, \"Spanish fever\".", "Influenza research is wide-ranging and includes efforts to understand how influenza viruses enter hosts, the relationship between influenza viruses and bacteria, how influenza symptoms progress, and what make some influenza viruses deadlier than others.", "Non-structural proteins encoded by influenza viruses are periodically discovered and their functions are continually under research.", "Past pandemics, and especially the 1918 pandemic, are the subject of much research to understand flu pandemics.", "As part of pandemic preparedness, the Global Influenza Surveillance and Response System is a global network of laboratories that monitors influenza transmission and epidemiology.", "Additional areas of research include ways to improve the diagnosis, treatment, and prevention of influenza.", "Existing diagnostic methods have a variety of limitations coupled with their advantages.", "For example, NATs have high sensitivity and specificity but are impractical in under-resourced regions due to their high cost, complexity, maintenance, and training required.", "Low-cost, portable RIDTs can rapidly diagnose influenza but have highly variable sensitivity and are unable to subtype IAV.", "As a result of these limitations and others, research into new diagnostic methods revolves around producing new methods that are cost-effective, less labor-intensive, and less complex than existing methods while also being able to differentiate influenza species and IAV subtypes.", "One approach in development are lab-on-a-chips, which are diagnostic devices that make use of a variety of diagnostic tests, such as RT-PCR and serological assays, in microchip form.", "These chips have many potential advantages, including high reaction efficiency, low energy consumption, and low waste generation.", "New antiviral drugs are also in development due to the elimination of adamantines as viable drugs and concerns over oseltamivir resistance.", "These include: NA inhibitors that can be injected intravenously, such as intravenous formulations of zanamivir; favipiravir, which is a polymerase inhibitor used against several RNA viruses; pimodivir, which prevents cap-binding required during viral transcription; and nitazoxanide, which inhibits HA maturation.", "Reducing excess inflammation in the respiratory tract is also subject to much research since this is one of the primary mechanisms of influenza pathology.", "Other forms of therapy in development include monoclonal and polyclonal antibodies that target viral proteins, convalescent plasma, different approaches to modify the host antiviral response, and stem cell-based therapies to repair lung damage.", "Much research on LAIVs focuses on identifying genome sequences that can be deleted to create harmless influenza viruses in vaccines that still confer immunity.", "The high variability and rapid evolution of influenza virus antigens, however, is a major obstacle in developing effective vaccines.", "Furthermore, it is hard to predict which strains will be in circulation during the next flu season, manufacturing a sufficient quantity of flu vaccines for the next season is difficult, LAIVs have limited efficacy, and repeated annual vaccination potentially has diminished efficacy.", "For these reasons, \"broadly-reactive\" or \"universal\" flu vaccines are being researched that can provide protection against many or all influenza viruses.", "Approaches to develop such a vaccine include HA stalk-based methods such as chimeras that have the same stalk but different heads, HA head-based methods such as computationally optimized broadly neutralizing antigens, anti-idiotypic antibodies, and vaccines to elicit immune responses to highly conserved viral proteins.", "mRNA vaccines to provide protection against influenza are also under research.", "Aquatic birds such as ducks, geese, shorebirds, and gulls are the primary reservoir of IAVs.", "In birds, AIVs may be either low pathogenic avian influenza (LPAI) viruses that produce little to no symptoms or highly pathogenic avian influenza (HPAI) viruses that cause severe illness.", "Symptoms of HPAI infection include lack of energy and appetite, decreased egg production, soft-shelled or misshapen eggs, swelling of the head, comb, wattles, and hocks, purple discoloration of wattles, combs, and legs, nasal discharge, coughing, sneezing, incoordination, and diarrhea.", "Birds infected with an HPAI virus may also die suddenly without any signs of infection.", "The distinction between LPAI and HPAI can generally be made based on how lethal an AIV is to chickens.", "At the genetic level, an AIV can be usually be identified as an HPAI virus if it has a multibasic cleavage site in the HA protein, which contains additional residues in the HA gene.", "Most AIVs are LPAI.", "Notable HPAI viruses include HPAI H5N1 and HPAI H7N9.", "HPAI viruses have been a major disease burden in the 21st century, resulting in the death of large numbers of birds.", "In H7N9's case, some circulating strains were originally LPAI but became HPAI by acquiring the HA multibasic cleavage site.", "Avian H9N2 is also of concern because although it is LPAI, it is a common donor of genes to H5N1 and H7N9 during reassortment.", "Migratory birds can spread influenza across long distances.", "An example of this was when an H5N1 strain in 2005 infected birds at Qinghai Lake, China, which is a stopover and breeding site for many migratory birds, subsequently spreading the virus to more than 20 countries across Asia, Europe, and the Middle East.", "AIVs can be transmitted from wild birds to domestic free-range ducks and in turn to poultry through contaminated water, aerosols, and fomites.", "Ducks therefore act as key intermediates between wild and domestic birds.", "Transmission to poultry typically occurs in backyard farming and live animal markets where multiple species interact with each other.", "From there, AIVs can spread to poultry farms in the absence of adequate biosecurity.", "Among poultry, HPAI transmission occurs through aerosols and contaminated feces, cages, feed, and dead animals.", "Back-transmission of HPAI viruses from poultry to wild birds has occurred and is implicated in mass die-offs and intercontinental spread.", "AIVs have occasionally infected humans through aerosols, fomites, and contaminated water.", "Direction transmission from wild birds is rare.", "Instead, most transmission involves domestic poultry, mainly chickens, ducks, and geese but also a variety of other birds such as guinea fowl, partridge, pheasants, and quails.", "The primary risk factor for infection with AIVs is exposure to birds in farms and live poultry markets.", "Typically, infection with an AIV has an incubation period of 3–5 days but can be up to 9 days.", "H5N1 and H7N9 cause severe lower respiratory tract illness, whereas other AIVs such as H9N2 cause a more mild upper respiratory tract illness, commonly with conjunctivitis.", "Limited transmission of avian H2, H5-7, H9, and H10 subtypes from one person to another through respiratory droplets, aerosols, and fomites has occurred, but sustained human-to-human transmission of AIVs has not occurred.", "Before 2013, H5N1 was the most common AIV to infect humans.", "Since then, H7N9 has been responsible for most human cases.", "Influenza in pigs is a respiratory disease similar to influenza in humans and is found worldwide.", "Asymptomatic infections are common.", "Symptoms typically appear 1–3 days after infection and include fever, lethargy, anorexia, weight loss, labored breathing, coughing, sneezing, and nasal discharge.", "In sows, pregnancy may be aborted.", "Complications include secondary infections and potentially fatal bronchopneumonia.", "Pigs become contagious within a day of infection and typically spread the virus for 7–10 days, which can spread rapidly within a herd.", "Pigs usually recover from infection within 3–7 days after symptoms appear.", "Prevention and control measures include inactivated vaccines and culling infected herds.", "The influenza viruses usually responsible for swine flu are IAV subtypes H1N1, H1N2, and H3N2.", "Some IAVs can be transmitted via aerosols from pigs to humans and vice versa.", "Furthermore, pigs, along with bats and quails, are recognized as a mixing vessel of influenza viruses because they have both α-2,3 and α-2,6 sialic acid receptors in their respiratory tract.", "Because of that, both avian and mammalian influenza viruses can infect pigs.", "If co-infection occurs, then reassortment is possible.", "A notable example of this was the reassortment of a swine, avian, and human influenza virus in 2009, resulting in a novel H1N1 strain that caused the 2009 flu pandemic.", "Spillover events from humans to pigs, however, appear to be more common than from pigs to humans.", "Influenza viruses have been found in many other animals, including cattle, horses, dogs, cats, and marine mammals.", "Nearly all IAVs are apparently descended from ancestral viruses in birds.", "The exception are bat influenza-like viruses, which have an uncertain origin.", "These bat viruses have HA and NA subtypes H17, H18, N10, and N11.", "H17N10 and H18N11 are unable to reassort with other IAVs, but they are still able to replicate in other mammals.", "AIVs sometimes crossover into mammals.", "For example, in late 2016 to early 2017, an avian H7N2 strain was found to be infecting cats in New York.", "Equine IAVs include H7N7 and two lineages of H3N8.", "H7N7, however, has not been detected in horses since the late 1970s, so it may have become extinct in horses.", "H3N8 in equines spreads via aerosols and causes respiratory illness.", "Equine H3N8 perferentially binds to α-2,3 sialic acids, so horses are usually considered dead-end hosts, but transmission to dogs and camels has occurred, raising concerns that horses may be mixing vessels for reassortment.", "In canines, the only IAVs in circulation are equine-derived H3N8 and avian-derived H3N2.", "Canine H3N8 has not been observed to reassort with other subtypes.", "H3N2 has a much broader host range and can reassort with H1N1 and H5N1.", "An isolated case of H6N1 likely from a chicken was found infecting a dog, so other AIVs may emerge in canines.", "Other mammals to be infected by IAVs include H7N7 and H4N5 in seals, H1N3 in whales, and H10N4 and H3N2 in minks.", "Various mutations have been identified that are associated with AIVs adapting to mammals.", "Since HA proteins vary in which sialic acids they bind to, mutations in the HA receptor binding site can allow AIVs to infect mammals.", "Other mutations include mutations affecting which sialic acids NA proteins cleave and a mutation in the PB2 polymerase subunit that improves tolerance of lower temperatures in mammalian respiratory tracts and enhances RNP assembly by stabilizing NP and PB2 binding.", "IBV is mainly found in humans but has also been detected in pigs, dogs, horses, and seals.", "Likewise, ICV primarily infects humans but has been observed in pigs, dogs, cattle, and dromedary camels.", "IDV causes an influenza-like illness in pigs but its impact in its natural reservoir, cattle, is relatively unknown.", "It may cause respiratory disease resembling human influenza on its own, or it may be part of a bovine respiratory disease (BRD) complex with other pathogens during co-infection.", "BRD is a concern for the cattle industry, so IDV's possible involvement in BRD has led to research on vaccines for cattle that can provide protection against IDV.", "Two antigenic lineages are in circulation: D/swine/Oklahoma/1334/2011 (D/OK) and D/bovine/Oklahoma/660/2013 (D/660)." ]

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[ "Frequent hand washing and covering one's mouth and nose when coughing and sneezing reduce transmission.", "Vaccines currently in use provide protection against IAV subtypes H1N1 and H3N2 and one or two IBV subtypes.", "The disease can be treated with supportive measures and, in severe cases, with antiviral drugs such as oseltamivir.", "Deaths most commonly occur in high-risk groups, including young children, the elderly, and people with chronic health conditions." ]

[ "The time between exposure to the virus and development of symptoms, called the incubation period, is 1–4 days, most commonly 1–2 days.", "Many infections, however, are asymptomatic.", "The onset of symptoms is sudden, and initial symptoms are predominately non-specific, including fever, chills, headaches, muscle pain or aching, a feeling of discomfort, loss of appetite, lack of energy/fatigue, and confusion.", "These symptoms are usually accompanied by respiratory symptoms such as a dry cough, sore or dry throat, hoarse voice, and a stuffy or runny nose.", "Coughing is the most common symptom.", "Gastrointestinal symptoms may also occur, including nausea, vomiting, diarrhea, and gastroenteritis, especially in children.", "The standard influenza symptoms typically last for 2–8 days.", "A 2021 study suggests influenza can cause long lasting symptoms in a similar way to long COVID.\nSymptomatic infections are usually mild and limited to the upper respiratory tract, but progression to pneumonia is relatively common.", "Pneumonia may be caused by the primary viral infection or by a secondary bacterial infection.", "Primary pneumonia is characterized by rapid progression of fever, cough, labored breathing, and low oxygen levels that cause bluish skin.", "It is especially common among those who have an underlying cardiovascular disease such as rheumatic heart disease.", "Secondary pneumonia typically has a period of improvement in symptoms for 1–3 weeks followed by recurrent fever, sputum production, and fluid buildup in the lungs, but can also occur just a few days after influenza symptoms appear.", "About a third of primary pneumonia cases are followed by secondary pneumonia, which is most frequently caused by the bacteria \"Streptococcus pneumoniae\" and \"Staphylococcus aureus\".", "Influenza viruses comprise four species.", "Each of the four species is the sole member of its own genus, and the four influenza genera comprise four of the seven genera in the family \"Orthomyxoviridae\".", "They are:\n\n\nIAV is responsible for most cases of severe illness as well as seasonal epidemics and occasional pandemics.", "It infects people of all ages but tends to disproportionately cause severe illness in the elderly, the very young, and those who have chronic health issues.", "Birds are the primary reservoir of IAV, especially aquatic birds such as ducks, geese, shorebirds, and gulls, but the virus also circulates among mammals, including pigs, horses, and marine mammals.", "IAV is classified into subtypes based on the viral proteins haemagglutinin (H) and neuraminidase (N).", "As of 2019, 18 H subtypes and 11 N subtypes have been identified.", "Most potential combinations have been reported in birds, but H17-18 and N10-11 have only been found in bats.", "Only H subtypes H1-3 and N subtypes N1-2 are known to have circulated in humans, the current IAV subtypes in circulation being H1N1 and H3N2.", "IAVs can be classified more specifically to also include natural host species, geographical origin, year of isolation, and strain number, such as H1N1/A/duck/Alberta/35/76.", "IBV mainly infects humans but has been identified in seals, horses, dogs, and pigs.", "IBV does not have subtypes like IAV but has two antigenically distinct lineages, termed the B/Victoria/2/1987-like and B/Yamagata/16/1988-like lineages, or simply (B/)Victoria(-like) and (B/)Yamagata(-like).", "Both lineages are in circulation in humans, disproportionately affecting children.", "IBVs contribute to seasonal epidemics alongside IAVs but have never been associated with a pandemic.", "ICV, like IBV, is primarily found in humans, though it also has been detected in pigs, feral dogs, dromedary camels, cattle, and dogs.", "ICV infection primarily affects children and is usually asymptomatic or has mild cold-like symptoms, though more severe symptoms such as gastroenteritis and pneumonia can occur.", "Unlike IAV and IBV, ICV has not been a major focus of research pertaining to antiviral drugs, vaccines, and other measures against influenza.", "ICV is subclassified into six genetic/antigenic lineages.", "IDV has been isolated from pigs and cattle, the latter being the natural reservoir.", "Infection has also been observed in humans, horses, dromedary camels, and small ruminants such as goats and sheep.", "IDV is distantly related to ICV.", "While cattle workers have occasionally tested positive to prior IDV infection, it is not known to cause disease in humans.", "ICV and IDV experience a slower rate of antigenic evolution than IAV and IBV.", "Because of this antigenic stability, relatively few novel lineages emerge.", "Influenza viruses have a negative-sense, single-stranded RNA genome that is segmented.", "The negative sense of the genome means it can be used as a template to synthesize messenger RNA (mRNA).", "IAV and IBV have eight genome segments that encode 10 major proteins.", "ICV and IDV have seven genome segments that encode nine major proteins.", "Three segments encode three subunits of an RNA-dependent RNA polymerase (RdRp) complex: PB1, a transcriptase, PB2, which recognizes 5' caps, and PA (P3 for ICV and IDV), an endonuclease.", "The matrix protein (M1) and membrane protein (M2) share a segment, as do the non-structural protein (NS1) and the nuclear export protein (NEP).", "For IAV and IBV, hemagglutinin (HA) and neuraminidase (NA) are encoded on one segment each, whereas ICV and IDV encode a hemagglutinin-esterase fusion (HEF) protein on one segment that merges the functions of HA and NA.", "The final genome segment encodes the viral nucleoprotein (NP).", "Influenza viruses also encode various accessory proteins, such as PB1-F2 and PA-X, that are expressed through alternative open reading frames and which are important in host defense suppression, virulence, and pathogenicity.", "The virus particle, called a virion, is pleomorphic and varies between being filamentous, bacilliform, or spherical in shape.", "Clinical isolates tend to be pleomorphic, whereas strains adapted to laboratory growth typically produce spherical virions.", "Filamentous virions are about 250 nanometers (nm) by 80 nm, bacilliform 120–250 by 95 nm, and spherical 120 nm in diameter.", "The virion consists of each segment of the genome bound to nucleoproteins in separate ribonucleoprotein (RNP) complexes for each segment, all of which are surrounded by a lipid bilayer membrane called the viral envelope.", "There is a copy of the RdRp, all subunits included, bound to each RNP.", "The envelope is reinforced structurally by matrix proteins on the interior that enclose the RNPs, and the envelope contains HA and NA (or HEF) proteins extending outward from the exterior surface of the envelope.", "HA and HEF proteins have a distinct \"head\" and \"stalk\" structure.", "M2 proteins form proton ion channels through the viral envelope that are required for viral entry and exit.", "IBVs contain a surface protein named NB that is anchored in the envelope, but its function is unknown.", "The viral life cycle begins by binding to a target cell.", "Binding is mediated by the viral HA proteins on the surface of the evelope, which bind to cells that contain sialic acid receptors on the surface of the cell membrane.", "For N1 subtypes with the \"G147R\" mutation and N2 subtypes, the NA protein can initiate entry.", "Prior to binding, NA proteins promote access to target cells by degrading mucous, which helps to remove extracellular decoy receptors that would impede access to target cells.", "After binding, the virus is internalized into the cell by an endosome that contains the virion inside it.", "The endosome is acidified by cellular vATPase to have lower pH, which triggers a conformational change in HA that allows fusion of the viral envelope with the endosomal membrane.", "At the same time, hydrogen ions diffuse into the virion through M2 ion channels, disrupting internal protein-protein interactions to release RNPs into the host cell's cytosol.", "The M1 protein shell surrounding RNPs is degraded, fully uncoating RNPs in the cytosol.", "RNPs are then imported into the nucleus with the help of viral localization signals.", "There, the viral RNA polymerase transcribes mRNA using the genomic negative-sense strand as a template.", "The polymerase snatches 5' caps for viral mRNA from cellular RNA to prime mRNA synthesis and the 3'-end of mRNA is polyadenylated at the end of transcription.", "Once viral mRNA is transcribed, it is exported out of the nucleus and translated by host ribosomes in a cap-dependent manner to synthesize viral proteins.", "RdRp also synthesizes complementary positive-sense strands of the viral genome in a complementary RNP complex which are then used as templates by viral polymerases to synthesize copies of the negative-sense genome.", "During these processes, RdRps of avian influenza viruses (AIVs) function optimally at a higher temperature than mammalian influenza viruses.", "Newly synthesized viral polymerase subunits and NP proteins are imported to the nucleus to further increase the rate of viral replication and form RNPs.", "HA, NA, and M2 proteins are trafficked with the aid of M1 and NEP proteins to the cell membrane through the Golgi apparatus and inserted into the cell's membrane.", "Viral non-structural proteins including NS1, PB1-F2, and PA-X regulate host cellular processes to disable antiviral responses.", "PB1-F2 aso interacts with PB1 to keep polymerases in the nucleus longer.", "M1 and NEP proteins localize to the nucleus during the later stages of infection, bind to viral RNPs and mediate their export to the cytoplasm where they migrate to the cell membrane with the aid of recycled endosomes and are bundled into the segments of the genome.", "Progenic viruses leave the cell by budding from the cell membrane, which is initiated by the accumulation of M1 proteins at the cytoplasmic side of the membrane.", "The viral genome is incorporated inside a viral envelope derived from portions of the cell membrane that have HA, NA, and M2 proteins.", "At the end of budding, HA proteins remain attached to cellular sialic acid until they are cleaved by the sialidase activity of NA proteins.", "The virion is then released from the cell.", "The sialidase activity of NA also cleaves any sialic acid residues from the viral surface, which helps prevent newly assembled viruses from aggregating near the cell surface and improving infectivity.", "Similar to other aspects of influenza replication, optimal NA activity is temperature- and pH-dependent.", "Ultimately, presence of large quantities of viral RNA in the cell triggers apoptosis, i.e. programmed cell death, which is initiated by cellular factors to restrict viral replication.", "Two key processes that influenza viruses evolve through are antigenic drift and antigenic shift.", "Antigenic drift is when an influenza virus's antigens change due to the gradual accumulation of mutations in the antigen's (HA or NA) gene.", "This can occur in response to evolutionary pressure exerted by the host immune response.", "Antigenic drift is especially common for the HA protein, in which just a few amino acid changes in the head region can constitute antigenic drift.", "The result is the production of novel strains that can evade pre-existing antibody-mediated immunity.", "Antigenic drift occurs in all influenza species but is slower in B than A and slowest in C and D. Antigenic drift is a major cause of seasonal influenza, and requires that flu vaccines be updated annually.", "HA is the main component of inactivated vaccines, so surveillance monitors antigenic drift of this antigen among circulating strains.", "Antigenic evolution of influenza viruses of humans appears to be faster than influenza viruses in swine and equines.", "In wild birds, within-subtype antigenic variation appears to be limited but has been observed in poultry.", "Antigenic shift is a sudden, drastic change in an influenza virus's antigen, usually HA.", "During antigenic shift, antigenically different strains that infect the same cell can reassort genome segments with each other, producing hybrid progeny.", "Since all influenza viruses have segmented genomes, all are capable of reassortment.", "Antigenic shift, however, only occurs among influenza viruses of the same genus and most commonly occurs among IAVs.", "In particular, reassortment is very common in AIVs, creating a large diversity of influenza viruses in birds, but is uncommon in human, equine, and canine lineages.", "Pigs, bats, and quails have receptors for both mammalian and avian IAVs, so they are potential \"mixing vessels\" for reassortment.", "If an animal strain reassorts with a human strain, then a novel strain can emerge that is capable of human-to-human transmission.", "This has caused pandemics, but only a limited number have occurred, so it is difficult to predict when the next will happen.", "People who are infected can transmit influenza viruses through breathing, talking, coughing, and sneezing, which spread respiratory droplets and aerosols that contain virus particles into the air.", "A person susceptible to infection can then contract influenza by coming into contact with these particles.", "Respiratory droplets are relatively large and travel less than two meters before falling onto nearby surfaces.", "Aerosols are smaller and remain suspended in the air longer, so they take longer to settle and can travel further than respiratory droplets.", "Inhalation of aerosols can lead to infection, but most transmission is in the area about two meters around an infected person via respiratory droplets that come into contact with mucosa of the upper respiratory tract.", "Transmission through contact with a person, bodily fluids, or intermediate objects (fomites) can also occur, such as through contaminated hands and surfaces since influenza viruses can survive for hours on non-porous surfaces.", "If one's hands are contaminated, then touching one's face can cause infection.", "Influenza is usually transmissible from one day before the onset of symptoms to 5–7 days after.", "In healthy adults, the virus is shed for up to 3–5 days.", "In children and the immunocompromised, the virus may be transmissible for several weeks.", "Children ages 2–17 are considered to be the primary and most efficient spreaders of influenza.", "Children who have not had multiple prior exposures to influenza viruses shed the virus at greater quantities and for a longer duration than other children.", "People who are at risk of exposure to influenza include health care workers, social care workers, and those who live with or care for people vulnerable to influenza.", "In long-term care facilities, the flu can spread rapidly after it is introduced.", "A variety of factors likely encourage influenza transmission, including lower temperature, lower absolute and relative humidity, less ultraviolet radiation from the Sun, and crowding.", "Influenza viruses that infect the upper respiratory tract like H1N1 tend to be more mild but more transmissible, whereas those that infect the lower respiratory tract like H5N1 tend to cause more severe illness but are less contagious.", "In humans, influenza viruses first cause infection by infecting epithelial cells in the respiratory tract.", "Illness during infection is primarily the result of lung inflammation and compromise caused by epithelial cell infection and death, combined with inflammation caused by the immune system's response to infection.", "Non-respiratory organs can become involved, but the mechanisms by which influenza is involved in these cases are unknown.", "Severe respiratory illness can be caused by multiple, non-exclusive mechanisms, including obstruction of the airways, loss of alveolar structure, loss of lung epithelial integrity due to epithelial cell infection and death, and degradation of the extracellular matrix that maintains lung structure.", "In particular, alveolar cell infection appears to drive severe symptoms since this results in impaired gas exchange and enables viruses to infect endothelial cells, which produce large quantities of pro-inflammatory cytokines.", "Pneumonia caused by influenza viruses is characterized by high levels of viral replication in the lower respiratory tract, accompanied by a strong pro-inflammatory response called a cytokine storm.", "Infection with H5N1 or H7N9 especially produces high levels of pro-inflammatory cytokines.", "In bacterial infections, early depletion of macrophages during influenza creates a favorable environment in the lungs for bacterial growth since these white blood cells are important in responding to bacterial infection.", "Host mechanisms to encourage tissue repair may inadvertently allow bacterial infection.", "Infection also induces production of systemic glucocorticoids that can reduce inflammation to preserve tissue integrity but allow increased bacterial growth.", "The pathophysiology of influenza is significantly influenced by which receptors influenza viruses bind to during entry into cells.", "Mammalian influenza viruses preferentially bind to sialic acids connected to the rest of the oligosaccharide by an α-2,6 link, most commonly found in various respiratory cells, such as respiratory and retinal epithelial cells.", "AIVs prefer sialic acids with an α-2,3 linkage, which are most common in birds in gastrointestinal epithelial cells and in humans in the lower respiratory tract.", "Furthermore, cleavage of the HA protein into HA, the binding subunit, and HA, the fusion subunit, is performed by different proteases, affecting which cells can be infected.", "For mammalian influenza viruses and low pathogenic AIVs, cleavage is extracellular, which limits infection to cells that have the appropriate proteases, whereas for highly pathogenic AIVs, cleavage is intracellular and performed by ubiquitous proteases, which allows for infection of a greater variety of cells, thereby contributing to more severe disease.", "Cells possess sensors to detect viral RNA, which can then induce interferon production.", "Interferons mediate expression of antiviral proteins and proteins that recruit immune cells to the infection site, and they also notify nearby uninfected cells of infection.", "Some infected cells release pro-inflammatory cytokines that recruit immune cells to the site of infection.", "Immune cells control viral infection by killing infected cells and phagocytizing viral particles and apoptotic cells.", "An exacerbated immune response, however, can harm the host organism through a cytokine storm.", "To counter the immune response, influenza viruses encode various non-structural proteins, including NS1, NEP, PB1-F2, and PA-X, that are involved in curtailing the host immune response by suppressing interferon production and host gene expression.", "B cells, a type of white blood cell, produce antibodies that bind to influenza antigens HA and NA (or HEF) and other proteins to a lesser degree.", "Once bound to these proteins, antibodies block virions from binding to cellular receptors, neutralizing the virus.", "In humans, a sizeable antibody response occurs ~1 week after viral exposure.", "This antibody response is typically robust and long-lasting, especially for ICV and IDV.", "In other words, people exposed to a certain strain in childhood still possess antibodies to that strain at a reasonable level later in life, which can provide some protection to related strains.", "There is, however, an \"original antigenic sin\", in which the first HA subtype a person is exposed to influences the antibody-based immune response to future infections and vaccines.", "Annual vaccination is the primary and most effective way to prevent influenza and influenza-associated complications, especially for high-risk groups.", "Vaccines against the flu are trivalent or quadrivalent, providing protection against an H1N1 strain, an H3N2 strain, and one or two IBV strains corresponding to the two IBV lineages.", "Two types of vaccines are in use: inactivated vaccines that contain \"killed\" (i.e. inactivated) viruses and live attenuated influenza vaccines (LAIVs) that contain weakened viruses.", "There are three types of inactivated vaccines: whole virus, split virus, in which the virus is disrupted by a detergent, and subunit, which only contains the viral antigens HA and NA.", "Most flu vaccines are inactivated and administered via intramuscular injection.", "LAIVs are sprayed into the nasal cavity.", "Vaccination recommendations vary by country.", "Some recommend vaccination for all people above a certain age, such as 6 months, whereas other countries recommendation is limited for high at risk groups, such as pregnant women, young children (excluding newborns), the elderly, people with chronic medical conditions, health care workers, people who come into contact with high-risk people, and people who transmit the virus easily.", "Young infants cannot receive flu vaccines for safety reasons, but they can inherit passive immunity from their mother if inactivated vaccines are administered to the mother during pregnancy.", "Influenza vaccination also helps to reduce the probability of reassortment.", "In general, influenza vaccines are only effective if there is an antigenic match between vaccine strains and circulating strains.", "Additionally, most commercially available flu vaccines are manufactured by propagation of influenza viruses in embryonated chicken eggs, taking 6–8 months.", "Flu seasons are different in the northern and southern hemisphere, so the WHO meets twice a year, one for each hemisphere, to discuss which strains should be included in flu vaccines based on observation from HA inhibition assays.", "Other manufacturing methods include an MDCK cell culture-based inactivated vaccine and a recombinant subunit vaccine manufactured from baculovirus overexpression in insect cells.", "Influenza can be prevented or reduced in severity by post-exposure prophylaxis with the antiviral drugs oseltamivir, which can be taken orally by those at least three months old, and zanamivir, which can be inhaled by those above seven years of age.", "Chemoprophylaxis is most useful for individuals at high-risk of developing complications and those who cannot receive the flu vaccine due to contraindications or lack of effectiveness.", "Post-exposure chemoprophylaxis is only recommended if oseltamivir is taken within 48 hours of contact with a confirmed or suspected influenza case and zanamivir within 36 hours.", "It is recommended that it be offered to people who have yet to receive a vaccine for the current flu season, who have been vaccinated less than two week since contact, if there is a significant mismatch between vaccine and circulating strains, or during an outbreak in a closed setting regardless of vaccination history.", "Hand hygiene is important in reducing the spread of influenza.", "This includes frequent hand washing with soap and water, using alcohol-based hand sanitizers, and not touching one's eyes, nose, and mouth with one's hands.", "Covering one's nose and mouth when coughing or sneezing is important.", "Other methods to limit influenza transmission include staying home when sick, avoiding contact with others until one day after symptoms end, and disinfecting surfaces likely to be contaminated by the virus, such as doorknobs.", "Health education through media and posters is often used to remind people of the aforementioned etiquette and hygiene.", "There is uncertainty about the use of masks since research thus far has not shown a significant reduction in seasonal influenza with mask usage.", "Likewise, the effectiveness of screening at points of entry into countries is not well researched.", "Social distancing measures such as school closures, avoiding contact with infected people via isolation or quarantine, and limiting mass gatherings may reduce transmission, but these measures are often expensive, unpopular, and difficult to implement.", "Consequently, the commonly recommended methods of infection control are respiratory etiquette, hand hygiene, and mask wearing, which are inexpensive and easy to perform.", "Pharmaceutical measures are effective but may not be available in the early stages of an outbreak.", "In health care settings, infected individuals may be cohorted or assigned to individual rooms.", "Protective clothing such as masks, gloves, and gowns is recommended when coming into contact with infected individuals if there is a risk of exposure to infected bodily fluids.", "Keeping patients in negative pressure rooms and avoiding aerosol-producing activities may help, but special air handling and ventilation systems are not considered necessary to prevent the spread of influenza in the air.", "In residential homes, new admissions may need to be closed until the spread of influenza is controlled.", "When discharging patients to care homes, it is important to take care if there is a known influenza outbreak.", "Since influenza viruses circulate in animals such as birds and pigs, prevention of transmission from these animals is important.", "Water treatment, indoor raising of animals, quarantining sick animals, vaccination, and biosecurity are the primary measures used.", "Placing poultry houses and piggeries on high ground away from high-density farms, backyard farms, live poultry markets, and bodies of water helps to minimize contact with wild birds.", "Closure of live poultry markets appears to the most effective measure and has shown to be effective at controlling the spread of H5N1, H7N9, and H9N2.", "Other biosecurity measures include cleaning and disinfecting facilities and vehicles, banning visits to poultry farms, not bringing birds intended for slaughter back to farms, changing clothes, disinfecting foot baths, and treating food and water.", "If live poultry markets are not closed, then \"clean days\" when unsold poultry is removed and facilities are disinfected and \"no carry-over\" policies to eliminate infectious material before new poultry arrive can be used to reduce the spread of influenza viruses.", "If a novel influenza viruses has breached the aforementioned biosecurity measures, then rapid detection to stamp it out via quarantining, decontamination, and culling may be necessary to prevent the virus from becoming endemic.", "Vaccines exist for avian H5, H7, and H9 subtypes that are used in some countries.", "In China, for example, vaccination of domestic birds against H7N9 successfully limited its spread, indicating that vaccination may be an effective strategy if used in combination with other measures to limit transmission.", "In pigs and horses, management of influenza is dependent on vaccination with biosecurity.", "Diagnosis based on symptoms is fairly accurate in otherwise healthy people during seasonal epidemics and should be suspected in cases of pneumonia, acute respiratory distress syndrome (ARDS), sepsis, or if encephalitis, myocarditis, or breaking down of muscle tissue occur.", "Because influenza is similar to other viral respiratory tract illnesses, laboratory diagnosis is necessary for confirmation.", "Common ways of collecting samples for testing include nasal and throat swabs.", "Samples may be taken from the lower respiratory tract if infection has cleared the upper but not lower respiratory tract.", "Influenza testing is recommended for anyone hospitalized with symptoms resembling influenza during flu season or who is connected to an influenza case.", "For severe cases, earlier diagnosis improves patient outcome.", "Diagnostic methods that can identify influenza include viral cultures, antibody- and antigen-detecting tests, and nucleic acid-based tests.", "Viruses can be grown in a culture of mammalian cells or embryonated eggs for 3–10 days to monitor cytopathic effect.", "Final confirmation can then be done via antibody staining, hemadsorption using red blood cells, or immunofluorescence microscopy.", "Shell vial cultures, which can identify infection via immunostaining before a cytopathic effect appears, are more sensitive than traditional cultures with results in 1–3 days.", "Cultures can be used to characterize novel viruses, observe sensitivity to antiviral drugs, and monitor antigenic drift, but they are relatively slow and require specialized skills and equipment.", "Serological assays can be used to detect an antibody response to influenza after natural infection or vaccination.", "Common serological assays include hemagglutination inhibition assays that detect HA-specific antibodies, virus neutralization assays that check whether antibodies have neutralized the virus, and enzyme-linked immunoabsorbant assays.", "These methods tend to be relatively inexpensive and fast but are less reliable than nucleic-acid based tests.", "Direct fluorescent or immunofluorescent antibody (DFA/IFA) tests involve staining respiratory epithelial cells in samples with fluorescently-labeled influenza-specific antibodies, followed by examination under a fluorescent microscope.", "They can differentiate between IAV and IBV but can't subtype IAV.", "Rapid influenza diagnostic tests (RIDTs) are a simple way of obtaining assay results, are low cost, and produce results quickly, at less than 30 minutes, so they are commonly used, but they can't distinguish between IAV and IBV or between IAV subtypes and are not as sensitive as nucleic-acid based tests.", "Nucleic acid-based tests (NATs) amplify and detect viral nucleic acid.", "Most of these tests take a few hours, but rapid molecular assays are as fast as RIDTs.", "Among NATs, reverse transcription polymerase chain reaction (RT-PCR) is the most traditional and considered the gold standard for diagnosing influenza because it is fast and can subtype IAV, but it is relatively expensive and more prone to false-positives than cultures.", "Other NATs that have been used include loop-mediated isothermal amplification-based assays, simple amplification-based assays, and nucleic acid sequence-based amplification.", "Nucleic acid sequencing methods can identify infection by obtaining the nucleic acid sequence of viral samples to identify the virus and antiviral drug resistance.", "The traditional method is Sanger sequencing, but it has been largely replaced by next-generation methods that have greater sequencing speed and throughput.", "Treatment of influenza in cases of mild or moderate illness is supportive and includes anti-fever medications such as acetaminophen and ibuprofen, adequate fluid intake to avoid dehydration, and resting at home.", "Cough drops and throat sprays may be beneficial for sore throat.", "It is recommended to avoid alcohol and tobacco use while sick with the flu.", "Aspirin is not recommended to treat influenza in children due to an elevated risk of developing Reye syndrome.", "Corticosteroids likewise are not recommended except when treating septic shock or an underlying medical condition, such as chronic obstructive pulmonary disease or asthma exacerbation, since they are associated with increased mortality.", "If a secondary bacterial infection occurs, then treatment with antibiotics may be necessary.", "Antiviral drugs are primarily used to treat severely ill patients, especially those with compromised immune systems.", "Antivirals are most effective when started in the first 48 hours after symptoms appear.", "Later administration may still be beneficial for those who have underlying immune defects, those with more severe symptoms, or those who have a higher risk of developing complications if these individuals are still shedding the virus.", "Antiviral treatment is also recommended if a person is hospitalized with suspected influenza instead of waiting for test results to return and if symptoms are worsening.", "Most antiviral drugs against influenza fall into two categories: neuraminidase (NA) inhibitors and M2 inhibitors.", "Baloxavir marboxil is a notable exception, which targets the endonuclease activity of the viral RNA polymerase and can be used as an alternative to NA and M2 inhibitors for IAV and IBV.", "NA inhibitors target the enzymatic activity of NA receptors, mimicking the binding of sialic acid in the active site of NA on IAV and IBV virions so that viral release from infected cells and the rate of viral replication are impaired.", "NA inhibitors include oseltamivir, which is consumed orally in a prodrug form and converted to its active form in the liver, and zanamivir, which is a powder that is inhaled nasally.", "Oseltamivir and zanamivir are effective for prophylaxis and post-exposure prophylaxis, and research overall indicates that NA inhibitors are effective at reducing rates of complications, hospitalization, and mortality and the duration of illness.", "Additionally, the earlier NA inhibitors are provided, the better the outcome, though late administration can still be beneficial in severe cases.", "Other NA inhibitors include laninamivir and peramivir, the latter of which can be used as an alternative to oseltamivir for people who cannot tolerate or absorb it.", "The adamantanes amantadine and rimantadine are orally administered drugs that block the influenza virus's M2 ion channel, preventing viral uncoating.", "These drugs are only functional against IAV but are no longer recommended for use because of widespread resistance to them among IAVs.", "Adamantane resistance first emerged in H3N2 in 2003, becoming worldwide by 2008.", "Oseltamivir resistance is no longer widespread because the 2009 pandemic H1N1 strain (H1N1 pdm09), which is resistant to adamantanes, seemingly replaced resistant strains in circulation.", "Since the 2009 pandemic, oseltamivir resistance has mainly been observed in patients undergoing therapy, especially the immunocompromised and young children.", "Oseltamivir resistance is usually reported in H1N1, but has been reported in H3N2 and IBVs less commonly.", "Because of this, oseltamivir is recommended as the first drug of choice for immunocompetent people, whereas for the immunocompromised, oseltamivir is recommended against H3N2 and IBV and zanamivir against H1N1 pdm09.", "Zanamivir resistance is observed less frequently, and resistance to peramivir and baloxavir marboxil is possible.", "In healthy individuals, influenza infection is usually self-limiting and rarely fatal.", "Symptoms usually last for 2–8 days.", "Influenza can cause people to miss work or school, and it is associated with decreased job performance and, in older adults, reduced independence.", "Fatigue and malaise may last for several weeks after recovery, and healthy adults may experience pulmonary abnormalities that can take several weeks to resolve.", "Complications and mortality primarily occur in high-risk populations and those who are hospitalized.", "Severe disease and mortality are usually attributable to pneumonia from the primary viral infection or a secondary bacterial infection, which can progress to ARDS.", "Other respiratory complications that may occur include sinusitis, bronchitis, bronchiolitis, excess fluid buildup in the lungs, and exacerbation of chronic bronchitis and asthma.", "Middle ear infection and croup may occur, most commonly in children.", "Secondary \"S. aureus\" infection has been observed, primarily in children, to cause toxic shock syndrome after influenza, with hypotension, fever, and reddening and peeling of the skin.", "Complications affecting the cardiovascular system are rare and include pericarditis, fulminant myocarditis with a fast, slow, or irregular heartbeat, and exacerbation of pre-existing cardiovascular disease.", "Inflammation or swelling of muscles accompanied by muscle tissue breaking down occurs rarely, usually in children, which presents as extreme tenderness and muscle pain in the legs and a reluctance to walk for 2–3 days.", "Influenza can affect pregnancy, including causing smaller neonatal size, increased risk of premature birth, and an increased risk of child death shortly before or after birth.", "Neurological complications have been associated with influenza on rare occasions, including aseptic meningitis, encephalitis, disseminated encephalomyelitis, transverse myelitis, and Guillain–Barré syndrome.", "Additionally, febrile seizures and Reye syndrome can occur, most commonly in children.", "Influenza-associated encephalopathy can occur directly from central nervous system infection from the presence of the virus in blood and presents as suddent onset of fever with convulsions, followed by rapid progression to coma.", "An atypical form of encephalitis called encephalitis lethargica, characterized by headache, drowsiness, and coma, may rarely occur sometime after infection.", "In survivors of influenza-associated encephalopathy, neurological defects may occur.", "Primarily in children, in severe cases the immune system may rarely dramatically overproduce white blood cells that release cytokines, causing severe inflammation.", "People who are at least 65 years of age, due to a weakened immune system from aging or a chronic illness, are a high-risk group for developing complications, as are children less than one year of age and children who have not been previously exposed to influenza viruses multiple times.", "Pregnant women are at an elevated risk, which increases by trimester and lasts up to two weeks after childbirth.", "Obesity, in particular a body mass index greater than 35–40, is associated with greater amounts of viral replication, increased severity of secondary bacterial infection, and reduced vaccination efficacy.", "People who have underlying health conditions are also considered at-risk, including those who have congenital or chronic heart problems or lung (e.g. asthma), kidney, liver, blood, neurological, or metabolic (e.g. diabetes) disorders, as are people who are immunocompromised from chemotherapy, asplenia, prolonged steroid treatment, splenic dysfunction, or HIV infection.", "Current or past tobacco use also places a person at risk.", "The role of genetics in influenza is not well researched, but it may be a factor in influenza mortality.", "Influenza is typically characterized by seasonal epidemics and sporadic pandemics.", "Most of the burden of influenza is a result of flu seasons caused by IAV and IBV.", "Among IAV subtypes, H1N1 and H3N2 currently circulate in humans and are responsible for seasonal influenza.", "Cases disproportionately occur in children, but most severe causes are among the elderly, the very young, and the immunocompromised.", "In a typical year, influenza viruses infect 5–15% of the global population, causing 3–5 million cases of severe illness annually and accounting for 290,000–650,000 deaths each year due to respiratory illness.", "5–10% of adults and 20–30% of children contract influenza each year.", "The reported number of influenza cases is usually much lower than the actual number of cases.", "During seasonal epidemics, it is estimated that about 80% of otherwise healthy people who have a cough or sore throat have the flu.", "Approximately 30–40% of people hospitalized for influenza develop pneumonia, and about 5% of all severe pneumonia cases in hospitals are due to influenza, which is also the most common cause of ARDS in adults.", "In children, influenza is one of the two most common causes of ARDS, the other being the respiratory syncytial virus.", "About 3–5% of children each year develop otitis media due to influenza.", "Adults who develop organ failure from influenza and children who have PIM scores and acute renal failure have higher rates of mortality.", "During seasonal influenza, mortality is concentrated in the very young and the elderly, whereas during flu pandemics, young adults are often affected at a high rate.", "In temperate regions, the number of influenza cases varies from season to season.", "Lower vitamin D levels, presumably due to less sunlight, lower humidity, lower temperature, and minor changes in virus proteins caused by antigenic drift contribute to annual epidemics that peak during the winter season.", "In the northern hemisphere, this is from October to May (more narrowly December to April), and in the southern hemisphere, this is from May to October (more narrowly June to September).", "There are therefore two distinct influenza seasons every year in temperate regions, one in the northern hemisphere and one in the southern hemisphere.", "In tropical and subtropical regions, seasonality is more complex and appears to be affected by various climatic factors such as minimum temperature, hours of sunshine, maximum rainfall, and high humidity.", "Influenza may therefore occur year-round in these regions.", "Influenza epidemics in modern times have the tendency to start in the eastern or southern hemisphere, with Asia being a key reservoir of influenza viruses.", "IAV and IBV co-circulate, so the two have the same patterns of transmission.", "The seasonality of ICV, however, is poorly understood.", "ICV infection is most common in children under the age of 2, and by adulthood most people have been exposed to it.", "ICV-associated hospitalization most commonly occurs in children under the age of 3 and is frequently accompanied by co-infection with another virus or a bacterium, which may increase the severity of disease.", "When considering all hospitalizations for respiratory illness among young children, ICV appears to account for only a small percentage of such cases.", "Large outbreaks of ICV infection can occur, so incidence varies significantly.", "Outbreaks of influenza caused by novel influenza viruses are common.", "Depending on the level of pre-existing immunity in the population, novel influenza viruses can spread rapidly and cause pandemics with millions of deaths.", "These pandemics, in contrast to seasonal influenza, are caused by antigenic shifts involving animal influenza viruses.", "To date, all known flu pandemics have been caused by IAVs, and they follow the same pattern of spreading from an origin point to the rest of the world over the course of multiple waves in a year.", "Pandemic strains tend to be associated with higher rates of pneumonia in otherwise healthy individuals.", "Generally after each influenza pandemic, the pandemic strain continues to circulate as the cause of seasonal influenza, replacing prior strains.", "From 1700 to 1889, influenza pandemics occurred about once every 50–60 years.", "Since then, pandemics have occurred about once every 10–50 years, so they may be getting more frequent over time.", "It is impossible to know when an influenza virus first infected humans or when the first influenza pandemic occurred.", "Possibly the first influenza epidemic occurred around 6,000 BC in China, and possible descriptions of influenza exist in Greek writings from the 5th century BC.", "In both 1173–1174 AD and 1387 AD, epidemics occurred across Europe that were named \"influenza\".", "Whether these epidemics and others were caused by influenza is unclear since there was no consistent naming pattern for epidemic respiratory diseases at that time, and \"influenza\" didn't become completely attached to respiratory disease until centuries later.", "Influenza may have been brought to the Americas as early as 1493, when an epidemic disease resembling influenza killed most of the population of the Antilles.", "The first convincing record of an influenza pandemic was chronicled in 1510; it began in East Asia before spreading to North Africa and then Europe.", "Following the pandemic, seasonal influenza occurred, with subsequent pandemics in 1557 and 1580.", "The flu pandemic in 1557 was potentially the first time influenza was connected to miscarriage and death of pregnant women.", "The 1580 flu pandemic originated in Asia during summer, spread to Africa, then Europe, and finally America.", "By the end of the 16th century, influenza was likely beginning to become understood as a specific, recognizable disease with epidemic and endemic forms.", "In 1648, it was discovered that horses also experience influenza.", "Influenza data after 1700 is more informative, so it is easier to identify flu pandemics after this point, each of which incrementally increased understanding of influenza.", "The first flu pandemic of the 18th century started in 1729 in Russia in spring, spreading worldwide over the course of three years with distinct waves, the later ones being more lethal.", "The second flu pandemic of the 18th century was in 1781–1782, starting in China in autumn.", "From this pandemic, influenza became associated with sudden outbreaks of febrile illness.", "The next flu pandemic was from 1830 to 1833, beginning in China in winter.", "This pandemic had a high attack rate, but the mortality rate was low.", "A minor influenza pandemic occurred from 1847 to 1851 at the same time as the third cholera pandemic and was the first flu pandemic to occur with vital statistics being recorded, so influenza mortality was clearly recorded for the first time.", "Highly pathogenic avian influenza was recognized in 1878 and was soon linked to transmission to humans.", "By the time of the 1889 pandemic, which may have been caused by an H2N2 strain, the flu had become an easily recognizable disease.", "Initially, the microbial agent responsible for influenza was incorrently identified in 1892 by R. F. J. Pfeiffer as the bacteria species \"Haemophilus influenzae\", which retains \"influenza\" in its name.", "In the following years, the field of virology began to form as viruses were identified as the cause of many diseases.", "From 1901 to 1903, Italian and Austrian researchers were able to show that avian influenza, then called \"fowl plague\", was caused by a microscopic agent smaller than bacteria by using filters with pores too small for bacteria to pass through.", "The fundamental differences between viruses and bacteria, however, were not yet fully understood.", "From 1918 to 1920, the Spanish flu pandemic became the most devastating influenza pandemic and one of the deadliest pandemics in history.", "The pandemic, probably caused by H1N1, likely began in the USA before spreading worldwide by soldiers during and after the First World War.", "The initial wave in the first half of 1918 was relatively minor and resembled past flu pandemics, but the second wave later that year had a much higher mortality rate, accounting for most deaths.", "A third wave with lower mortality occurred in many places a few months after the second.", "By the end of 1920, it is estimated that about a third to half of all people in the world had been infected, with tens of millions of deaths, disproportionately young adults.", "During the 1918 pandemic, the respiratory route of transmission was clearly identified and influenza was shown to be caused by a \"filter passer\", not a bacterium, but there remained a lack of agreement about influenza's cause for another decade and research on influenza declined.", "After the pandemic, H1N1 circulated in humans in seasonal form up until the next pandemic.", "In 1931, Richard Shope published three papers identifying a virus as the cause of swine influenza, a then newly recognized disease among pigs that was first characterized during the second wave of the 1918 pandemic.", "Shope's research reinvigorated research on human influenza, and many advances in virology, serology, immunology, experimental animal models, vaccinology, and immunotherapy have since arisen from influenza research.", "Just two years after influenza viruses were discovered, in 1933, IAV was identified as the agent responsible for human influenza.", "Subtypes of IAV were discovered throughout the 1930s, and IBV was discovered in 1940.", "During the Second World War, the US government worked on developing inactivated vaccines for influenza, resulting in the first influenza vaccine being licensed in 1945 in the United States.", "ICV was discovered two years later in 1947.", "In 1955, avian influenza was confirmed to be caused by IAV.", "Four influenza pandemics have occurred since WWII, each less severe than the 1918 pandemic.", "The first of these was the Asian flu from 1957 to 1958, caused by an H2N2 strain and beginning in China's Yunnan province.", "The number of deaths probably exceeded one million, mostly among the very young and very old.", "Notably, the 1957 pandemic was the first flu pandemic to occur in the presence of a global surveillance system and laboratories able to study the novel influenza virus.", "After the pandemic, H2N2 was the IAV subtype responsible for seasonal influenza.", "The first antiviral drug against influenza, amantadine, was approved for use in 1966, with additional antiviral drugs being used since the 1990s.", "In 1968, H3N2 was introduced into humans as a result of a reassortment between an avian H3N2 strain and an H2N2 strain that was circulating in humans.", "The novel H3N2 strain first emerged in Hong Kong and spread worldwide, causing the Hong Kong flu pandemic, which resulted in 500,000–2,000,000 deaths.", "This was the first pandemic to spread significantly by air travel.", "H2N2 and H3N2 co-circulated after the pandemic until 1971 when H2N2 waned in prevalence and was completely replaced by H3N2.", "In 1977, H1N1 reemerged in humans, possibly after it was released from a freezer in a laboratory accident, and caused a pseudo-pandemic.", "Whether the 1977 \"pandemic\" deserves to be included in the natural history of flu pandemics is debatable.", "This H1N1 strain was antigenically similar to the H1N1 strains that circulated prior to 1957.", "Since 1977, both H1N1 and H3N2 have circulated in humans as part of seasonal influenza.", "In 1980, the current classification system used to subtype influenza viruses was introduced.", "At some point, IBV diverged into two lineages, named the B/Victoria-like and B/Yamagata-like lineages, both of which have been circulating in humans since 1983.", "In 1996, HPAI H5N1 was detected in Guangdong, China and a year later emerged in poultry in Hong Kong, gradually spreading worldwide from there.", "A small H5N1 outbreak in humans in Hong Kong occurred then, and sporadic human cases have occurred since 1997, carrying a high case fatality rate.", "The most recent flu pandemic was the 2009 swine flu pandemic, which originated in Mexico and resulted in hundreds of thousands of deaths.", "It was caused by a novel H1N1 strain that was a reassortment of human, swine, and avian influenza viruses.", "The 2009 pandemic had the effect of replacing prior H1N1 strains in circulation with the novel strain but not any other influenza viruses.", "Consequently, H1N1, H3N2, and both IBV lineages have been in circulation in seasonal form since the 2009 pandemic.", "In 2011, IDV was discovered in pigs in Oklahoma, USA, and cattle were later identified as the primary reservoir of IDV.", "In the same year, avian H7N9 was detected in China and began to cause human infections in 2013, starting in Shanghai and Anhui and remaining mostly in China.", "HPAI H7N9 emerged sometime in 2016 and has occasionally infected humans incidentally.", "Other AIVs have less commonly infected humans since the 1990s, including H5N6, H6N1, H7N2-4, H7N7, and H10N7-8, and HPAI H subtypes such as H5N1-3, H5N5-6, and H5N8 have begun to spread throughout much of the world since the 2010s.", "Future flu pandemics, which may be caused by an influenza virus of avian origin, are viewed as almost inevitable, and increased globalization has made it easier for novel viruses to spread, so there are continual efforts to prepare for future pandemics and improve the prevention and treatment of influenza.", "The word \"influenza\" comes from the Italian word \"influenza\", from medieval Latin \"influentia\", originally meaning \"visitation\" or \"influence\".", "Terms such as \"influenza di freddo\", meaning \"influence of the cold\", and \"influenza di stelle\", meaning \"influence of the stars\" are attested from the 14th century.", "The latter referred to the disease's cause, which at the time was ascribed by some to unfavorable astrological conditions.", "As early as 1504, \"influenza\" began to mean a \"visitation\" or \"outbreak\" of any disease affecting many people in a single place at once.", "During an outbreak of influenza in 1743 that started in Italy and spread throughout Europe, the word reached the English language and was anglicized in pronunciation.", "Since the mid-1800s, \"influenza\" has also been used to refer to severe colds.", "The shortened form of the word, \"(the) flu\", is first attested in 1839 as \"flue\" with the spelling \"flu\" first attested in 1893.", "Other names that have been used for influenza include \"epidemic catarrh\", \"la grippe\" from French, \"sweating sickness\", and, especially when referring to the 1918 pandemic strain, \"Spanish fever\".", "Influenza research is wide-ranging and includes efforts to understand how influenza viruses enter hosts, the relationship between influenza viruses and bacteria, how influenza symptoms progress, and what make some influenza viruses deadlier than others.", "Non-structural proteins encoded by influenza viruses are periodically discovered and their functions are continually under research.", "Past pandemics, and especially the 1918 pandemic, are the subject of much research to understand flu pandemics.", "As part of pandemic preparedness, the Global Influenza Surveillance and Response System is a global network of laboratories that monitors influenza transmission and epidemiology.", "Additional areas of research include ways to improve the diagnosis, treatment, and prevention of influenza.", "Existing diagnostic methods have a variety of limitations coupled with their advantages.", "For example, NATs have high sensitivity and specificity but are impractical in under-resourced regions due to their high cost, complexity, maintenance, and training required.", "Low-cost, portable RIDTs can rapidly diagnose influenza but have highly variable sensitivity and are unable to subtype IAV.", "As a result of these limitations and others, research into new diagnostic methods revolves around producing new methods that are cost-effective, less labor-intensive, and less complex than existing methods while also being able to differentiate influenza species and IAV subtypes.", "One approach in development are lab-on-a-chips, which are diagnostic devices that make use of a variety of diagnostic tests, such as RT-PCR and serological assays, in microchip form.", "These chips have many potential advantages, including high reaction efficiency, low energy consumption, and low waste generation.", "New antiviral drugs are also in development due to the elimination of adamantines as viable drugs and concerns over oseltamivir resistance.", "These include: NA inhibitors that can be injected intravenously, such as intravenous formulations of zanamivir; favipiravir, which is a polymerase inhibitor used against several RNA viruses; pimodivir, which prevents cap-binding required during viral transcription; and nitazoxanide, which inhibits HA maturation.", "Reducing excess inflammation in the respiratory tract is also subject to much research since this is one of the primary mechanisms of influenza pathology.", "Other forms of therapy in development include monoclonal and polyclonal antibodies that target viral proteins, convalescent plasma, different approaches to modify the host antiviral response, and stem cell-based therapies to repair lung damage.", "Much research on LAIVs focuses on identifying genome sequences that can be deleted to create harmless influenza viruses in vaccines that still confer immunity.", "The high variability and rapid evolution of influenza virus antigens, however, is a major obstacle in developing effective vaccines.", "Furthermore, it is hard to predict which strains will be in circulation during the next flu season, manufacturing a sufficient quantity of flu vaccines for the next season is difficult, LAIVs have limited efficacy, and repeated annual vaccination potentially has diminished efficacy.", "For these reasons, \"broadly-reactive\" or \"universal\" flu vaccines are being researched that can provide protection against many or all influenza viruses.", "Approaches to develop such a vaccine include HA stalk-based methods such as chimeras that have the same stalk but different heads, HA head-based methods such as computationally optimized broadly neutralizing antigens, anti-idiotypic antibodies, and vaccines to elicit immune responses to highly conserved viral proteins.", "mRNA vaccines to provide protection against influenza are also under research.", "Aquatic birds such as ducks, geese, shorebirds, and gulls are the primary reservoir of IAVs.", "In birds, AIVs may be either low pathogenic avian influenza (LPAI) viruses that produce little to no symptoms or highly pathogenic avian influenza (HPAI) viruses that cause severe illness.", "Symptoms of HPAI infection include lack of energy and appetite, decreased egg production, soft-shelled or misshapen eggs, swelling of the head, comb, wattles, and hocks, purple discoloration of wattles, combs, and legs, nasal discharge, coughing, sneezing, incoordination, and diarrhea.", "Birds infected with an HPAI virus may also die suddenly without any signs of infection.", "The distinction between LPAI and HPAI can generally be made based on how lethal an AIV is to chickens.", "At the genetic level, an AIV can be usually be identified as an HPAI virus if it has a multibasic cleavage site in the HA protein, which contains additional residues in the HA gene.", "Most AIVs are LPAI.", "Notable HPAI viruses include HPAI H5N1 and HPAI H7N9.", "HPAI viruses have been a major disease burden in the 21st century, resulting in the death of large numbers of birds.", "In H7N9's case, some circulating strains were originally LPAI but became HPAI by acquiring the HA multibasic cleavage site.", "Avian H9N2 is also of concern because although it is LPAI, it is a common donor of genes to H5N1 and H7N9 during reassortment.", "Migratory birds can spread influenza across long distances.", "An example of this was when an H5N1 strain in 2005 infected birds at Qinghai Lake, China, which is a stopover and breeding site for many migratory birds, subsequently spreading the virus to more than 20 countries across Asia, Europe, and the Middle East.", "AIVs can be transmitted from wild birds to domestic free-range ducks and in turn to poultry through contaminated water, aerosols, and fomites.", "Ducks therefore act as key intermediates between wild and domestic birds.", "Transmission to poultry typically occurs in backyard farming and live animal markets where multiple species interact with each other.", "From there, AIVs can spread to poultry farms in the absence of adequate biosecurity.", "Among poultry, HPAI transmission occurs through aerosols and contaminated feces, cages, feed, and dead animals.", "Back-transmission of HPAI viruses from poultry to wild birds has occurred and is implicated in mass die-offs and intercontinental spread.", "AIVs have occasionally infected humans through aerosols, fomites, and contaminated water.", "Direction transmission from wild birds is rare.", "Instead, most transmission involves domestic poultry, mainly chickens, ducks, and geese but also a variety of other birds such as guinea fowl, partridge, pheasants, and quails.", "The primary risk factor for infection with AIVs is exposure to birds in farms and live poultry markets.", "Typically, infection with an AIV has an incubation period of 3–5 days but can be up to 9 days.", "H5N1 and H7N9 cause severe lower respiratory tract illness, whereas other AIVs such as H9N2 cause a more mild upper respiratory tract illness, commonly with conjunctivitis.", "Limited transmission of avian H2, H5-7, H9, and H10 subtypes from one person to another through respiratory droplets, aerosols, and fomites has occurred, but sustained human-to-human transmission of AIVs has not occurred.", "Before 2013, H5N1 was the most common AIV to infect humans.", "Since then, H7N9 has been responsible for most human cases.", "Influenza in pigs is a respiratory disease similar to influenza in humans and is found worldwide.", "Asymptomatic infections are common.", "Symptoms typically appear 1–3 days after infection and include fever, lethargy, anorexia, weight loss, labored breathing, coughing, sneezing, and nasal discharge.", "In sows, pregnancy may be aborted.", "Complications include secondary infections and potentially fatal bronchopneumonia.", "Pigs become contagious within a day of infection and typically spread the virus for 7–10 days, which can spread rapidly within a herd.", "Pigs usually recover from infection within 3–7 days after symptoms appear.", "Prevention and control measures include inactivated vaccines and culling infected herds.", "The influenza viruses usually responsible for swine flu are IAV subtypes H1N1, H1N2, and H3N2.", "Some IAVs can be transmitted via aerosols from pigs to humans and vice versa.", "Furthermore, pigs, along with bats and quails, are recognized as a mixing vessel of influenza viruses because they have both α-2,3 and α-2,6 sialic acid receptors in their respiratory tract.", "Because of that, both avian and mammalian influenza viruses can infect pigs.", "If co-infection occurs, then reassortment is possible.", "A notable example of this was the reassortment of a swine, avian, and human influenza virus in 2009, resulting in a novel H1N1 strain that caused the 2009 flu pandemic.", "Spillover events from humans to pigs, however, appear to be more common than from pigs to humans.", "Influenza viruses have been found in many other animals, including cattle, horses, dogs, cats, and marine mammals.", "Nearly all IAVs are apparently descended from ancestral viruses in birds.", "The exception are bat influenza-like viruses, which have an uncertain origin.", "These bat viruses have HA and NA subtypes H17, H18, N10, and N11.", "H17N10 and H18N11 are unable to reassort with other IAVs, but they are still able to replicate in other mammals.", "AIVs sometimes crossover into mammals.", "For example, in late 2016 to early 2017, an avian H7N2 strain was found to be infecting cats in New York.", "Equine IAVs include H7N7 and two lineages of H3N8.", "H7N7, however, has not been detected in horses since the late 1970s, so it may have become extinct in horses.", "H3N8 in equines spreads via aerosols and causes respiratory illness.", "Equine H3N8 perferentially binds to α-2,3 sialic acids, so horses are usually considered dead-end hosts, but transmission to dogs and camels has occurred, raising concerns that horses may be mixing vessels for reassortment.", "In canines, the only IAVs in circulation are equine-derived H3N8 and avian-derived H3N2.", "Canine H3N8 has not been observed to reassort with other subtypes.", "H3N2 has a much broader host range and can reassort with H1N1 and H5N1.", "An isolated case of H6N1 likely from a chicken was found infecting a dog, so other AIVs may emerge in canines.", "Other mammals to be infected by IAVs include H7N7 and H4N5 in seals, H1N3 in whales, and H10N4 and H3N2 in minks.", "Various mutations have been identified that are associated with AIVs adapting to mammals.", "Since HA proteins vary in which sialic acids they bind to, mutations in the HA receptor binding site can allow AIVs to infect mammals.", "Other mutations include mutations affecting which sialic acids NA proteins cleave and a mutation in the PB2 polymerase subunit that improves tolerance of lower temperatures in mammalian respiratory tracts and enhances RNP assembly by stabilizing NP and PB2 binding.", "IBV is mainly found in humans but has also been detected in pigs, dogs, horses, and seals.", "Likewise, ICV primarily infects humans but has been observed in pigs, dogs, cattle, and dromedary camels.", "IDV causes an influenza-like illness in pigs but its impact in its natural reservoir, cattle, is relatively unknown.", "It may cause respiratory disease resembling human influenza on its own, or it may be part of a bovine respiratory disease (BRD) complex with other pathogens during co-infection.", "BRD is a concern for the cattle industry, so IDV's possible involvement in BRD has led to research on vaccines for cattle that can provide protection against IDV.", "Two antigenic lineages are in circulation: D/swine/Oklahoma/1334/2011 (D/OK) and D/bovine/Oklahoma/660/2013 (D/660)." ]

[ 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154 ]

[ "Vaccines currently in use provide protection against IAV subtypes H1N1 and H3N2 and one or two IBV subtypes.", "Deaths most commonly occur in high-risk groups, including young children, the elderly, and people with chronic health conditions." ]

[ "The time between exposure to the virus and development of symptoms, called the incubation period, is 1–4 days, most commonly 1–2 days.", "Many infections, however, are asymptomatic.", "The onset of symptoms is sudden, and initial symptoms are predominately non-specific, including fever, chills, headaches, muscle pain or aching, a feeling of discomfort, loss of appetite, lack of energy/fatigue, and confusion.", "These symptoms are usually accompanied by respiratory symptoms such as a dry cough, sore or dry throat, hoarse voice, and a stuffy or runny nose.", "Coughing is the most common symptom.", "Gastrointestinal symptoms may also occur, including nausea, vomiting, diarrhea, and gastroenteritis, especially in children.", "The standard influenza symptoms typically last for 2–8 days.", "A 2021 study suggests influenza can cause long lasting symptoms in a similar way to long COVID.\nSymptomatic infections are usually mild and limited to the upper respiratory tract, but progression to pneumonia is relatively common.", "Pneumonia may be caused by the primary viral infection or by a secondary bacterial infection.", "Primary pneumonia is characterized by rapid progression of fever, cough, labored breathing, and low oxygen levels that cause bluish skin.", "It is especially common among those who have an underlying cardiovascular disease such as rheumatic heart disease.", "Secondary pneumonia typically has a period of improvement in symptoms for 1–3 weeks followed by recurrent fever, sputum production, and fluid buildup in the lungs, but can also occur just a few days after influenza symptoms appear.", "About a third of primary pneumonia cases are followed by secondary pneumonia, which is most frequently caused by the bacteria \"Streptococcus pneumoniae\" and \"Staphylococcus aureus\".", "Influenza viruses comprise four species.", "Each of the four species is the sole member of its own genus, and the four influenza genera comprise four of the seven genera in the family \"Orthomyxoviridae\".", "They are:\n\n\nIAV is responsible for most cases of severe illness as well as seasonal epidemics and occasional pandemics.", "It infects people of all ages but tends to disproportionately cause severe illness in the elderly, the very young, and those who have chronic health issues.", "Birds are the primary reservoir of IAV, especially aquatic birds such as ducks, geese, shorebirds, and gulls, but the virus also circulates among mammals, including pigs, horses, and marine mammals.", "IAV is classified into subtypes based on the viral proteins haemagglutinin (H) and neuraminidase (N).", "As of 2019, 18 H subtypes and 11 N subtypes have been identified.", "Most potential combinations have been reported in birds, but H17-18 and N10-11 have only been found in bats.", "Only H subtypes H1-3 and N subtypes N1-2 are known to have circulated in humans, the current IAV subtypes in circulation being H1N1 and H3N2.", "IAVs can be classified more specifically to also include natural host species, geographical origin, year of isolation, and strain number, such as H1N1/A/duck/Alberta/35/76.", "IBV mainly infects humans but has been identified in seals, horses, dogs, and pigs.", "IBV does not have subtypes like IAV but has two antigenically distinct lineages, termed the B/Victoria/2/1987-like and B/Yamagata/16/1988-like lineages, or simply (B/)Victoria(-like) and (B/)Yamagata(-like).", "Both lineages are in circulation in humans, disproportionately affecting children.", "IBVs contribute to seasonal epidemics alongside IAVs but have never been associated with a pandemic.", "ICV, like IBV, is primarily found in humans, though it also has been detected in pigs, feral dogs, dromedary camels, cattle, and dogs.", "ICV infection primarily affects children and is usually asymptomatic or has mild cold-like symptoms, though more severe symptoms such as gastroenteritis and pneumonia can occur.", "Unlike IAV and IBV, ICV has not been a major focus of research pertaining to antiviral drugs, vaccines, and other measures against influenza.", "ICV is subclassified into six genetic/antigenic lineages.", "IDV has been isolated from pigs and cattle, the latter being the natural reservoir.", "Infection has also been observed in humans, horses, dromedary camels, and small ruminants such as goats and sheep.", "IDV is distantly related to ICV.", "While cattle workers have occasionally tested positive to prior IDV infection, it is not known to cause disease in humans.", "ICV and IDV experience a slower rate of antigenic evolution than IAV and IBV.", "Because of this antigenic stability, relatively few novel lineages emerge.", "Influenza viruses have a negative-sense, single-stranded RNA genome that is segmented.", "The negative sense of the genome means it can be used as a template to synthesize messenger RNA (mRNA).", "IAV and IBV have eight genome segments that encode 10 major proteins.", "ICV and IDV have seven genome segments that encode nine major proteins.", "Three segments encode three subunits of an RNA-dependent RNA polymerase (RdRp) complex: PB1, a transcriptase, PB2, which recognizes 5' caps, and PA (P3 for ICV and IDV), an endonuclease.", "The matrix protein (M1) and membrane protein (M2) share a segment, as do the non-structural protein (NS1) and the nuclear export protein (NEP).", "For IAV and IBV, hemagglutinin (HA) and neuraminidase (NA) are encoded on one segment each, whereas ICV and IDV encode a hemagglutinin-esterase fusion (HEF) protein on one segment that merges the functions of HA and NA.", "The final genome segment encodes the viral nucleoprotein (NP).", "Influenza viruses also encode various accessory proteins, such as PB1-F2 and PA-X, that are expressed through alternative open reading frames and which are important in host defense suppression, virulence, and pathogenicity.", "The virus particle, called a virion, is pleomorphic and varies between being filamentous, bacilliform, or spherical in shape.", "Clinical isolates tend to be pleomorphic, whereas strains adapted to laboratory growth typically produce spherical virions.", "Filamentous virions are about 250 nanometers (nm) by 80 nm, bacilliform 120–250 by 95 nm, and spherical 120 nm in diameter.", "The virion consists of each segment of the genome bound to nucleoproteins in separate ribonucleoprotein (RNP) complexes for each segment, all of which are surrounded by a lipid bilayer membrane called the viral envelope.", "There is a copy of the RdRp, all subunits included, bound to each RNP.", "The envelope is reinforced structurally by matrix proteins on the interior that enclose the RNPs, and the envelope contains HA and NA (or HEF) proteins extending outward from the exterior surface of the envelope.", "HA and HEF proteins have a distinct \"head\" and \"stalk\" structure.", "M2 proteins form proton ion channels through the viral envelope that are required for viral entry and exit.", "IBVs contain a surface protein named NB that is anchored in the envelope, but its function is unknown.", "The viral life cycle begins by binding to a target cell.", "Binding is mediated by the viral HA proteins on the surface of the evelope, which bind to cells that contain sialic acid receptors on the surface of the cell membrane.", "For N1 subtypes with the \"G147R\" mutation and N2 subtypes, the NA protein can initiate entry.", "Prior to binding, NA proteins promote access to target cells by degrading mucous, which helps to remove extracellular decoy receptors that would impede access to target cells.", "After binding, the virus is internalized into the cell by an endosome that contains the virion inside it.", "The endosome is acidified by cellular vATPase to have lower pH, which triggers a conformational change in HA that allows fusion of the viral envelope with the endosomal membrane.", "At the same time, hydrogen ions diffuse into the virion through M2 ion channels, disrupting internal protein-protein interactions to release RNPs into the host cell's cytosol.", "The M1 protein shell surrounding RNPs is degraded, fully uncoating RNPs in the cytosol.", "RNPs are then imported into the nucleus with the help of viral localization signals.", "There, the viral RNA polymerase transcribes mRNA using the genomic negative-sense strand as a template.", "The polymerase snatches 5' caps for viral mRNA from cellular RNA to prime mRNA synthesis and the 3'-end of mRNA is polyadenylated at the end of transcription.", "Once viral mRNA is transcribed, it is exported out of the nucleus and translated by host ribosomes in a cap-dependent manner to synthesize viral proteins.", "RdRp also synthesizes complementary positive-sense strands of the viral genome in a complementary RNP complex which are then used as templates by viral polymerases to synthesize copies of the negative-sense genome.", "During these processes, RdRps of avian influenza viruses (AIVs) function optimally at a higher temperature than mammalian influenza viruses.", "Newly synthesized viral polymerase subunits and NP proteins are imported to the nucleus to further increase the rate of viral replication and form RNPs.", "HA, NA, and M2 proteins are trafficked with the aid of M1 and NEP proteins to the cell membrane through the Golgi apparatus and inserted into the cell's membrane.", "Viral non-structural proteins including NS1, PB1-F2, and PA-X regulate host cellular processes to disable antiviral responses.", "PB1-F2 aso interacts with PB1 to keep polymerases in the nucleus longer.", "M1 and NEP proteins localize to the nucleus during the later stages of infection, bind to viral RNPs and mediate their export to the cytoplasm where they migrate to the cell membrane with the aid of recycled endosomes and are bundled into the segments of the genome.", "Progenic viruses leave the cell by budding from the cell membrane, which is initiated by the accumulation of M1 proteins at the cytoplasmic side of the membrane.", "The viral genome is incorporated inside a viral envelope derived from portions of the cell membrane that have HA, NA, and M2 proteins.", "At the end of budding, HA proteins remain attached to cellular sialic acid until they are cleaved by the sialidase activity of NA proteins.", "The virion is then released from the cell.", "The sialidase activity of NA also cleaves any sialic acid residues from the viral surface, which helps prevent newly assembled viruses from aggregating near the cell surface and improving infectivity.", "Similar to other aspects of influenza replication, optimal NA activity is temperature- and pH-dependent.", "Ultimately, presence of large quantities of viral RNA in the cell triggers apoptosis, i.e. programmed cell death, which is initiated by cellular factors to restrict viral replication.", "Two key processes that influenza viruses evolve through are antigenic drift and antigenic shift.", "Antigenic drift is when an influenza virus's antigens change due to the gradual accumulation of mutations in the antigen's (HA or NA) gene.", "This can occur in response to evolutionary pressure exerted by the host immune response.", "Antigenic drift is especially common for the HA protein, in which just a few amino acid changes in the head region can constitute antigenic drift.", "The result is the production of novel strains that can evade pre-existing antibody-mediated immunity.", "Antigenic drift occurs in all influenza species but is slower in B than A and slowest in C and D. Antigenic drift is a major cause of seasonal influenza, and requires that flu vaccines be updated annually.", "HA is the main component of inactivated vaccines, so surveillance monitors antigenic drift of this antigen among circulating strains.", "Antigenic evolution of influenza viruses of humans appears to be faster than influenza viruses in swine and equines.", "In wild birds, within-subtype antigenic variation appears to be limited but has been observed in poultry.", "Antigenic shift is a sudden, drastic change in an influenza virus's antigen, usually HA.", "During antigenic shift, antigenically different strains that infect the same cell can reassort genome segments with each other, producing hybrid progeny.", "Since all influenza viruses have segmented genomes, all are capable of reassortment.", "Antigenic shift, however, only occurs among influenza viruses of the same genus and most commonly occurs among IAVs.", "In particular, reassortment is very common in AIVs, creating a large diversity of influenza viruses in birds, but is uncommon in human, equine, and canine lineages.", "Pigs, bats, and quails have receptors for both mammalian and avian IAVs, so they are potential \"mixing vessels\" for reassortment.", "If an animal strain reassorts with a human strain, then a novel strain can emerge that is capable of human-to-human transmission.", "This has caused pandemics, but only a limited number have occurred, so it is difficult to predict when the next will happen.", "People who are infected can transmit influenza viruses through breathing, talking, coughing, and sneezing, which spread respiratory droplets and aerosols that contain virus particles into the air.", "A person susceptible to infection can then contract influenza by coming into contact with these particles.", "Respiratory droplets are relatively large and travel less than two meters before falling onto nearby surfaces.", "Aerosols are smaller and remain suspended in the air longer, so they take longer to settle and can travel further than respiratory droplets.", "Inhalation of aerosols can lead to infection, but most transmission is in the area about two meters around an infected person via respiratory droplets that come into contact with mucosa of the upper respiratory tract.", "Transmission through contact with a person, bodily fluids, or intermediate objects (fomites) can also occur, such as through contaminated hands and surfaces since influenza viruses can survive for hours on non-porous surfaces.", "If one's hands are contaminated, then touching one's face can cause infection.", "Influenza is usually transmissible from one day before the onset of symptoms to 5–7 days after.", "In healthy adults, the virus is shed for up to 3–5 days.", "In children and the immunocompromised, the virus may be transmissible for several weeks.", "Children ages 2–17 are considered to be the primary and most efficient spreaders of influenza.", "Children who have not had multiple prior exposures to influenza viruses shed the virus at greater quantities and for a longer duration than other children.", "People who are at risk of exposure to influenza include health care workers, social care workers, and those who live with or care for people vulnerable to influenza.", "In long-term care facilities, the flu can spread rapidly after it is introduced.", "A variety of factors likely encourage influenza transmission, including lower temperature, lower absolute and relative humidity, less ultraviolet radiation from the Sun, and crowding.", "Influenza viruses that infect the upper respiratory tract like H1N1 tend to be more mild but more transmissible, whereas those that infect the lower respiratory tract like H5N1 tend to cause more severe illness but are less contagious.", "In humans, influenza viruses first cause infection by infecting epithelial cells in the respiratory tract.", "Illness during infection is primarily the result of lung inflammation and compromise caused by epithelial cell infection and death, combined with inflammation caused by the immune system's response to infection.", "Non-respiratory organs can become involved, but the mechanisms by which influenza is involved in these cases are unknown.", "Severe respiratory illness can be caused by multiple, non-exclusive mechanisms, including obstruction of the airways, loss of alveolar structure, loss of lung epithelial integrity due to epithelial cell infection and death, and degradation of the extracellular matrix that maintains lung structure.", "In particular, alveolar cell infection appears to drive severe symptoms since this results in impaired gas exchange and enables viruses to infect endothelial cells, which produce large quantities of pro-inflammatory cytokines.", "Pneumonia caused by influenza viruses is characterized by high levels of viral replication in the lower respiratory tract, accompanied by a strong pro-inflammatory response called a cytokine storm.", "Infection with H5N1 or H7N9 especially produces high levels of pro-inflammatory cytokines.", "In bacterial infections, early depletion of macrophages during influenza creates a favorable environment in the lungs for bacterial growth since these white blood cells are important in responding to bacterial infection.", "Host mechanisms to encourage tissue repair may inadvertently allow bacterial infection.", "Infection also induces production of systemic glucocorticoids that can reduce inflammation to preserve tissue integrity but allow increased bacterial growth.", "The pathophysiology of influenza is significantly influenced by which receptors influenza viruses bind to during entry into cells.", "Mammalian influenza viruses preferentially bind to sialic acids connected to the rest of the oligosaccharide by an α-2,6 link, most commonly found in various respiratory cells, such as respiratory and retinal epithelial cells.", "AIVs prefer sialic acids with an α-2,3 linkage, which are most common in birds in gastrointestinal epithelial cells and in humans in the lower respiratory tract.", "Furthermore, cleavage of the HA protein into HA, the binding subunit, and HA, the fusion subunit, is performed by different proteases, affecting which cells can be infected.", "For mammalian influenza viruses and low pathogenic AIVs, cleavage is extracellular, which limits infection to cells that have the appropriate proteases, whereas for highly pathogenic AIVs, cleavage is intracellular and performed by ubiquitous proteases, which allows for infection of a greater variety of cells, thereby contributing to more severe disease.", "Cells possess sensors to detect viral RNA, which can then induce interferon production.", "Interferons mediate expression of antiviral proteins and proteins that recruit immune cells to the infection site, and they also notify nearby uninfected cells of infection.", "Some infected cells release pro-inflammatory cytokines that recruit immune cells to the site of infection.", "Immune cells control viral infection by killing infected cells and phagocytizing viral particles and apoptotic cells.", "An exacerbated immune response, however, can harm the host organism through a cytokine storm.", "To counter the immune response, influenza viruses encode various non-structural proteins, including NS1, NEP, PB1-F2, and PA-X, that are involved in curtailing the host immune response by suppressing interferon production and host gene expression.", "B cells, a type of white blood cell, produce antibodies that bind to influenza antigens HA and NA (or HEF) and other proteins to a lesser degree.", "Once bound to these proteins, antibodies block virions from binding to cellular receptors, neutralizing the virus.", "In humans, a sizeable antibody response occurs ~1 week after viral exposure.", "This antibody response is typically robust and long-lasting, especially for ICV and IDV.", "In other words, people exposed to a certain strain in childhood still possess antibodies to that strain at a reasonable level later in life, which can provide some protection to related strains.", "There is, however, an \"original antigenic sin\", in which the first HA subtype a person is exposed to influences the antibody-based immune response to future infections and vaccines.", "Annual vaccination is the primary and most effective way to prevent influenza and influenza-associated complications, especially for high-risk groups.", "Vaccines against the flu are trivalent or quadrivalent, providing protection against an H1N1 strain, an H3N2 strain, and one or two IBV strains corresponding to the two IBV lineages.", "Two types of vaccines are in use: inactivated vaccines that contain \"killed\" (i.e. inactivated) viruses and live attenuated influenza vaccines (LAIVs) that contain weakened viruses.", "There are three types of inactivated vaccines: whole virus, split virus, in which the virus is disrupted by a detergent, and subunit, which only contains the viral antigens HA and NA.", "Most flu vaccines are inactivated and administered via intramuscular injection.", "LAIVs are sprayed into the nasal cavity.", "Vaccination recommendations vary by country.", "Some recommend vaccination for all people above a certain age, such as 6 months, whereas other countries recommendation is limited for high at risk groups, such as pregnant women, young children (excluding newborns), the elderly, people with chronic medical conditions, health care workers, people who come into contact with high-risk people, and people who transmit the virus easily.", "Young infants cannot receive flu vaccines for safety reasons, but they can inherit passive immunity from their mother if inactivated vaccines are administered to the mother during pregnancy.", "Influenza vaccination also helps to reduce the probability of reassortment.", "In general, influenza vaccines are only effective if there is an antigenic match between vaccine strains and circulating strains.", "Additionally, most commercially available flu vaccines are manufactured by propagation of influenza viruses in embryonated chicken eggs, taking 6–8 months.", "Flu seasons are different in the northern and southern hemisphere, so the WHO meets twice a year, one for each hemisphere, to discuss which strains should be included in flu vaccines based on observation from HA inhibition assays.", "Other manufacturing methods include an MDCK cell culture-based inactivated vaccine and a recombinant subunit vaccine manufactured from baculovirus overexpression in insect cells.", "Influenza can be prevented or reduced in severity by post-exposure prophylaxis with the antiviral drugs oseltamivir, which can be taken orally by those at least three months old, and zanamivir, which can be inhaled by those above seven years of age.", "Chemoprophylaxis is most useful for individuals at high-risk of developing complications and those who cannot receive the flu vaccine due to contraindications or lack of effectiveness.", "Post-exposure chemoprophylaxis is only recommended if oseltamivir is taken within 48 hours of contact with a confirmed or suspected influenza case and zanamivir within 36 hours.", "It is recommended that it be offered to people who have yet to receive a vaccine for the current flu season, who have been vaccinated less than two week since contact, if there is a significant mismatch between vaccine and circulating strains, or during an outbreak in a closed setting regardless of vaccination history.", "Hand hygiene is important in reducing the spread of influenza.", "This includes frequent hand washing with soap and water, using alcohol-based hand sanitizers, and not touching one's eyes, nose, and mouth with one's hands.", "Covering one's nose and mouth when coughing or sneezing is important.", "Other methods to limit influenza transmission include staying home when sick, avoiding contact with others until one day after symptoms end, and disinfecting surfaces likely to be contaminated by the virus, such as doorknobs.", "Health education through media and posters is often used to remind people of the aforementioned etiquette and hygiene.", "There is uncertainty about the use of masks since research thus far has not shown a significant reduction in seasonal influenza with mask usage.", "Likewise, the effectiveness of screening at points of entry into countries is not well researched.", "Social distancing measures such as school closures, avoiding contact with infected people via isolation or quarantine, and limiting mass gatherings may reduce transmission, but these measures are often expensive, unpopular, and difficult to implement.", "Consequently, the commonly recommended methods of infection control are respiratory etiquette, hand hygiene, and mask wearing, which are inexpensive and easy to perform.", "Pharmaceutical measures are effective but may not be available in the early stages of an outbreak.", "In health care settings, infected individuals may be cohorted or assigned to individual rooms.", "Protective clothing such as masks, gloves, and gowns is recommended when coming into contact with infected individuals if there is a risk of exposure to infected bodily fluids.", "Keeping patients in negative pressure rooms and avoiding aerosol-producing activities may help, but special air handling and ventilation systems are not considered necessary to prevent the spread of influenza in the air.", "In residential homes, new admissions may need to be closed until the spread of influenza is controlled.", "When discharging patients to care homes, it is important to take care if there is a known influenza outbreak.", "Since influenza viruses circulate in animals such as birds and pigs, prevention of transmission from these animals is important.", "Water treatment, indoor raising of animals, quarantining sick animals, vaccination, and biosecurity are the primary measures used.", "Placing poultry houses and piggeries on high ground away from high-density farms, backyard farms, live poultry markets, and bodies of water helps to minimize contact with wild birds.", "Closure of live poultry markets appears to the most effective measure and has shown to be effective at controlling the spread of H5N1, H7N9, and H9N2.", "Other biosecurity measures include cleaning and disinfecting facilities and vehicles, banning visits to poultry farms, not bringing birds intended for slaughter back to farms, changing clothes, disinfecting foot baths, and treating food and water.", "If live poultry markets are not closed, then \"clean days\" when unsold poultry is removed and facilities are disinfected and \"no carry-over\" policies to eliminate infectious material before new poultry arrive can be used to reduce the spread of influenza viruses.", "If a novel influenza viruses has breached the aforementioned biosecurity measures, then rapid detection to stamp it out via quarantining, decontamination, and culling may be necessary to prevent the virus from becoming endemic.", "Vaccines exist for avian H5, H7, and H9 subtypes that are used in some countries.", "In China, for example, vaccination of domestic birds against H7N9 successfully limited its spread, indicating that vaccination may be an effective strategy if used in combination with other measures to limit transmission.", "In pigs and horses, management of influenza is dependent on vaccination with biosecurity.", "Diagnosis based on symptoms is fairly accurate in otherwise healthy people during seasonal epidemics and should be suspected in cases of pneumonia, acute respiratory distress syndrome (ARDS), sepsis, or if encephalitis, myocarditis, or breaking down of muscle tissue occur.", "Because influenza is similar to other viral respiratory tract illnesses, laboratory diagnosis is necessary for confirmation.", "Common ways of collecting samples for testing include nasal and throat swabs.", "Samples may be taken from the lower respiratory tract if infection has cleared the upper but not lower respiratory tract.", "Influenza testing is recommended for anyone hospitalized with symptoms resembling influenza during flu season or who is connected to an influenza case.", "For severe cases, earlier diagnosis improves patient outcome.", "Diagnostic methods that can identify influenza include viral cultures, antibody- and antigen-detecting tests, and nucleic acid-based tests.", "Viruses can be grown in a culture of mammalian cells or embryonated eggs for 3–10 days to monitor cytopathic effect.", "Final confirmation can then be done via antibody staining, hemadsorption using red blood cells, or immunofluorescence microscopy.", "Shell vial cultures, which can identify infection via immunostaining before a cytopathic effect appears, are more sensitive than traditional cultures with results in 1–3 days.", "Cultures can be used to characterize novel viruses, observe sensitivity to antiviral drugs, and monitor antigenic drift, but they are relatively slow and require specialized skills and equipment.", "Serological assays can be used to detect an antibody response to influenza after natural infection or vaccination.", "Common serological assays include hemagglutination inhibition assays that detect HA-specific antibodies, virus neutralization assays that check whether antibodies have neutralized the virus, and enzyme-linked immunoabsorbant assays.", "These methods tend to be relatively inexpensive and fast but are less reliable than nucleic-acid based tests.", "Direct fluorescent or immunofluorescent antibody (DFA/IFA) tests involve staining respiratory epithelial cells in samples with fluorescently-labeled influenza-specific antibodies, followed by examination under a fluorescent microscope.", "They can differentiate between IAV and IBV but can't subtype IAV.", "Rapid influenza diagnostic tests (RIDTs) are a simple way of obtaining assay results, are low cost, and produce results quickly, at less than 30 minutes, so they are commonly used, but they can't distinguish between IAV and IBV or between IAV subtypes and are not as sensitive as nucleic-acid based tests.", "Nucleic acid-based tests (NATs) amplify and detect viral nucleic acid.", "Most of these tests take a few hours, but rapid molecular assays are as fast as RIDTs.", "Among NATs, reverse transcription polymerase chain reaction (RT-PCR) is the most traditional and considered the gold standard for diagnosing influenza because it is fast and can subtype IAV, but it is relatively expensive and more prone to false-positives than cultures.", "Other NATs that have been used include loop-mediated isothermal amplification-based assays, simple amplification-based assays, and nucleic acid sequence-based amplification.", "Nucleic acid sequencing methods can identify infection by obtaining the nucleic acid sequence of viral samples to identify the virus and antiviral drug resistance.", "The traditional method is Sanger sequencing, but it has been largely replaced by next-generation methods that have greater sequencing speed and throughput.", "Treatment of influenza in cases of mild or moderate illness is supportive and includes anti-fever medications such as acetaminophen and ibuprofen, adequate fluid intake to avoid dehydration, and resting at home.", "Cough drops and throat sprays may be beneficial for sore throat.", "It is recommended to avoid alcohol and tobacco use while sick with the flu.", "Aspirin is not recommended to treat influenza in children due to an elevated risk of developing Reye syndrome.", "Corticosteroids likewise are not recommended except when treating septic shock or an underlying medical condition, such as chronic obstructive pulmonary disease or asthma exacerbation, since they are associated with increased mortality.", "If a secondary bacterial infection occurs, then treatment with antibiotics may be necessary.", "Antiviral drugs are primarily used to treat severely ill patients, especially those with compromised immune systems.", "Antivirals are most effective when started in the first 48 hours after symptoms appear.", "Later administration may still be beneficial for those who have underlying immune defects, those with more severe symptoms, or those who have a higher risk of developing complications if these individuals are still shedding the virus.", "Antiviral treatment is also recommended if a person is hospitalized with suspected influenza instead of waiting for test results to return and if symptoms are worsening.", "Most antiviral drugs against influenza fall into two categories: neuraminidase (NA) inhibitors and M2 inhibitors.", "Baloxavir marboxil is a notable exception, which targets the endonuclease activity of the viral RNA polymerase and can be used as an alternative to NA and M2 inhibitors for IAV and IBV.", "NA inhibitors target the enzymatic activity of NA receptors, mimicking the binding of sialic acid in the active site of NA on IAV and IBV virions so that viral release from infected cells and the rate of viral replication are impaired.", "NA inhibitors include oseltamivir, which is consumed orally in a prodrug form and converted to its active form in the liver, and zanamivir, which is a powder that is inhaled nasally.", "Oseltamivir and zanamivir are effective for prophylaxis and post-exposure prophylaxis, and research overall indicates that NA inhibitors are effective at reducing rates of complications, hospitalization, and mortality and the duration of illness.", "Additionally, the earlier NA inhibitors are provided, the better the outcome, though late administration can still be beneficial in severe cases.", "Other NA inhibitors include laninamivir and peramivir, the latter of which can be used as an alternative to oseltamivir for people who cannot tolerate or absorb it.", "The adamantanes amantadine and rimantadine are orally administered drugs that block the influenza virus's M2 ion channel, preventing viral uncoating.", "These drugs are only functional against IAV but are no longer recommended for use because of widespread resistance to them among IAVs.", "Adamantane resistance first emerged in H3N2 in 2003, becoming worldwide by 2008.", "Oseltamivir resistance is no longer widespread because the 2009 pandemic H1N1 strain (H1N1 pdm09), which is resistant to adamantanes, seemingly replaced resistant strains in circulation.", "Since the 2009 pandemic, oseltamivir resistance has mainly been observed in patients undergoing therapy, especially the immunocompromised and young children.", "Oseltamivir resistance is usually reported in H1N1, but has been reported in H3N2 and IBVs less commonly.", "Because of this, oseltamivir is recommended as the first drug of choice for immunocompetent people, whereas for the immunocompromised, oseltamivir is recommended against H3N2 and IBV and zanamivir against H1N1 pdm09.", "Zanamivir resistance is observed less frequently, and resistance to peramivir and baloxavir marboxil is possible.", "In healthy individuals, influenza infection is usually self-limiting and rarely fatal.", "Symptoms usually last for 2–8 days.", "Influenza can cause people to miss work or school, and it is associated with decreased job performance and, in older adults, reduced independence.", "Fatigue and malaise may last for several weeks after recovery, and healthy adults may experience pulmonary abnormalities that can take several weeks to resolve.", "Complications and mortality primarily occur in high-risk populations and those who are hospitalized.", "Severe disease and mortality are usually attributable to pneumonia from the primary viral infection or a secondary bacterial infection, which can progress to ARDS.", "Other respiratory complications that may occur include sinusitis, bronchitis, bronchiolitis, excess fluid buildup in the lungs, and exacerbation of chronic bronchitis and asthma.", "Middle ear infection and croup may occur, most commonly in children.", "Secondary \"S. aureus\" infection has been observed, primarily in children, to cause toxic shock syndrome after influenza, with hypotension, fever, and reddening and peeling of the skin.", "Complications affecting the cardiovascular system are rare and include pericarditis, fulminant myocarditis with a fast, slow, or irregular heartbeat, and exacerbation of pre-existing cardiovascular disease.", "Inflammation or swelling of muscles accompanied by muscle tissue breaking down occurs rarely, usually in children, which presents as extreme tenderness and muscle pain in the legs and a reluctance to walk for 2–3 days.", "Influenza can affect pregnancy, including causing smaller neonatal size, increased risk of premature birth, and an increased risk of child death shortly before or after birth.", "Neurological complications have been associated with influenza on rare occasions, including aseptic meningitis, encephalitis, disseminated encephalomyelitis, transverse myelitis, and Guillain–Barré syndrome.", "Additionally, febrile seizures and Reye syndrome can occur, most commonly in children.", "Influenza-associated encephalopathy can occur directly from central nervous system infection from the presence of the virus in blood and presents as suddent onset of fever with convulsions, followed by rapid progression to coma.", "An atypical form of encephalitis called encephalitis lethargica, characterized by headache, drowsiness, and coma, may rarely occur sometime after infection.", "In survivors of influenza-associated encephalopathy, neurological defects may occur.", "Primarily in children, in severe cases the immune system may rarely dramatically overproduce white blood cells that release cytokines, causing severe inflammation.", "People who are at least 65 years of age, due to a weakened immune system from aging or a chronic illness, are a high-risk group for developing complications, as are children less than one year of age and children who have not been previously exposed to influenza viruses multiple times.", "Pregnant women are at an elevated risk, which increases by trimester and lasts up to two weeks after childbirth.", "Obesity, in particular a body mass index greater than 35–40, is associated with greater amounts of viral replication, increased severity of secondary bacterial infection, and reduced vaccination efficacy.", "People who have underlying health conditions are also considered at-risk, including those who have congenital or chronic heart problems or lung (e.g. asthma), kidney, liver, blood, neurological, or metabolic (e.g. diabetes) disorders, as are people who are immunocompromised from chemotherapy, asplenia, prolonged steroid treatment, splenic dysfunction, or HIV infection.", "Current or past tobacco use also places a person at risk.", "The role of genetics in influenza is not well researched, but it may be a factor in influenza mortality.", "Influenza is typically characterized by seasonal epidemics and sporadic pandemics.", "Most of the burden of influenza is a result of flu seasons caused by IAV and IBV.", "Among IAV subtypes, H1N1 and H3N2 currently circulate in humans and are responsible for seasonal influenza.", "Cases disproportionately occur in children, but most severe causes are among the elderly, the very young, and the immunocompromised.", "In a typical year, influenza viruses infect 5–15% of the global population, causing 3–5 million cases of severe illness annually and accounting for 290,000–650,000 deaths each year due to respiratory illness.", "5–10% of adults and 20–30% of children contract influenza each year.", "The reported number of influenza cases is usually much lower than the actual number of cases.", "During seasonal epidemics, it is estimated that about 80% of otherwise healthy people who have a cough or sore throat have the flu.", "Approximately 30–40% of people hospitalized for influenza develop pneumonia, and about 5% of all severe pneumonia cases in hospitals are due to influenza, which is also the most common cause of ARDS in adults.", "In children, influenza is one of the two most common causes of ARDS, the other being the respiratory syncytial virus.", "About 3–5% of children each year develop otitis media due to influenza.", "Adults who develop organ failure from influenza and children who have PIM scores and acute renal failure have higher rates of mortality.", "During seasonal influenza, mortality is concentrated in the very young and the elderly, whereas during flu pandemics, young adults are often affected at a high rate.", "In temperate regions, the number of influenza cases varies from season to season.", "Lower vitamin D levels, presumably due to less sunlight, lower humidity, lower temperature, and minor changes in virus proteins caused by antigenic drift contribute to annual epidemics that peak during the winter season.", "In the northern hemisphere, this is from October to May (more narrowly December to April), and in the southern hemisphere, this is from May to October (more narrowly June to September).", "There are therefore two distinct influenza seasons every year in temperate regions, one in the northern hemisphere and one in the southern hemisphere.", "In tropical and subtropical regions, seasonality is more complex and appears to be affected by various climatic factors such as minimum temperature, hours of sunshine, maximum rainfall, and high humidity.", "Influenza may therefore occur year-round in these regions.", "Influenza epidemics in modern times have the tendency to start in the eastern or southern hemisphere, with Asia being a key reservoir of influenza viruses.", "IAV and IBV co-circulate, so the two have the same patterns of transmission.", "The seasonality of ICV, however, is poorly understood.", "ICV infection is most common in children under the age of 2, and by adulthood most people have been exposed to it.", "ICV-associated hospitalization most commonly occurs in children under the age of 3 and is frequently accompanied by co-infection with another virus or a bacterium, which may increase the severity of disease.", "When considering all hospitalizations for respiratory illness among young children, ICV appears to account for only a small percentage of such cases.", "Large outbreaks of ICV infection can occur, so incidence varies significantly.", "Outbreaks of influenza caused by novel influenza viruses are common.", "Depending on the level of pre-existing immunity in the population, novel influenza viruses can spread rapidly and cause pandemics with millions of deaths.", "These pandemics, in contrast to seasonal influenza, are caused by antigenic shifts involving animal influenza viruses.", "To date, all known flu pandemics have been caused by IAVs, and they follow the same pattern of spreading from an origin point to the rest of the world over the course of multiple waves in a year.", "Pandemic strains tend to be associated with higher rates of pneumonia in otherwise healthy individuals.", "Generally after each influenza pandemic, the pandemic strain continues to circulate as the cause of seasonal influenza, replacing prior strains.", "From 1700 to 1889, influenza pandemics occurred about once every 50–60 years.", "Since then, pandemics have occurred about once every 10–50 years, so they may be getting more frequent over time.", "It is impossible to know when an influenza virus first infected humans or when the first influenza pandemic occurred.", "Possibly the first influenza epidemic occurred around 6,000 BC in China, and possible descriptions of influenza exist in Greek writings from the 5th century BC.", "In both 1173–1174 AD and 1387 AD, epidemics occurred across Europe that were named \"influenza\".", "Whether these epidemics and others were caused by influenza is unclear since there was no consistent naming pattern for epidemic respiratory diseases at that time, and \"influenza\" didn't become completely attached to respiratory disease until centuries later.", "Influenza may have been brought to the Americas as early as 1493, when an epidemic disease resembling influenza killed most of the population of the Antilles.", "The first convincing record of an influenza pandemic was chronicled in 1510; it began in East Asia before spreading to North Africa and then Europe.", "Following the pandemic, seasonal influenza occurred, with subsequent pandemics in 1557 and 1580.", "The flu pandemic in 1557 was potentially the first time influenza was connected to miscarriage and death of pregnant women.", "The 1580 flu pandemic originated in Asia during summer, spread to Africa, then Europe, and finally America.", "By the end of the 16th century, influenza was likely beginning to become understood as a specific, recognizable disease with epidemic and endemic forms.", "In 1648, it was discovered that horses also experience influenza.", "Influenza data after 1700 is more informative, so it is easier to identify flu pandemics after this point, each of which incrementally increased understanding of influenza.", "The first flu pandemic of the 18th century started in 1729 in Russia in spring, spreading worldwide over the course of three years with distinct waves, the later ones being more lethal.", "The second flu pandemic of the 18th century was in 1781–1782, starting in China in autumn.", "From this pandemic, influenza became associated with sudden outbreaks of febrile illness.", "The next flu pandemic was from 1830 to 1833, beginning in China in winter.", "This pandemic had a high attack rate, but the mortality rate was low.", "A minor influenza pandemic occurred from 1847 to 1851 at the same time as the third cholera pandemic and was the first flu pandemic to occur with vital statistics being recorded, so influenza mortality was clearly recorded for the first time.", "Highly pathogenic avian influenza was recognized in 1878 and was soon linked to transmission to humans.", "By the time of the 1889 pandemic, which may have been caused by an H2N2 strain, the flu had become an easily recognizable disease.", "Initially, the microbial agent responsible for influenza was incorrently identified in 1892 by R. F. J. Pfeiffer as the bacteria species \"Haemophilus influenzae\", which retains \"influenza\" in its name.", "In the following years, the field of virology began to form as viruses were identified as the cause of many diseases.", "From 1901 to 1903, Italian and Austrian researchers were able to show that avian influenza, then called \"fowl plague\", was caused by a microscopic agent smaller than bacteria by using filters with pores too small for bacteria to pass through.", "The fundamental differences between viruses and bacteria, however, were not yet fully understood.", "From 1918 to 1920, the Spanish flu pandemic became the most devastating influenza pandemic and one of the deadliest pandemics in history.", "The pandemic, probably caused by H1N1, likely began in the USA before spreading worldwide by soldiers during and after the First World War.", "The initial wave in the first half of 1918 was relatively minor and resembled past flu pandemics, but the second wave later that year had a much higher mortality rate, accounting for most deaths.", "A third wave with lower mortality occurred in many places a few months after the second.", "By the end of 1920, it is estimated that about a third to half of all people in the world had been infected, with tens of millions of deaths, disproportionately young adults.", "During the 1918 pandemic, the respiratory route of transmission was clearly identified and influenza was shown to be caused by a \"filter passer\", not a bacterium, but there remained a lack of agreement about influenza's cause for another decade and research on influenza declined.", "After the pandemic, H1N1 circulated in humans in seasonal form up until the next pandemic.", "In 1931, Richard Shope published three papers identifying a virus as the cause of swine influenza, a then newly recognized disease among pigs that was first characterized during the second wave of the 1918 pandemic.", "Shope's research reinvigorated research on human influenza, and many advances in virology, serology, immunology, experimental animal models, vaccinology, and immunotherapy have since arisen from influenza research.", "Just two years after influenza viruses were discovered, in 1933, IAV was identified as the agent responsible for human influenza.", "Subtypes of IAV were discovered throughout the 1930s, and IBV was discovered in 1940.", "During the Second World War, the US government worked on developing inactivated vaccines for influenza, resulting in the first influenza vaccine being licensed in 1945 in the United States.", "ICV was discovered two years later in 1947.", "In 1955, avian influenza was confirmed to be caused by IAV.", "Four influenza pandemics have occurred since WWII, each less severe than the 1918 pandemic.", "The first of these was the Asian flu from 1957 to 1958, caused by an H2N2 strain and beginning in China's Yunnan province.", "The number of deaths probably exceeded one million, mostly among the very young and very old.", "Notably, the 1957 pandemic was the first flu pandemic to occur in the presence of a global surveillance system and laboratories able to study the novel influenza virus.", "After the pandemic, H2N2 was the IAV subtype responsible for seasonal influenza.", "The first antiviral drug against influenza, amantadine, was approved for use in 1966, with additional antiviral drugs being used since the 1990s.", "In 1968, H3N2 was introduced into humans as a result of a reassortment between an avian H3N2 strain and an H2N2 strain that was circulating in humans.", "The novel H3N2 strain first emerged in Hong Kong and spread worldwide, causing the Hong Kong flu pandemic, which resulted in 500,000–2,000,000 deaths.", "This was the first pandemic to spread significantly by air travel.", "H2N2 and H3N2 co-circulated after the pandemic until 1971 when H2N2 waned in prevalence and was completely replaced by H3N2.", "In 1977, H1N1 reemerged in humans, possibly after it was released from a freezer in a laboratory accident, and caused a pseudo-pandemic.", "Whether the 1977 \"pandemic\" deserves to be included in the natural history of flu pandemics is debatable.", "This H1N1 strain was antigenically similar to the H1N1 strains that circulated prior to 1957.", "Since 1977, both H1N1 and H3N2 have circulated in humans as part of seasonal influenza.", "In 1980, the current classification system used to subtype influenza viruses was introduced.", "At some point, IBV diverged into two lineages, named the B/Victoria-like and B/Yamagata-like lineages, both of which have been circulating in humans since 1983.", "In 1996, HPAI H5N1 was detected in Guangdong, China and a year later emerged in poultry in Hong Kong, gradually spreading worldwide from there.", "A small H5N1 outbreak in humans in Hong Kong occurred then, and sporadic human cases have occurred since 1997, carrying a high case fatality rate.", "The most recent flu pandemic was the 2009 swine flu pandemic, which originated in Mexico and resulted in hundreds of thousands of deaths.", "It was caused by a novel H1N1 strain that was a reassortment of human, swine, and avian influenza viruses.", "The 2009 pandemic had the effect of replacing prior H1N1 strains in circulation with the novel strain but not any other influenza viruses.", "Consequently, H1N1, H3N2, and both IBV lineages have been in circulation in seasonal form since the 2009 pandemic.", "In 2011, IDV was discovered in pigs in Oklahoma, USA, and cattle were later identified as the primary reservoir of IDV.", "In the same year, avian H7N9 was detected in China and began to cause human infections in 2013, starting in Shanghai and Anhui and remaining mostly in China.", "HPAI H7N9 emerged sometime in 2016 and has occasionally infected humans incidentally.", "Other AIVs have less commonly infected humans since the 1990s, including H5N6, H6N1, H7N2-4, H7N7, and H10N7-8, and HPAI H subtypes such as H5N1-3, H5N5-6, and H5N8 have begun to spread throughout much of the world since the 2010s.", "Future flu pandemics, which may be caused by an influenza virus of avian origin, are viewed as almost inevitable, and increased globalization has made it easier for novel viruses to spread, so there are continual efforts to prepare for future pandemics and improve the prevention and treatment of influenza.", "The word \"influenza\" comes from the Italian word \"influenza\", from medieval Latin \"influentia\", originally meaning \"visitation\" or \"influence\".", "Terms such as \"influenza di freddo\", meaning \"influence of the cold\", and \"influenza di stelle\", meaning \"influence of the stars\" are attested from the 14th century.", "The latter referred to the disease's cause, which at the time was ascribed by some to unfavorable astrological conditions.", "As early as 1504, \"influenza\" began to mean a \"visitation\" or \"outbreak\" of any disease affecting many people in a single place at once.", "During an outbreak of influenza in 1743 that started in Italy and spread throughout Europe, the word reached the English language and was anglicized in pronunciation.", "Since the mid-1800s, \"influenza\" has also been used to refer to severe colds.", "The shortened form of the word, \"(the) flu\", is first attested in 1839 as \"flue\" with the spelling \"flu\" first attested in 1893.", "Other names that have been used for influenza include \"epidemic catarrh\", \"la grippe\" from French, \"sweating sickness\", and, especially when referring to the 1918 pandemic strain, \"Spanish fever\".", "Influenza research is wide-ranging and includes efforts to understand how influenza viruses enter hosts, the relationship between influenza viruses and bacteria, how influenza symptoms progress, and what make some influenza viruses deadlier than others.", "Non-structural proteins encoded by influenza viruses are periodically discovered and their functions are continually under research.", "Past pandemics, and especially the 1918 pandemic, are the subject of much research to understand flu pandemics.", "As part of pandemic preparedness, the Global Influenza Surveillance and Response System is a global network of laboratories that monitors influenza transmission and epidemiology.", "Additional areas of research include ways to improve the diagnosis, treatment, and prevention of influenza.", "Existing diagnostic methods have a variety of limitations coupled with their advantages.", "For example, NATs have high sensitivity and specificity but are impractical in under-resourced regions due to their high cost, complexity, maintenance, and training required.", "Low-cost, portable RIDTs can rapidly diagnose influenza but have highly variable sensitivity and are unable to subtype IAV.", "As a result of these limitations and others, research into new diagnostic methods revolves around producing new methods that are cost-effective, less labor-intensive, and less complex than existing methods while also being able to differentiate influenza species and IAV subtypes.", "One approach in development are lab-on-a-chips, which are diagnostic devices that make use of a variety of diagnostic tests, such as RT-PCR and serological assays, in microchip form.", "These chips have many potential advantages, including high reaction efficiency, low energy consumption, and low waste generation.", "New antiviral drugs are also in development due to the elimination of adamantines as viable drugs and concerns over oseltamivir resistance.", "These include: NA inhibitors that can be injected intravenously, such as intravenous formulations of zanamivir; favipiravir, which is a polymerase inhibitor used against several RNA viruses; pimodivir, which prevents cap-binding required during viral transcription; and nitazoxanide, which inhibits HA maturation.", "Reducing excess inflammation in the respiratory tract is also subject to much research since this is one of the primary mechanisms of influenza pathology.", "Other forms of therapy in development include monoclonal and polyclonal antibodies that target viral proteins, convalescent plasma, different approaches to modify the host antiviral response, and stem cell-based therapies to repair lung damage.", "Much research on LAIVs focuses on identifying genome sequences that can be deleted to create harmless influenza viruses in vaccines that still confer immunity.", "The high variability and rapid evolution of influenza virus antigens, however, is a major obstacle in developing effective vaccines.", "Furthermore, it is hard to predict which strains will be in circulation during the next flu season, manufacturing a sufficient quantity of flu vaccines for the next season is difficult, LAIVs have limited efficacy, and repeated annual vaccination potentially has diminished efficacy.", "For these reasons, \"broadly-reactive\" or \"universal\" flu vaccines are being researched that can provide protection against many or all influenza viruses.", "Approaches to develop such a vaccine include HA stalk-based methods such as chimeras that have the same stalk but different heads, HA head-based methods such as computationally optimized broadly neutralizing antigens, anti-idiotypic antibodies, and vaccines to elicit immune responses to highly conserved viral proteins.", "mRNA vaccines to provide protection against influenza are also under research.", "Aquatic birds such as ducks, geese, shorebirds, and gulls are the primary reservoir of IAVs.", "In birds, AIVs may be either low pathogenic avian influenza (LPAI) viruses that produce little to no symptoms or highly pathogenic avian influenza (HPAI) viruses that cause severe illness.", "Symptoms of HPAI infection include lack of energy and appetite, decreased egg production, soft-shelled or misshapen eggs, swelling of the head, comb, wattles, and hocks, purple discoloration of wattles, combs, and legs, nasal discharge, coughing, sneezing, incoordination, and diarrhea.", "Birds infected with an HPAI virus may also die suddenly without any signs of infection.", "The distinction between LPAI and HPAI can generally be made based on how lethal an AIV is to chickens.", "At the genetic level, an AIV can be usually be identified as an HPAI virus if it has a multibasic cleavage site in the HA protein, which contains additional residues in the HA gene.", "Most AIVs are LPAI.", "Notable HPAI viruses include HPAI H5N1 and HPAI H7N9.", "HPAI viruses have been a major disease burden in the 21st century, resulting in the death of large numbers of birds.", "In H7N9's case, some circulating strains were originally LPAI but became HPAI by acquiring the HA multibasic cleavage site.", "Avian H9N2 is also of concern because although it is LPAI, it is a common donor of genes to H5N1 and H7N9 during reassortment.", "Migratory birds can spread influenza across long distances.", "An example of this was when an H5N1 strain in 2005 infected birds at Qinghai Lake, China, which is a stopover and breeding site for many migratory birds, subsequently spreading the virus to more than 20 countries across Asia, Europe, and the Middle East.", "AIVs can be transmitted from wild birds to domestic free-range ducks and in turn to poultry through contaminated water, aerosols, and fomites.", "Ducks therefore act as key intermediates between wild and domestic birds.", "Transmission to poultry typically occurs in backyard farming and live animal markets where multiple species interact with each other.", "From there, AIVs can spread to poultry farms in the absence of adequate biosecurity.", "Among poultry, HPAI transmission occurs through aerosols and contaminated feces, cages, feed, and dead animals.", "Back-transmission of HPAI viruses from poultry to wild birds has occurred and is implicated in mass die-offs and intercontinental spread.", "AIVs have occasionally infected humans through aerosols, fomites, and contaminated water.", "Direction transmission from wild birds is rare.", "Instead, most transmission involves domestic poultry, mainly chickens, ducks, and geese but also a variety of other birds such as guinea fowl, partridge, pheasants, and quails.", "The primary risk factor for infection with AIVs is exposure to birds in farms and live poultry markets.", "Typically, infection with an AIV has an incubation period of 3–5 days but can be up to 9 days.", "H5N1 and H7N9 cause severe lower respiratory tract illness, whereas other AIVs such as H9N2 cause a more mild upper respiratory tract illness, commonly with conjunctivitis.", "Limited transmission of avian H2, H5-7, H9, and H10 subtypes from one person to another through respiratory droplets, aerosols, and fomites has occurred, but sustained human-to-human transmission of AIVs has not occurred.", "Before 2013, H5N1 was the most common AIV to infect humans.", "Since then, H7N9 has been responsible for most human cases.", "Influenza in pigs is a respiratory disease similar to influenza in humans and is found worldwide.", "Asymptomatic infections are common.", "Symptoms typically appear 1–3 days after infection and include fever, lethargy, anorexia, weight loss, labored breathing, coughing, sneezing, and nasal discharge.", "In sows, pregnancy may be aborted.", "Complications include secondary infections and potentially fatal bronchopneumonia.", "Pigs become contagious within a day of infection and typically spread the virus for 7–10 days, which can spread rapidly within a herd.", "Pigs usually recover from infection within 3–7 days after symptoms appear.", "Prevention and control measures include inactivated vaccines and culling infected herds.", "The influenza viruses usually responsible for swine flu are IAV subtypes H1N1, H1N2, and H3N2.", "Some IAVs can be transmitted via aerosols from pigs to humans and vice versa.", "Furthermore, pigs, along with bats and quails, are recognized as a mixing vessel of influenza viruses because they have both α-2,3 and α-2,6 sialic acid receptors in their respiratory tract.", "Because of that, both avian and mammalian influenza viruses can infect pigs.", "If co-infection occurs, then reassortment is possible.", "A notable example of this was the reassortment of a swine, avian, and human influenza virus in 2009, resulting in a novel H1N1 strain that caused the 2009 flu pandemic.", "Spillover events from humans to pigs, however, appear to be more common than from pigs to humans.", "Influenza viruses have been found in many other animals, including cattle, horses, dogs, cats, and marine mammals.", "Nearly all IAVs are apparently descended from ancestral viruses in birds.", "The exception are bat influenza-like viruses, which have an uncertain origin.", "These bat viruses have HA and NA subtypes H17, H18, N10, and N11.", "H17N10 and H18N11 are unable to reassort with other IAVs, but they are still able to replicate in other mammals.", "AIVs sometimes crossover into mammals.", "For example, in late 2016 to early 2017, an avian H7N2 strain was found to be infecting cats in New York.", "Equine IAVs include H7N7 and two lineages of H3N8.", "H7N7, however, has not been detected in horses since the late 1970s, so it may have become extinct in horses.", "H3N8 in equines spreads via aerosols and causes respiratory illness.", "Equine H3N8 perferentially binds to α-2,3 sialic acids, so horses are usually considered dead-end hosts, but transmission to dogs and camels has occurred, raising concerns that horses may be mixing vessels for reassortment.", "In canines, the only IAVs in circulation are equine-derived H3N8 and avian-derived H3N2.", "Canine H3N8 has not been observed to reassort with other subtypes.", "H3N2 has a much broader host range and can reassort with H1N1 and H5N1.", "An isolated case of H6N1 likely from a chicken was found infecting a dog, so other AIVs may emerge in canines.", "Other mammals to be infected by IAVs include H7N7 and H4N5 in seals, H1N3 in whales, and H10N4 and H3N2 in minks.", "Various mutations have been identified that are associated with AIVs adapting to mammals.", "Since HA proteins vary in which sialic acids they bind to, mutations in the HA receptor binding site can allow AIVs to infect mammals.", "Other mutations include mutations affecting which sialic acids NA proteins cleave and a mutation in the PB2 polymerase subunit that improves tolerance of lower temperatures in mammalian respiratory tracts and enhances RNP assembly by stabilizing NP and PB2 binding.", "IBV is mainly found in humans but has also been detected in pigs, dogs, horses, and seals.", "Likewise, ICV primarily infects humans but has been observed in pigs, dogs, cattle, and dromedary camels.", "IDV causes an influenza-like illness in pigs but its impact in its natural reservoir, cattle, is relatively unknown.", "It may cause respiratory disease resembling human influenza on its own, or it may be part of a bovine respiratory disease (BRD) complex with other pathogens during co-infection.", "BRD is a concern for the cattle industry, so IDV's possible involvement in BRD has led to research on vaccines for cattle that can provide protection against IDV.", "Two antigenic lineages are in circulation: D/swine/Oklahoma/1334/2011 (D/OK) and D/bovine/Oklahoma/660/2013 (D/660)." ]

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[ "Frequent hand washing and covering one's mouth and nose when coughing and sneezing reduce transmission." ]

[ "The time between exposure to the virus and development of symptoms, called the incubation period, is 1–4 days, most commonly 1–2 days.", "Many infections, however, are asymptomatic.", "The onset of symptoms is sudden, and initial symptoms are predominately non-specific, including fever, chills, headaches, muscle pain or aching, a feeling of discomfort, loss of appetite, lack of energy/fatigue, and confusion.", "These symptoms are usually accompanied by respiratory symptoms such as a dry cough, sore or dry throat, hoarse voice, and a stuffy or runny nose.", "Coughing is the most common symptom.", "Gastrointestinal symptoms may also occur, including nausea, vomiting, diarrhea, and gastroenteritis, especially in children.", "The standard influenza symptoms typically last for 2–8 days.", "A 2021 study suggests influenza can cause long lasting symptoms in a similar way to long COVID.\nSymptomatic infections are usually mild and limited to the upper respiratory tract, but progression to pneumonia is relatively common.", "Pneumonia may be caused by the primary viral infection or by a secondary bacterial infection.", "Primary pneumonia is characterized by rapid progression of fever, cough, labored breathing, and low oxygen levels that cause bluish skin.", "It is especially common among those who have an underlying cardiovascular disease such as rheumatic heart disease.", "Secondary pneumonia typically has a period of improvement in symptoms for 1–3 weeks followed by recurrent fever, sputum production, and fluid buildup in the lungs, but can also occur just a few days after influenza symptoms appear.", "About a third of primary pneumonia cases are followed by secondary pneumonia, which is most frequently caused by the bacteria \"Streptococcus pneumoniae\" and \"Staphylococcus aureus\".", "Influenza viruses comprise four species.", "Each of the four species is the sole member of its own genus, and the four influenza genera comprise four of the seven genera in the family \"Orthomyxoviridae\".", "They are:\n\n\nIAV is responsible for most cases of severe illness as well as seasonal epidemics and occasional pandemics.", "It infects people of all ages but tends to disproportionately cause severe illness in the elderly, the very young, and those who have chronic health issues.", "Birds are the primary reservoir of IAV, especially aquatic birds such as ducks, geese, shorebirds, and gulls, but the virus also circulates among mammals, including pigs, horses, and marine mammals.", "IAV is classified into subtypes based on the viral proteins haemagglutinin (H) and neuraminidase (N).", "As of 2019, 18 H subtypes and 11 N subtypes have been identified.", "Most potential combinations have been reported in birds, but H17-18 and N10-11 have only been found in bats.", "Only H subtypes H1-3 and N subtypes N1-2 are known to have circulated in humans, the current IAV subtypes in circulation being H1N1 and H3N2.", "IAVs can be classified more specifically to also include natural host species, geographical origin, year of isolation, and strain number, such as H1N1/A/duck/Alberta/35/76.", "IBV mainly infects humans but has been identified in seals, horses, dogs, and pigs.", "IBV does not have subtypes like IAV but has two antigenically distinct lineages, termed the B/Victoria/2/1987-like and B/Yamagata/16/1988-like lineages, or simply (B/)Victoria(-like) and (B/)Yamagata(-like).", "Both lineages are in circulation in humans, disproportionately affecting children.", "IBVs contribute to seasonal epidemics alongside IAVs but have never been associated with a pandemic.", "ICV, like IBV, is primarily found in humans, though it also has been detected in pigs, feral dogs, dromedary camels, cattle, and dogs.", "ICV infection primarily affects children and is usually asymptomatic or has mild cold-like symptoms, though more severe symptoms such as gastroenteritis and pneumonia can occur.", "Unlike IAV and IBV, ICV has not been a major focus of research pertaining to antiviral drugs, vaccines, and other measures against influenza.", "ICV is subclassified into six genetic/antigenic lineages.", "IDV has been isolated from pigs and cattle, the latter being the natural reservoir.", "Infection has also been observed in humans, horses, dromedary camels, and small ruminants such as goats and sheep.", "IDV is distantly related to ICV.", "While cattle workers have occasionally tested positive to prior IDV infection, it is not known to cause disease in humans.", "ICV and IDV experience a slower rate of antigenic evolution than IAV and IBV.", "Because of this antigenic stability, relatively few novel lineages emerge.", "Influenza viruses have a negative-sense, single-stranded RNA genome that is segmented.", "The negative sense of the genome means it can be used as a template to synthesize messenger RNA (mRNA).", "IAV and IBV have eight genome segments that encode 10 major proteins.", "ICV and IDV have seven genome segments that encode nine major proteins.", "Three segments encode three subunits of an RNA-dependent RNA polymerase (RdRp) complex: PB1, a transcriptase, PB2, which recognizes 5' caps, and PA (P3 for ICV and IDV), an endonuclease.", "The matrix protein (M1) and membrane protein (M2) share a segment, as do the non-structural protein (NS1) and the nuclear export protein (NEP).", "For IAV and IBV, hemagglutinin (HA) and neuraminidase (NA) are encoded on one segment each, whereas ICV and IDV encode a hemagglutinin-esterase fusion (HEF) protein on one segment that merges the functions of HA and NA.", "The final genome segment encodes the viral nucleoprotein (NP).", "Influenza viruses also encode various accessory proteins, such as PB1-F2 and PA-X, that are expressed through alternative open reading frames and which are important in host defense suppression, virulence, and pathogenicity.", "The virus particle, called a virion, is pleomorphic and varies between being filamentous, bacilliform, or spherical in shape.", "Clinical isolates tend to be pleomorphic, whereas strains adapted to laboratory growth typically produce spherical virions.", "Filamentous virions are about 250 nanometers (nm) by 80 nm, bacilliform 120–250 by 95 nm, and spherical 120 nm in diameter.", "The virion consists of each segment of the genome bound to nucleoproteins in separate ribonucleoprotein (RNP) complexes for each segment, all of which are surrounded by a lipid bilayer membrane called the viral envelope.", "There is a copy of the RdRp, all subunits included, bound to each RNP.", "The envelope is reinforced structurally by matrix proteins on the interior that enclose the RNPs, and the envelope contains HA and NA (or HEF) proteins extending outward from the exterior surface of the envelope.", "HA and HEF proteins have a distinct \"head\" and \"stalk\" structure.", "M2 proteins form proton ion channels through the viral envelope that are required for viral entry and exit.", "IBVs contain a surface protein named NB that is anchored in the envelope, but its function is unknown.", "The viral life cycle begins by binding to a target cell.", "Binding is mediated by the viral HA proteins on the surface of the evelope, which bind to cells that contain sialic acid receptors on the surface of the cell membrane.", "For N1 subtypes with the \"G147R\" mutation and N2 subtypes, the NA protein can initiate entry.", "Prior to binding, NA proteins promote access to target cells by degrading mucous, which helps to remove extracellular decoy receptors that would impede access to target cells.", "After binding, the virus is internalized into the cell by an endosome that contains the virion inside it.", "The endosome is acidified by cellular vATPase to have lower pH, which triggers a conformational change in HA that allows fusion of the viral envelope with the endosomal membrane.", "At the same time, hydrogen ions diffuse into the virion through M2 ion channels, disrupting internal protein-protein interactions to release RNPs into the host cell's cytosol.", "The M1 protein shell surrounding RNPs is degraded, fully uncoating RNPs in the cytosol.", "RNPs are then imported into the nucleus with the help of viral localization signals.", "There, the viral RNA polymerase transcribes mRNA using the genomic negative-sense strand as a template.", "The polymerase snatches 5' caps for viral mRNA from cellular RNA to prime mRNA synthesis and the 3'-end of mRNA is polyadenylated at the end of transcription.", "Once viral mRNA is transcribed, it is exported out of the nucleus and translated by host ribosomes in a cap-dependent manner to synthesize viral proteins.", "RdRp also synthesizes complementary positive-sense strands of the viral genome in a complementary RNP complex which are then used as templates by viral polymerases to synthesize copies of the negative-sense genome.", "During these processes, RdRps of avian influenza viruses (AIVs) function optimally at a higher temperature than mammalian influenza viruses.", "Newly synthesized viral polymerase subunits and NP proteins are imported to the nucleus to further increase the rate of viral replication and form RNPs.", "HA, NA, and M2 proteins are trafficked with the aid of M1 and NEP proteins to the cell membrane through the Golgi apparatus and inserted into the cell's membrane.", "Viral non-structural proteins including NS1, PB1-F2, and PA-X regulate host cellular processes to disable antiviral responses.", "PB1-F2 aso interacts with PB1 to keep polymerases in the nucleus longer.", "M1 and NEP proteins localize to the nucleus during the later stages of infection, bind to viral RNPs and mediate their export to the cytoplasm where they migrate to the cell membrane with the aid of recycled endosomes and are bundled into the segments of the genome.", "Progenic viruses leave the cell by budding from the cell membrane, which is initiated by the accumulation of M1 proteins at the cytoplasmic side of the membrane.", "The viral genome is incorporated inside a viral envelope derived from portions of the cell membrane that have HA, NA, and M2 proteins.", "At the end of budding, HA proteins remain attached to cellular sialic acid until they are cleaved by the sialidase activity of NA proteins.", "The virion is then released from the cell.", "The sialidase activity of NA also cleaves any sialic acid residues from the viral surface, which helps prevent newly assembled viruses from aggregating near the cell surface and improving infectivity.", "Similar to other aspects of influenza replication, optimal NA activity is temperature- and pH-dependent.", "Ultimately, presence of large quantities of viral RNA in the cell triggers apoptosis, i.e. programmed cell death, which is initiated by cellular factors to restrict viral replication.", "Two key processes that influenza viruses evolve through are antigenic drift and antigenic shift.", "Antigenic drift is when an influenza virus's antigens change due to the gradual accumulation of mutations in the antigen's (HA or NA) gene.", "This can occur in response to evolutionary pressure exerted by the host immune response.", "Antigenic drift is especially common for the HA protein, in which just a few amino acid changes in the head region can constitute antigenic drift.", "The result is the production of novel strains that can evade pre-existing antibody-mediated immunity.", "Antigenic drift occurs in all influenza species but is slower in B than A and slowest in C and D. Antigenic drift is a major cause of seasonal influenza, and requires that flu vaccines be updated annually.", "HA is the main component of inactivated vaccines, so surveillance monitors antigenic drift of this antigen among circulating strains.", "Antigenic evolution of influenza viruses of humans appears to be faster than influenza viruses in swine and equines.", "In wild birds, within-subtype antigenic variation appears to be limited but has been observed in poultry.", "Antigenic shift is a sudden, drastic change in an influenza virus's antigen, usually HA.", "During antigenic shift, antigenically different strains that infect the same cell can reassort genome segments with each other, producing hybrid progeny.", "Since all influenza viruses have segmented genomes, all are capable of reassortment.", "Antigenic shift, however, only occurs among influenza viruses of the same genus and most commonly occurs among IAVs.", "In particular, reassortment is very common in AIVs, creating a large diversity of influenza viruses in birds, but is uncommon in human, equine, and canine lineages.", "Pigs, bats, and quails have receptors for both mammalian and avian IAVs, so they are potential \"mixing vessels\" for reassortment.", "If an animal strain reassorts with a human strain, then a novel strain can emerge that is capable of human-to-human transmission.", "This has caused pandemics, but only a limited number have occurred, so it is difficult to predict when the next will happen.", "People who are infected can transmit influenza viruses through breathing, talking, coughing, and sneezing, which spread respiratory droplets and aerosols that contain virus particles into the air.", "A person susceptible to infection can then contract influenza by coming into contact with these particles.", "Respiratory droplets are relatively large and travel less than two meters before falling onto nearby surfaces.", "Aerosols are smaller and remain suspended in the air longer, so they take longer to settle and can travel further than respiratory droplets.", "Inhalation of aerosols can lead to infection, but most transmission is in the area about two meters around an infected person via respiratory droplets that come into contact with mucosa of the upper respiratory tract.", "Transmission through contact with a person, bodily fluids, or intermediate objects (fomites) can also occur, such as through contaminated hands and surfaces since influenza viruses can survive for hours on non-porous surfaces.", "If one's hands are contaminated, then touching one's face can cause infection.", "Influenza is usually transmissible from one day before the onset of symptoms to 5–7 days after.", "In healthy adults, the virus is shed for up to 3–5 days.", "In children and the immunocompromised, the virus may be transmissible for several weeks.", "Children ages 2–17 are considered to be the primary and most efficient spreaders of influenza.", "Children who have not had multiple prior exposures to influenza viruses shed the virus at greater quantities and for a longer duration than other children.", "People who are at risk of exposure to influenza include health care workers, social care workers, and those who live with or care for people vulnerable to influenza.", "In long-term care facilities, the flu can spread rapidly after it is introduced.", "A variety of factors likely encourage influenza transmission, including lower temperature, lower absolute and relative humidity, less ultraviolet radiation from the Sun, and crowding.", "Influenza viruses that infect the upper respiratory tract like H1N1 tend to be more mild but more transmissible, whereas those that infect the lower respiratory tract like H5N1 tend to cause more severe illness but are less contagious.", "In humans, influenza viruses first cause infection by infecting epithelial cells in the respiratory tract.", "Illness during infection is primarily the result of lung inflammation and compromise caused by epithelial cell infection and death, combined with inflammation caused by the immune system's response to infection.", "Non-respiratory organs can become involved, but the mechanisms by which influenza is involved in these cases are unknown.", "Severe respiratory illness can be caused by multiple, non-exclusive mechanisms, including obstruction of the airways, loss of alveolar structure, loss of lung epithelial integrity due to epithelial cell infection and death, and degradation of the extracellular matrix that maintains lung structure.", "In particular, alveolar cell infection appears to drive severe symptoms since this results in impaired gas exchange and enables viruses to infect endothelial cells, which produce large quantities of pro-inflammatory cytokines.", "Pneumonia caused by influenza viruses is characterized by high levels of viral replication in the lower respiratory tract, accompanied by a strong pro-inflammatory response called a cytokine storm.", "Infection with H5N1 or H7N9 especially produces high levels of pro-inflammatory cytokines.", "In bacterial infections, early depletion of macrophages during influenza creates a favorable environment in the lungs for bacterial growth since these white blood cells are important in responding to bacterial infection.", "Host mechanisms to encourage tissue repair may inadvertently allow bacterial infection.", "Infection also induces production of systemic glucocorticoids that can reduce inflammation to preserve tissue integrity but allow increased bacterial growth.", "The pathophysiology of influenza is significantly influenced by which receptors influenza viruses bind to during entry into cells.", "Mammalian influenza viruses preferentially bind to sialic acids connected to the rest of the oligosaccharide by an α-2,6 link, most commonly found in various respiratory cells, such as respiratory and retinal epithelial cells.", "AIVs prefer sialic acids with an α-2,3 linkage, which are most common in birds in gastrointestinal epithelial cells and in humans in the lower respiratory tract.", "Furthermore, cleavage of the HA protein into HA, the binding subunit, and HA, the fusion subunit, is performed by different proteases, affecting which cells can be infected.", "For mammalian influenza viruses and low pathogenic AIVs, cleavage is extracellular, which limits infection to cells that have the appropriate proteases, whereas for highly pathogenic AIVs, cleavage is intracellular and performed by ubiquitous proteases, which allows for infection of a greater variety of cells, thereby contributing to more severe disease.", "Cells possess sensors to detect viral RNA, which can then induce interferon production.", "Interferons mediate expression of antiviral proteins and proteins that recruit immune cells to the infection site, and they also notify nearby uninfected cells of infection.", "Some infected cells release pro-inflammatory cytokines that recruit immune cells to the site of infection.", "Immune cells control viral infection by killing infected cells and phagocytizing viral particles and apoptotic cells.", "An exacerbated immune response, however, can harm the host organism through a cytokine storm.", "To counter the immune response, influenza viruses encode various non-structural proteins, including NS1, NEP, PB1-F2, and PA-X, that are involved in curtailing the host immune response by suppressing interferon production and host gene expression.", "B cells, a type of white blood cell, produce antibodies that bind to influenza antigens HA and NA (or HEF) and other proteins to a lesser degree.", "Once bound to these proteins, antibodies block virions from binding to cellular receptors, neutralizing the virus.", "In humans, a sizeable antibody response occurs ~1 week after viral exposure.", "This antibody response is typically robust and long-lasting, especially for ICV and IDV.", "In other words, people exposed to a certain strain in childhood still possess antibodies to that strain at a reasonable level later in life, which can provide some protection to related strains.", "There is, however, an \"original antigenic sin\", in which the first HA subtype a person is exposed to influences the antibody-based immune response to future infections and vaccines.", "Annual vaccination is the primary and most effective way to prevent influenza and influenza-associated complications, especially for high-risk groups.", "Vaccines against the flu are trivalent or quadrivalent, providing protection against an H1N1 strain, an H3N2 strain, and one or two IBV strains corresponding to the two IBV lineages.", "Two types of vaccines are in use: inactivated vaccines that contain \"killed\" (i.e. inactivated) viruses and live attenuated influenza vaccines (LAIVs) that contain weakened viruses.", "There are three types of inactivated vaccines: whole virus, split virus, in which the virus is disrupted by a detergent, and subunit, which only contains the viral antigens HA and NA.", "Most flu vaccines are inactivated and administered via intramuscular injection.", "LAIVs are sprayed into the nasal cavity.", "Vaccination recommendations vary by country.", "Some recommend vaccination for all people above a certain age, such as 6 months, whereas other countries recommendation is limited for high at risk groups, such as pregnant women, young children (excluding newborns), the elderly, people with chronic medical conditions, health care workers, people who come into contact with high-risk people, and people who transmit the virus easily.", "Young infants cannot receive flu vaccines for safety reasons, but they can inherit passive immunity from their mother if inactivated vaccines are administered to the mother during pregnancy.", "Influenza vaccination also helps to reduce the probability of reassortment.", "In general, influenza vaccines are only effective if there is an antigenic match between vaccine strains and circulating strains.", "Additionally, most commercially available flu vaccines are manufactured by propagation of influenza viruses in embryonated chicken eggs, taking 6–8 months.", "Flu seasons are different in the northern and southern hemisphere, so the WHO meets twice a year, one for each hemisphere, to discuss which strains should be included in flu vaccines based on observation from HA inhibition assays.", "Other manufacturing methods include an MDCK cell culture-based inactivated vaccine and a recombinant subunit vaccine manufactured from baculovirus overexpression in insect cells.", "Influenza can be prevented or reduced in severity by post-exposure prophylaxis with the antiviral drugs oseltamivir, which can be taken orally by those at least three months old, and zanamivir, which can be inhaled by those above seven years of age.", "Chemoprophylaxis is most useful for individuals at high-risk of developing complications and those who cannot receive the flu vaccine due to contraindications or lack of effectiveness.", "Post-exposure chemoprophylaxis is only recommended if oseltamivir is taken within 48 hours of contact with a confirmed or suspected influenza case and zanamivir within 36 hours.", "It is recommended that it be offered to people who have yet to receive a vaccine for the current flu season, who have been vaccinated less than two week since contact, if there is a significant mismatch between vaccine and circulating strains, or during an outbreak in a closed setting regardless of vaccination history.", "Hand hygiene is important in reducing the spread of influenza.", "This includes frequent hand washing with soap and water, using alcohol-based hand sanitizers, and not touching one's eyes, nose, and mouth with one's hands.", "Covering one's nose and mouth when coughing or sneezing is important.", "Other methods to limit influenza transmission include staying home when sick, avoiding contact with others until one day after symptoms end, and disinfecting surfaces likely to be contaminated by the virus, such as doorknobs.", "Health education through media and posters is often used to remind people of the aforementioned etiquette and hygiene.", "There is uncertainty about the use of masks since research thus far has not shown a significant reduction in seasonal influenza with mask usage.", "Likewise, the effectiveness of screening at points of entry into countries is not well researched.", "Social distancing measures such as school closures, avoiding contact with infected people via isolation or quarantine, and limiting mass gatherings may reduce transmission, but these measures are often expensive, unpopular, and difficult to implement.", "Consequently, the commonly recommended methods of infection control are respiratory etiquette, hand hygiene, and mask wearing, which are inexpensive and easy to perform.", "Pharmaceutical measures are effective but may not be available in the early stages of an outbreak.", "In health care settings, infected individuals may be cohorted or assigned to individual rooms.", "Protective clothing such as masks, gloves, and gowns is recommended when coming into contact with infected individuals if there is a risk of exposure to infected bodily fluids.", "Keeping patients in negative pressure rooms and avoiding aerosol-producing activities may help, but special air handling and ventilation systems are not considered necessary to prevent the spread of influenza in the air.", "In residential homes, new admissions may need to be closed until the spread of influenza is controlled.", "When discharging patients to care homes, it is important to take care if there is a known influenza outbreak.", "Since influenza viruses circulate in animals such as birds and pigs, prevention of transmission from these animals is important.", "Water treatment, indoor raising of animals, quarantining sick animals, vaccination, and biosecurity are the primary measures used.", "Placing poultry houses and piggeries on high ground away from high-density farms, backyard farms, live poultry markets, and bodies of water helps to minimize contact with wild birds.", "Closure of live poultry markets appears to the most effective measure and has shown to be effective at controlling the spread of H5N1, H7N9, and H9N2.", "Other biosecurity measures include cleaning and disinfecting facilities and vehicles, banning visits to poultry farms, not bringing birds intended for slaughter back to farms, changing clothes, disinfecting foot baths, and treating food and water.", "If live poultry markets are not closed, then \"clean days\" when unsold poultry is removed and facilities are disinfected and \"no carry-over\" policies to eliminate infectious material before new poultry arrive can be used to reduce the spread of influenza viruses.", "If a novel influenza viruses has breached the aforementioned biosecurity measures, then rapid detection to stamp it out via quarantining, decontamination, and culling may be necessary to prevent the virus from becoming endemic.", "Vaccines exist for avian H5, H7, and H9 subtypes that are used in some countries.", "In China, for example, vaccination of domestic birds against H7N9 successfully limited its spread, indicating that vaccination may be an effective strategy if used in combination with other measures to limit transmission.", "In pigs and horses, management of influenza is dependent on vaccination with biosecurity.", "Diagnosis based on symptoms is fairly accurate in otherwise healthy people during seasonal epidemics and should be suspected in cases of pneumonia, acute respiratory distress syndrome (ARDS), sepsis, or if encephalitis, myocarditis, or breaking down of muscle tissue occur.", "Because influenza is similar to other viral respiratory tract illnesses, laboratory diagnosis is necessary for confirmation.", "Common ways of collecting samples for testing include nasal and throat swabs.", "Samples may be taken from the lower respiratory tract if infection has cleared the upper but not lower respiratory tract.", "Influenza testing is recommended for anyone hospitalized with symptoms resembling influenza during flu season or who is connected to an influenza case.", "For severe cases, earlier diagnosis improves patient outcome.", "Diagnostic methods that can identify influenza include viral cultures, antibody- and antigen-detecting tests, and nucleic acid-based tests.", "Viruses can be grown in a culture of mammalian cells or embryonated eggs for 3–10 days to monitor cytopathic effect.", "Final confirmation can then be done via antibody staining, hemadsorption using red blood cells, or immunofluorescence microscopy.", "Shell vial cultures, which can identify infection via immunostaining before a cytopathic effect appears, are more sensitive than traditional cultures with results in 1–3 days.", "Cultures can be used to characterize novel viruses, observe sensitivity to antiviral drugs, and monitor antigenic drift, but they are relatively slow and require specialized skills and equipment.", "Serological assays can be used to detect an antibody response to influenza after natural infection or vaccination.", "Common serological assays include hemagglutination inhibition assays that detect HA-specific antibodies, virus neutralization assays that check whether antibodies have neutralized the virus, and enzyme-linked immunoabsorbant assays.", "These methods tend to be relatively inexpensive and fast but are less reliable than nucleic-acid based tests.", "Direct fluorescent or immunofluorescent antibody (DFA/IFA) tests involve staining respiratory epithelial cells in samples with fluorescently-labeled influenza-specific antibodies, followed by examination under a fluorescent microscope.", "They can differentiate between IAV and IBV but can't subtype IAV.", "Rapid influenza diagnostic tests (RIDTs) are a simple way of obtaining assay results, are low cost, and produce results quickly, at less than 30 minutes, so they are commonly used, but they can't distinguish between IAV and IBV or between IAV subtypes and are not as sensitive as nucleic-acid based tests.", "Nucleic acid-based tests (NATs) amplify and detect viral nucleic acid.", "Most of these tests take a few hours, but rapid molecular assays are as fast as RIDTs.", "Among NATs, reverse transcription polymerase chain reaction (RT-PCR) is the most traditional and considered the gold standard for diagnosing influenza because it is fast and can subtype IAV, but it is relatively expensive and more prone to false-positives than cultures.", "Other NATs that have been used include loop-mediated isothermal amplification-based assays, simple amplification-based assays, and nucleic acid sequence-based amplification.", "Nucleic acid sequencing methods can identify infection by obtaining the nucleic acid sequence of viral samples to identify the virus and antiviral drug resistance.", "The traditional method is Sanger sequencing, but it has been largely replaced by next-generation methods that have greater sequencing speed and throughput.", "Treatment of influenza in cases of mild or moderate illness is supportive and includes anti-fever medications such as acetaminophen and ibuprofen, adequate fluid intake to avoid dehydration, and resting at home.", "Cough drops and throat sprays may be beneficial for sore throat.", "It is recommended to avoid alcohol and tobacco use while sick with the flu.", "Aspirin is not recommended to treat influenza in children due to an elevated risk of developing Reye syndrome.", "Corticosteroids likewise are not recommended except when treating septic shock or an underlying medical condition, such as chronic obstructive pulmonary disease or asthma exacerbation, since they are associated with increased mortality.", "If a secondary bacterial infection occurs, then treatment with antibiotics may be necessary.", "Antiviral drugs are primarily used to treat severely ill patients, especially those with compromised immune systems.", "Antivirals are most effective when started in the first 48 hours after symptoms appear.", "Later administration may still be beneficial for those who have underlying immune defects, those with more severe symptoms, or those who have a higher risk of developing complications if these individuals are still shedding the virus.", "Antiviral treatment is also recommended if a person is hospitalized with suspected influenza instead of waiting for test results to return and if symptoms are worsening.", "Most antiviral drugs against influenza fall into two categories: neuraminidase (NA) inhibitors and M2 inhibitors.", "Baloxavir marboxil is a notable exception, which targets the endonuclease activity of the viral RNA polymerase and can be used as an alternative to NA and M2 inhibitors for IAV and IBV.", "NA inhibitors target the enzymatic activity of NA receptors, mimicking the binding of sialic acid in the active site of NA on IAV and IBV virions so that viral release from infected cells and the rate of viral replication are impaired.", "NA inhibitors include oseltamivir, which is consumed orally in a prodrug form and converted to its active form in the liver, and zanamivir, which is a powder that is inhaled nasally.", "Oseltamivir and zanamivir are effective for prophylaxis and post-exposure prophylaxis, and research overall indicates that NA inhibitors are effective at reducing rates of complications, hospitalization, and mortality and the duration of illness.", "Additionally, the earlier NA inhibitors are provided, the better the outcome, though late administration can still be beneficial in severe cases.", "Other NA inhibitors include laninamivir and peramivir, the latter of which can be used as an alternative to oseltamivir for people who cannot tolerate or absorb it.", "The adamantanes amantadine and rimantadine are orally administered drugs that block the influenza virus's M2 ion channel, preventing viral uncoating.", "These drugs are only functional against IAV but are no longer recommended for use because of widespread resistance to them among IAVs.", "Adamantane resistance first emerged in H3N2 in 2003, becoming worldwide by 2008.", "Oseltamivir resistance is no longer widespread because the 2009 pandemic H1N1 strain (H1N1 pdm09), which is resistant to adamantanes, seemingly replaced resistant strains in circulation.", "Since the 2009 pandemic, oseltamivir resistance has mainly been observed in patients undergoing therapy, especially the immunocompromised and young children.", "Oseltamivir resistance is usually reported in H1N1, but has been reported in H3N2 and IBVs less commonly.", "Because of this, oseltamivir is recommended as the first drug of choice for immunocompetent people, whereas for the immunocompromised, oseltamivir is recommended against H3N2 and IBV and zanamivir against H1N1 pdm09.", "Zanamivir resistance is observed less frequently, and resistance to peramivir and baloxavir marboxil is possible.", "In healthy individuals, influenza infection is usually self-limiting and rarely fatal.", "Symptoms usually last for 2–8 days.", "Influenza can cause people to miss work or school, and it is associated with decreased job performance and, in older adults, reduced independence.", "Fatigue and malaise may last for several weeks after recovery, and healthy adults may experience pulmonary abnormalities that can take several weeks to resolve.", "Complications and mortality primarily occur in high-risk populations and those who are hospitalized.", "Severe disease and mortality are usually attributable to pneumonia from the primary viral infection or a secondary bacterial infection, which can progress to ARDS.", "Other respiratory complications that may occur include sinusitis, bronchitis, bronchiolitis, excess fluid buildup in the lungs, and exacerbation of chronic bronchitis and asthma.", "Middle ear infection and croup may occur, most commonly in children.", "Secondary \"S. aureus\" infection has been observed, primarily in children, to cause toxic shock syndrome after influenza, with hypotension, fever, and reddening and peeling of the skin.", "Complications affecting the cardiovascular system are rare and include pericarditis, fulminant myocarditis with a fast, slow, or irregular heartbeat, and exacerbation of pre-existing cardiovascular disease.", "Inflammation or swelling of muscles accompanied by muscle tissue breaking down occurs rarely, usually in children, which presents as extreme tenderness and muscle pain in the legs and a reluctance to walk for 2–3 days.", "Influenza can affect pregnancy, including causing smaller neonatal size, increased risk of premature birth, and an increased risk of child death shortly before or after birth.", "Neurological complications have been associated with influenza on rare occasions, including aseptic meningitis, encephalitis, disseminated encephalomyelitis, transverse myelitis, and Guillain–Barré syndrome.", "Additionally, febrile seizures and Reye syndrome can occur, most commonly in children.", "Influenza-associated encephalopathy can occur directly from central nervous system infection from the presence of the virus in blood and presents as suddent onset of fever with convulsions, followed by rapid progression to coma.", "An atypical form of encephalitis called encephalitis lethargica, characterized by headache, drowsiness, and coma, may rarely occur sometime after infection.", "In survivors of influenza-associated encephalopathy, neurological defects may occur.", "Primarily in children, in severe cases the immune system may rarely dramatically overproduce white blood cells that release cytokines, causing severe inflammation.", "People who are at least 65 years of age, due to a weakened immune system from aging or a chronic illness, are a high-risk group for developing complications, as are children less than one year of age and children who have not been previously exposed to influenza viruses multiple times.", "Pregnant women are at an elevated risk, which increases by trimester and lasts up to two weeks after childbirth.", "Obesity, in particular a body mass index greater than 35–40, is associated with greater amounts of viral replication, increased severity of secondary bacterial infection, and reduced vaccination efficacy.", "People who have underlying health conditions are also considered at-risk, including those who have congenital or chronic heart problems or lung (e.g. asthma), kidney, liver, blood, neurological, or metabolic (e.g. diabetes) disorders, as are people who are immunocompromised from chemotherapy, asplenia, prolonged steroid treatment, splenic dysfunction, or HIV infection.", "Current or past tobacco use also places a person at risk.", "The role of genetics in influenza is not well researched, but it may be a factor in influenza mortality.", "Influenza is typically characterized by seasonal epidemics and sporadic pandemics.", "Most of the burden of influenza is a result of flu seasons caused by IAV and IBV.", "Among IAV subtypes, H1N1 and H3N2 currently circulate in humans and are responsible for seasonal influenza.", "Cases disproportionately occur in children, but most severe causes are among the elderly, the very young, and the immunocompromised.", "In a typical year, influenza viruses infect 5–15% of the global population, causing 3–5 million cases of severe illness annually and accounting for 290,000–650,000 deaths each year due to respiratory illness.", "5–10% of adults and 20–30% of children contract influenza each year.", "The reported number of influenza cases is usually much lower than the actual number of cases.", "During seasonal epidemics, it is estimated that about 80% of otherwise healthy people who have a cough or sore throat have the flu.", "Approximately 30–40% of people hospitalized for influenza develop pneumonia, and about 5% of all severe pneumonia cases in hospitals are due to influenza, which is also the most common cause of ARDS in adults.", "In children, influenza is one of the two most common causes of ARDS, the other being the respiratory syncytial virus.", "About 3–5% of children each year develop otitis media due to influenza.", "Adults who develop organ failure from influenza and children who have PIM scores and acute renal failure have higher rates of mortality.", "During seasonal influenza, mortality is concentrated in the very young and the elderly, whereas during flu pandemics, young adults are often affected at a high rate.", "In temperate regions, the number of influenza cases varies from season to season.", "Lower vitamin D levels, presumably due to less sunlight, lower humidity, lower temperature, and minor changes in virus proteins caused by antigenic drift contribute to annual epidemics that peak during the winter season.", "In the northern hemisphere, this is from October to May (more narrowly December to April), and in the southern hemisphere, this is from May to October (more narrowly June to September).", "There are therefore two distinct influenza seasons every year in temperate regions, one in the northern hemisphere and one in the southern hemisphere.", "In tropical and subtropical regions, seasonality is more complex and appears to be affected by various climatic factors such as minimum temperature, hours of sunshine, maximum rainfall, and high humidity.", "Influenza may therefore occur year-round in these regions.", "Influenza epidemics in modern times have the tendency to start in the eastern or southern hemisphere, with Asia being a key reservoir of influenza viruses.", "IAV and IBV co-circulate, so the two have the same patterns of transmission.", "The seasonality of ICV, however, is poorly understood.", "ICV infection is most common in children under the age of 2, and by adulthood most people have been exposed to it.", "ICV-associated hospitalization most commonly occurs in children under the age of 3 and is frequently accompanied by co-infection with another virus or a bacterium, which may increase the severity of disease.", "When considering all hospitalizations for respiratory illness among young children, ICV appears to account for only a small percentage of such cases.", "Large outbreaks of ICV infection can occur, so incidence varies significantly.", "Outbreaks of influenza caused by novel influenza viruses are common.", "Depending on the level of pre-existing immunity in the population, novel influenza viruses can spread rapidly and cause pandemics with millions of deaths.", "These pandemics, in contrast to seasonal influenza, are caused by antigenic shifts involving animal influenza viruses.", "To date, all known flu pandemics have been caused by IAVs, and they follow the same pattern of spreading from an origin point to the rest of the world over the course of multiple waves in a year.", "Pandemic strains tend to be associated with higher rates of pneumonia in otherwise healthy individuals.", "Generally after each influenza pandemic, the pandemic strain continues to circulate as the cause of seasonal influenza, replacing prior strains.", "From 1700 to 1889, influenza pandemics occurred about once every 50–60 years.", "Since then, pandemics have occurred about once every 10–50 years, so they may be getting more frequent over time.", "It is impossible to know when an influenza virus first infected humans or when the first influenza pandemic occurred.", "Possibly the first influenza epidemic occurred around 6,000 BC in China, and possible descriptions of influenza exist in Greek writings from the 5th century BC.", "In both 1173–1174 AD and 1387 AD, epidemics occurred across Europe that were named \"influenza\".", "Whether these epidemics and others were caused by influenza is unclear since there was no consistent naming pattern for epidemic respiratory diseases at that time, and \"influenza\" didn't become completely attached to respiratory disease until centuries later.", "Influenza may have been brought to the Americas as early as 1493, when an epidemic disease resembling influenza killed most of the population of the Antilles.", "The first convincing record of an influenza pandemic was chronicled in 1510; it began in East Asia before spreading to North Africa and then Europe.", "Following the pandemic, seasonal influenza occurred, with subsequent pandemics in 1557 and 1580.", "The flu pandemic in 1557 was potentially the first time influenza was connected to miscarriage and death of pregnant women.", "The 1580 flu pandemic originated in Asia during summer, spread to Africa, then Europe, and finally America.", "By the end of the 16th century, influenza was likely beginning to become understood as a specific, recognizable disease with epidemic and endemic forms.", "In 1648, it was discovered that horses also experience influenza.", "Influenza data after 1700 is more informative, so it is easier to identify flu pandemics after this point, each of which incrementally increased understanding of influenza.", "The first flu pandemic of the 18th century started in 1729 in Russia in spring, spreading worldwide over the course of three years with distinct waves, the later ones being more lethal.", "The second flu pandemic of the 18th century was in 1781–1782, starting in China in autumn.", "From this pandemic, influenza became associated with sudden outbreaks of febrile illness.", "The next flu pandemic was from 1830 to 1833, beginning in China in winter.", "This pandemic had a high attack rate, but the mortality rate was low.", "A minor influenza pandemic occurred from 1847 to 1851 at the same time as the third cholera pandemic and was the first flu pandemic to occur with vital statistics being recorded, so influenza mortality was clearly recorded for the first time.", "Highly pathogenic avian influenza was recognized in 1878 and was soon linked to transmission to humans.", "By the time of the 1889 pandemic, which may have been caused by an H2N2 strain, the flu had become an easily recognizable disease.", "Initially, the microbial agent responsible for influenza was incorrently identified in 1892 by R. F. J. Pfeiffer as the bacteria species \"Haemophilus influenzae\", which retains \"influenza\" in its name.", "In the following years, the field of virology began to form as viruses were identified as the cause of many diseases.", "From 1901 to 1903, Italian and Austrian researchers were able to show that avian influenza, then called \"fowl plague\", was caused by a microscopic agent smaller than bacteria by using filters with pores too small for bacteria to pass through.", "The fundamental differences between viruses and bacteria, however, were not yet fully understood.", "From 1918 to 1920, the Spanish flu pandemic became the most devastating influenza pandemic and one of the deadliest pandemics in history.", "The pandemic, probably caused by H1N1, likely began in the USA before spreading worldwide by soldiers during and after the First World War.", "The initial wave in the first half of 1918 was relatively minor and resembled past flu pandemics, but the second wave later that year had a much higher mortality rate, accounting for most deaths.", "A third wave with lower mortality occurred in many places a few months after the second.", "By the end of 1920, it is estimated that about a third to half of all people in the world had been infected, with tens of millions of deaths, disproportionately young adults.", "During the 1918 pandemic, the respiratory route of transmission was clearly identified and influenza was shown to be caused by a \"filter passer\", not a bacterium, but there remained a lack of agreement about influenza's cause for another decade and research on influenza declined.", "After the pandemic, H1N1 circulated in humans in seasonal form up until the next pandemic.", "In 1931, Richard Shope published three papers identifying a virus as the cause of swine influenza, a then newly recognized disease among pigs that was first characterized during the second wave of the 1918 pandemic.", "Shope's research reinvigorated research on human influenza, and many advances in virology, serology, immunology, experimental animal models, vaccinology, and immunotherapy have since arisen from influenza research.", "Just two years after influenza viruses were discovered, in 1933, IAV was identified as the agent responsible for human influenza.", "Subtypes of IAV were discovered throughout the 1930s, and IBV was discovered in 1940.", "During the Second World War, the US government worked on developing inactivated vaccines for influenza, resulting in the first influenza vaccine being licensed in 1945 in the United States.", "ICV was discovered two years later in 1947.", "In 1955, avian influenza was confirmed to be caused by IAV.", "Four influenza pandemics have occurred since WWII, each less severe than the 1918 pandemic.", "The first of these was the Asian flu from 1957 to 1958, caused by an H2N2 strain and beginning in China's Yunnan province.", "The number of deaths probably exceeded one million, mostly among the very young and very old.", "Notably, the 1957 pandemic was the first flu pandemic to occur in the presence of a global surveillance system and laboratories able to study the novel influenza virus.", "After the pandemic, H2N2 was the IAV subtype responsible for seasonal influenza.", "The first antiviral drug against influenza, amantadine, was approved for use in 1966, with additional antiviral drugs being used since the 1990s.", "In 1968, H3N2 was introduced into humans as a result of a reassortment between an avian H3N2 strain and an H2N2 strain that was circulating in humans.", "The novel H3N2 strain first emerged in Hong Kong and spread worldwide, causing the Hong Kong flu pandemic, which resulted in 500,000–2,000,000 deaths.", "This was the first pandemic to spread significantly by air travel.", "H2N2 and H3N2 co-circulated after the pandemic until 1971 when H2N2 waned in prevalence and was completely replaced by H3N2.", "In 1977, H1N1 reemerged in humans, possibly after it was released from a freezer in a laboratory accident, and caused a pseudo-pandemic.", "Whether the 1977 \"pandemic\" deserves to be included in the natural history of flu pandemics is debatable.", "This H1N1 strain was antigenically similar to the H1N1 strains that circulated prior to 1957.", "Since 1977, both H1N1 and H3N2 have circulated in humans as part of seasonal influenza.", "In 1980, the current classification system used to subtype influenza viruses was introduced.", "At some point, IBV diverged into two lineages, named the B/Victoria-like and B/Yamagata-like lineages, both of which have been circulating in humans since 1983.", "In 1996, HPAI H5N1 was detected in Guangdong, China and a year later emerged in poultry in Hong Kong, gradually spreading worldwide from there.", "A small H5N1 outbreak in humans in Hong Kong occurred then, and sporadic human cases have occurred since 1997, carrying a high case fatality rate.", "The most recent flu pandemic was the 2009 swine flu pandemic, which originated in Mexico and resulted in hundreds of thousands of deaths.", "It was caused by a novel H1N1 strain that was a reassortment of human, swine, and avian influenza viruses.", "The 2009 pandemic had the effect of replacing prior H1N1 strains in circulation with the novel strain but not any other influenza viruses.", "Consequently, H1N1, H3N2, and both IBV lineages have been in circulation in seasonal form since the 2009 pandemic.", "In 2011, IDV was discovered in pigs in Oklahoma, USA, and cattle were later identified as the primary reservoir of IDV.", "In the same year, avian H7N9 was detected in China and began to cause human infections in 2013, starting in Shanghai and Anhui and remaining mostly in China.", "HPAI H7N9 emerged sometime in 2016 and has occasionally infected humans incidentally.", "Other AIVs have less commonly infected humans since the 1990s, including H5N6, H6N1, H7N2-4, H7N7, and H10N7-8, and HPAI H subtypes such as H5N1-3, H5N5-6, and H5N8 have begun to spread throughout much of the world since the 2010s.", "Future flu pandemics, which may be caused by an influenza virus of avian origin, are viewed as almost inevitable, and increased globalization has made it easier for novel viruses to spread, so there are continual efforts to prepare for future pandemics and improve the prevention and treatment of influenza.", "The word \"influenza\" comes from the Italian word \"influenza\", from medieval Latin \"influentia\", originally meaning \"visitation\" or \"influence\".", "Terms such as \"influenza di freddo\", meaning \"influence of the cold\", and \"influenza di stelle\", meaning \"influence of the stars\" are attested from the 14th century.", "The latter referred to the disease's cause, which at the time was ascribed by some to unfavorable astrological conditions.", "As early as 1504, \"influenza\" began to mean a \"visitation\" or \"outbreak\" of any disease affecting many people in a single place at once.", "During an outbreak of influenza in 1743 that started in Italy and spread throughout Europe, the word reached the English language and was anglicized in pronunciation.", "Since the mid-1800s, \"influenza\" has also been used to refer to severe colds.", "The shortened form of the word, \"(the) flu\", is first attested in 1839 as \"flue\" with the spelling \"flu\" first attested in 1893.", "Other names that have been used for influenza include \"epidemic catarrh\", \"la grippe\" from French, \"sweating sickness\", and, especially when referring to the 1918 pandemic strain, \"Spanish fever\".", "Influenza research is wide-ranging and includes efforts to understand how influenza viruses enter hosts, the relationship between influenza viruses and bacteria, how influenza symptoms progress, and what make some influenza viruses deadlier than others.", "Non-structural proteins encoded by influenza viruses are periodically discovered and their functions are continually under research.", "Past pandemics, and especially the 1918 pandemic, are the subject of much research to understand flu pandemics.", "As part of pandemic preparedness, the Global Influenza Surveillance and Response System is a global network of laboratories that monitors influenza transmission and epidemiology.", "Additional areas of research include ways to improve the diagnosis, treatment, and prevention of influenza.", "Existing diagnostic methods have a variety of limitations coupled with their advantages.", "For example, NATs have high sensitivity and specificity but are impractical in under-resourced regions due to their high cost, complexity, maintenance, and training required.", "Low-cost, portable RIDTs can rapidly diagnose influenza but have highly variable sensitivity and are unable to subtype IAV.", "As a result of these limitations and others, research into new diagnostic methods revolves around producing new methods that are cost-effective, less labor-intensive, and less complex than existing methods while also being able to differentiate influenza species and IAV subtypes.", "One approach in development are lab-on-a-chips, which are diagnostic devices that make use of a variety of diagnostic tests, such as RT-PCR and serological assays, in microchip form.", "These chips have many potential advantages, including high reaction efficiency, low energy consumption, and low waste generation.", "New antiviral drugs are also in development due to the elimination of adamantines as viable drugs and concerns over oseltamivir resistance.", "These include: NA inhibitors that can be injected intravenously, such as intravenous formulations of zanamivir; favipiravir, which is a polymerase inhibitor used against several RNA viruses; pimodivir, which prevents cap-binding required during viral transcription; and nitazoxanide, which inhibits HA maturation.", "Reducing excess inflammation in the respiratory tract is also subject to much research since this is one of the primary mechanisms of influenza pathology.", "Other forms of therapy in development include monoclonal and polyclonal antibodies that target viral proteins, convalescent plasma, different approaches to modify the host antiviral response, and stem cell-based therapies to repair lung damage.", "Much research on LAIVs focuses on identifying genome sequences that can be deleted to create harmless influenza viruses in vaccines that still confer immunity.", "The high variability and rapid evolution of influenza virus antigens, however, is a major obstacle in developing effective vaccines.", "Furthermore, it is hard to predict which strains will be in circulation during the next flu season, manufacturing a sufficient quantity of flu vaccines for the next season is difficult, LAIVs have limited efficacy, and repeated annual vaccination potentially has diminished efficacy.", "For these reasons, \"broadly-reactive\" or \"universal\" flu vaccines are being researched that can provide protection against many or all influenza viruses.", "Approaches to develop such a vaccine include HA stalk-based methods such as chimeras that have the same stalk but different heads, HA head-based methods such as computationally optimized broadly neutralizing antigens, anti-idiotypic antibodies, and vaccines to elicit immune responses to highly conserved viral proteins.", "mRNA vaccines to provide protection against influenza are also under research.", "Aquatic birds such as ducks, geese, shorebirds, and gulls are the primary reservoir of IAVs.", "In birds, AIVs may be either low pathogenic avian influenza (LPAI) viruses that produce little to no symptoms or highly pathogenic avian influenza (HPAI) viruses that cause severe illness.", "Symptoms of HPAI infection include lack of energy and appetite, decreased egg production, soft-shelled or misshapen eggs, swelling of the head, comb, wattles, and hocks, purple discoloration of wattles, combs, and legs, nasal discharge, coughing, sneezing, incoordination, and diarrhea.", "Birds infected with an HPAI virus may also die suddenly without any signs of infection.", "The distinction between LPAI and HPAI can generally be made based on how lethal an AIV is to chickens.", "At the genetic level, an AIV can be usually be identified as an HPAI virus if it has a multibasic cleavage site in the HA protein, which contains additional residues in the HA gene.", "Most AIVs are LPAI.", "Notable HPAI viruses include HPAI H5N1 and HPAI H7N9.", "HPAI viruses have been a major disease burden in the 21st century, resulting in the death of large numbers of birds.", "In H7N9's case, some circulating strains were originally LPAI but became HPAI by acquiring the HA multibasic cleavage site.", "Avian H9N2 is also of concern because although it is LPAI, it is a common donor of genes to H5N1 and H7N9 during reassortment.", "Migratory birds can spread influenza across long distances.", "An example of this was when an H5N1 strain in 2005 infected birds at Qinghai Lake, China, which is a stopover and breeding site for many migratory birds, subsequently spreading the virus to more than 20 countries across Asia, Europe, and the Middle East.", "AIVs can be transmitted from wild birds to domestic free-range ducks and in turn to poultry through contaminated water, aerosols, and fomites.", "Ducks therefore act as key intermediates between wild and domestic birds.", "Transmission to poultry typically occurs in backyard farming and live animal markets where multiple species interact with each other.", "From there, AIVs can spread to poultry farms in the absence of adequate biosecurity.", "Among poultry, HPAI transmission occurs through aerosols and contaminated feces, cages, feed, and dead animals.", "Back-transmission of HPAI viruses from poultry to wild birds has occurred and is implicated in mass die-offs and intercontinental spread.", "AIVs have occasionally infected humans through aerosols, fomites, and contaminated water.", "Direction transmission from wild birds is rare.", "Instead, most transmission involves domestic poultry, mainly chickens, ducks, and geese but also a variety of other birds such as guinea fowl, partridge, pheasants, and quails.", "The primary risk factor for infection with AIVs is exposure to birds in farms and live poultry markets.", "Typically, infection with an AIV has an incubation period of 3–5 days but can be up to 9 days.", "H5N1 and H7N9 cause severe lower respiratory tract illness, whereas other AIVs such as H9N2 cause a more mild upper respiratory tract illness, commonly with conjunctivitis.", "Limited transmission of avian H2, H5-7, H9, and H10 subtypes from one person to another through respiratory droplets, aerosols, and fomites has occurred, but sustained human-to-human transmission of AIVs has not occurred.", "Before 2013, H5N1 was the most common AIV to infect humans.", "Since then, H7N9 has been responsible for most human cases.", "Influenza in pigs is a respiratory disease similar to influenza in humans and is found worldwide.", "Asymptomatic infections are common.", "Symptoms typically appear 1–3 days after infection and include fever, lethargy, anorexia, weight loss, labored breathing, coughing, sneezing, and nasal discharge.", "In sows, pregnancy may be aborted.", "Complications include secondary infections and potentially fatal bronchopneumonia.", "Pigs become contagious within a day of infection and typically spread the virus for 7–10 days, which can spread rapidly within a herd.", "Pigs usually recover from infection within 3–7 days after symptoms appear.", "Prevention and control measures include inactivated vaccines and culling infected herds.", "The influenza viruses usually responsible for swine flu are IAV subtypes H1N1, H1N2, and H3N2.", "Some IAVs can be transmitted via aerosols from pigs to humans and vice versa.", "Furthermore, pigs, along with bats and quails, are recognized as a mixing vessel of influenza viruses because they have both α-2,3 and α-2,6 sialic acid receptors in their respiratory tract.", "Because of that, both avian and mammalian influenza viruses can infect pigs.", "If co-infection occurs, then reassortment is possible.", "A notable example of this was the reassortment of a swine, avian, and human influenza virus in 2009, resulting in a novel H1N1 strain that caused the 2009 flu pandemic.", "Spillover events from humans to pigs, however, appear to be more common than from pigs to humans.", "Influenza viruses have been found in many other animals, including cattle, horses, dogs, cats, and marine mammals.", "Nearly all IAVs are apparently descended from ancestral viruses in birds.", "The exception are bat influenza-like viruses, which have an uncertain origin.", "These bat viruses have HA and NA subtypes H17, H18, N10, and N11.", "H17N10 and H18N11 are unable to reassort with other IAVs, but they are still able to replicate in other mammals.", "AIVs sometimes crossover into mammals.", "For example, in late 2016 to early 2017, an avian H7N2 strain was found to be infecting cats in New York.", "Equine IAVs include H7N7 and two lineages of H3N8.", "H7N7, however, has not been detected in horses since the late 1970s, so it may have become extinct in horses.", "H3N8 in equines spreads via aerosols and causes respiratory illness.", "Equine H3N8 perferentially binds to α-2,3 sialic acids, so horses are usually considered dead-end hosts, but transmission to dogs and camels has occurred, raising concerns that horses may be mixing vessels for reassortment.", "In canines, the only IAVs in circulation are equine-derived H3N8 and avian-derived H3N2.", "Canine H3N8 has not been observed to reassort with other subtypes.", "H3N2 has a much broader host range and can reassort with H1N1 and H5N1.", "An isolated case of H6N1 likely from a chicken was found infecting a dog, so other AIVs may emerge in canines.", "Other mammals to be infected by IAVs include H7N7 and H4N5 in seals, H1N3 in whales, and H10N4 and H3N2 in minks.", "Various mutations have been identified that are associated with AIVs adapting to mammals.", "Since HA proteins vary in which sialic acids they bind to, mutations in the HA receptor binding site can allow AIVs to infect mammals.", "Other mutations include mutations affecting which sialic acids NA proteins cleave and a mutation in the PB2 polymerase subunit that improves tolerance of lower temperatures in mammalian respiratory tracts and enhances RNP assembly by stabilizing NP and PB2 binding.", "IBV is mainly found in humans but has also been detected in pigs, dogs, horses, and seals.", "Likewise, ICV primarily infects humans but has been observed in pigs, dogs, cattle, and dromedary camels.", "IDV causes an influenza-like illness in pigs but its impact in its natural reservoir, cattle, is relatively unknown.", "It may cause respiratory disease resembling human influenza on its own, or it may be part of a bovine respiratory disease (BRD) complex with other pathogens during co-infection.", "BRD is a concern for the cattle industry, so IDV's possible involvement in BRD has led to research on vaccines for cattle that can provide protection against IDV.", "Two antigenic lineages are in circulation: D/swine/Oklahoma/1334/2011 (D/OK) and D/bovine/Oklahoma/660/2013 (D/660)." ]

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[ "Influenza infection is diagnosed with laboratory methods such as antibody or antigen tests and a polymerase chain reaction (PCR) to identify viral nucleic acid." ]

[ "The time between exposure to the virus and development of symptoms, called the incubation period, is 1–4 days, most commonly 1–2 days.", "Many infections, however, are asymptomatic.", "The onset of symptoms is sudden, and initial symptoms are predominately non-specific, including fever, chills, headaches, muscle pain or aching, a feeling of discomfort, loss of appetite, lack of energy/fatigue, and confusion.", "These symptoms are usually accompanied by respiratory symptoms such as a dry cough, sore or dry throat, hoarse voice, and a stuffy or runny nose.", "Coughing is the most common symptom.", "Gastrointestinal symptoms may also occur, including nausea, vomiting, diarrhea, and gastroenteritis, especially in children.", "The standard influenza symptoms typically last for 2–8 days.", "A 2021 study suggests influenza can cause long lasting symptoms in a similar way to long COVID.\nSymptomatic infections are usually mild and limited to the upper respiratory tract, but progression to pneumonia is relatively common.", "Pneumonia may be caused by the primary viral infection or by a secondary bacterial infection.", "Primary pneumonia is characterized by rapid progression of fever, cough, labored breathing, and low oxygen levels that cause bluish skin.", "It is especially common among those who have an underlying cardiovascular disease such as rheumatic heart disease.", "Secondary pneumonia typically has a period of improvement in symptoms for 1–3 weeks followed by recurrent fever, sputum production, and fluid buildup in the lungs, but can also occur just a few days after influenza symptoms appear.", "About a third of primary pneumonia cases are followed by secondary pneumonia, which is most frequently caused by the bacteria \"Streptococcus pneumoniae\" and \"Staphylococcus aureus\".", "Influenza viruses comprise four species.", "Each of the four species is the sole member of its own genus, and the four influenza genera comprise four of the seven genera in the family \"Orthomyxoviridae\".", "They are:\n\n\nIAV is responsible for most cases of severe illness as well as seasonal epidemics and occasional pandemics.", "It infects people of all ages but tends to disproportionately cause severe illness in the elderly, the very young, and those who have chronic health issues.", "Birds are the primary reservoir of IAV, especially aquatic birds such as ducks, geese, shorebirds, and gulls, but the virus also circulates among mammals, including pigs, horses, and marine mammals.", "IAV is classified into subtypes based on the viral proteins haemagglutinin (H) and neuraminidase (N).", "As of 2019, 18 H subtypes and 11 N subtypes have been identified.", "Most potential combinations have been reported in birds, but H17-18 and N10-11 have only been found in bats.", "Only H subtypes H1-3 and N subtypes N1-2 are known to have circulated in humans, the current IAV subtypes in circulation being H1N1 and H3N2.", "IAVs can be classified more specifically to also include natural host species, geographical origin, year of isolation, and strain number, such as H1N1/A/duck/Alberta/35/76.", "IBV mainly infects humans but has been identified in seals, horses, dogs, and pigs.", "IBV does not have subtypes like IAV but has two antigenically distinct lineages, termed the B/Victoria/2/1987-like and B/Yamagata/16/1988-like lineages, or simply (B/)Victoria(-like) and (B/)Yamagata(-like).", "Both lineages are in circulation in humans, disproportionately affecting children.", "IBVs contribute to seasonal epidemics alongside IAVs but have never been associated with a pandemic.", "ICV, like IBV, is primarily found in humans, though it also has been detected in pigs, feral dogs, dromedary camels, cattle, and dogs.", "ICV infection primarily affects children and is usually asymptomatic or has mild cold-like symptoms, though more severe symptoms such as gastroenteritis and pneumonia can occur.", "Unlike IAV and IBV, ICV has not been a major focus of research pertaining to antiviral drugs, vaccines, and other measures against influenza.", "ICV is subclassified into six genetic/antigenic lineages.", "IDV has been isolated from pigs and cattle, the latter being the natural reservoir.", "Infection has also been observed in humans, horses, dromedary camels, and small ruminants such as goats and sheep.", "IDV is distantly related to ICV.", "While cattle workers have occasionally tested positive to prior IDV infection, it is not known to cause disease in humans.", "ICV and IDV experience a slower rate of antigenic evolution than IAV and IBV.", "Because of this antigenic stability, relatively few novel lineages emerge.", "Influenza viruses have a negative-sense, single-stranded RNA genome that is segmented.", "The negative sense of the genome means it can be used as a template to synthesize messenger RNA (mRNA).", "IAV and IBV have eight genome segments that encode 10 major proteins.", "ICV and IDV have seven genome segments that encode nine major proteins.", "Three segments encode three subunits of an RNA-dependent RNA polymerase (RdRp) complex: PB1, a transcriptase, PB2, which recognizes 5' caps, and PA (P3 for ICV and IDV), an endonuclease.", "The matrix protein (M1) and membrane protein (M2) share a segment, as do the non-structural protein (NS1) and the nuclear export protein (NEP).", "For IAV and IBV, hemagglutinin (HA) and neuraminidase (NA) are encoded on one segment each, whereas ICV and IDV encode a hemagglutinin-esterase fusion (HEF) protein on one segment that merges the functions of HA and NA.", "The final genome segment encodes the viral nucleoprotein (NP).", "Influenza viruses also encode various accessory proteins, such as PB1-F2 and PA-X, that are expressed through alternative open reading frames and which are important in host defense suppression, virulence, and pathogenicity.", "The virus particle, called a virion, is pleomorphic and varies between being filamentous, bacilliform, or spherical in shape.", "Clinical isolates tend to be pleomorphic, whereas strains adapted to laboratory growth typically produce spherical virions.", "Filamentous virions are about 250 nanometers (nm) by 80 nm, bacilliform 120–250 by 95 nm, and spherical 120 nm in diameter.", "The virion consists of each segment of the genome bound to nucleoproteins in separate ribonucleoprotein (RNP) complexes for each segment, all of which are surrounded by a lipid bilayer membrane called the viral envelope.", "There is a copy of the RdRp, all subunits included, bound to each RNP.", "The envelope is reinforced structurally by matrix proteins on the interior that enclose the RNPs, and the envelope contains HA and NA (or HEF) proteins extending outward from the exterior surface of the envelope.", "HA and HEF proteins have a distinct \"head\" and \"stalk\" structure.", "M2 proteins form proton ion channels through the viral envelope that are required for viral entry and exit.", "IBVs contain a surface protein named NB that is anchored in the envelope, but its function is unknown.", "The viral life cycle begins by binding to a target cell.", "Binding is mediated by the viral HA proteins on the surface of the evelope, which bind to cells that contain sialic acid receptors on the surface of the cell membrane.", "For N1 subtypes with the \"G147R\" mutation and N2 subtypes, the NA protein can initiate entry.", "Prior to binding, NA proteins promote access to target cells by degrading mucous, which helps to remove extracellular decoy receptors that would impede access to target cells.", "After binding, the virus is internalized into the cell by an endosome that contains the virion inside it.", "The endosome is acidified by cellular vATPase to have lower pH, which triggers a conformational change in HA that allows fusion of the viral envelope with the endosomal membrane.", "At the same time, hydrogen ions diffuse into the virion through M2 ion channels, disrupting internal protein-protein interactions to release RNPs into the host cell's cytosol.", "The M1 protein shell surrounding RNPs is degraded, fully uncoating RNPs in the cytosol.", "RNPs are then imported into the nucleus with the help of viral localization signals.", "There, the viral RNA polymerase transcribes mRNA using the genomic negative-sense strand as a template.", "The polymerase snatches 5' caps for viral mRNA from cellular RNA to prime mRNA synthesis and the 3'-end of mRNA is polyadenylated at the end of transcription.", "Once viral mRNA is transcribed, it is exported out of the nucleus and translated by host ribosomes in a cap-dependent manner to synthesize viral proteins.", "RdRp also synthesizes complementary positive-sense strands of the viral genome in a complementary RNP complex which are then used as templates by viral polymerases to synthesize copies of the negative-sense genome.", "During these processes, RdRps of avian influenza viruses (AIVs) function optimally at a higher temperature than mammalian influenza viruses.", "Newly synthesized viral polymerase subunits and NP proteins are imported to the nucleus to further increase the rate of viral replication and form RNPs.", "HA, NA, and M2 proteins are trafficked with the aid of M1 and NEP proteins to the cell membrane through the Golgi apparatus and inserted into the cell's membrane.", "Viral non-structural proteins including NS1, PB1-F2, and PA-X regulate host cellular processes to disable antiviral responses.", "PB1-F2 aso interacts with PB1 to keep polymerases in the nucleus longer.", "M1 and NEP proteins localize to the nucleus during the later stages of infection, bind to viral RNPs and mediate their export to the cytoplasm where they migrate to the cell membrane with the aid of recycled endosomes and are bundled into the segments of the genome.", "Progenic viruses leave the cell by budding from the cell membrane, which is initiated by the accumulation of M1 proteins at the cytoplasmic side of the membrane.", "The viral genome is incorporated inside a viral envelope derived from portions of the cell membrane that have HA, NA, and M2 proteins.", "At the end of budding, HA proteins remain attached to cellular sialic acid until they are cleaved by the sialidase activity of NA proteins.", "The virion is then released from the cell.", "The sialidase activity of NA also cleaves any sialic acid residues from the viral surface, which helps prevent newly assembled viruses from aggregating near the cell surface and improving infectivity.", "Similar to other aspects of influenza replication, optimal NA activity is temperature- and pH-dependent.", "Ultimately, presence of large quantities of viral RNA in the cell triggers apoptosis, i.e. programmed cell death, which is initiated by cellular factors to restrict viral replication.", "Two key processes that influenza viruses evolve through are antigenic drift and antigenic shift.", "Antigenic drift is when an influenza virus's antigens change due to the gradual accumulation of mutations in the antigen's (HA or NA) gene.", "This can occur in response to evolutionary pressure exerted by the host immune response.", "Antigenic drift is especially common for the HA protein, in which just a few amino acid changes in the head region can constitute antigenic drift.", "The result is the production of novel strains that can evade pre-existing antibody-mediated immunity.", "Antigenic drift occurs in all influenza species but is slower in B than A and slowest in C and D. Antigenic drift is a major cause of seasonal influenza, and requires that flu vaccines be updated annually.", "HA is the main component of inactivated vaccines, so surveillance monitors antigenic drift of this antigen among circulating strains.", "Antigenic evolution of influenza viruses of humans appears to be faster than influenza viruses in swine and equines.", "In wild birds, within-subtype antigenic variation appears to be limited but has been observed in poultry.", "Antigenic shift is a sudden, drastic change in an influenza virus's antigen, usually HA.", "During antigenic shift, antigenically different strains that infect the same cell can reassort genome segments with each other, producing hybrid progeny.", "Since all influenza viruses have segmented genomes, all are capable of reassortment.", "Antigenic shift, however, only occurs among influenza viruses of the same genus and most commonly occurs among IAVs.", "In particular, reassortment is very common in AIVs, creating a large diversity of influenza viruses in birds, but is uncommon in human, equine, and canine lineages.", "Pigs, bats, and quails have receptors for both mammalian and avian IAVs, so they are potential \"mixing vessels\" for reassortment.", "If an animal strain reassorts with a human strain, then a novel strain can emerge that is capable of human-to-human transmission.", "This has caused pandemics, but only a limited number have occurred, so it is difficult to predict when the next will happen.", "People who are infected can transmit influenza viruses through breathing, talking, coughing, and sneezing, which spread respiratory droplets and aerosols that contain virus particles into the air.", "A person susceptible to infection can then contract influenza by coming into contact with these particles.", "Respiratory droplets are relatively large and travel less than two meters before falling onto nearby surfaces.", "Aerosols are smaller and remain suspended in the air longer, so they take longer to settle and can travel further than respiratory droplets.", "Inhalation of aerosols can lead to infection, but most transmission is in the area about two meters around an infected person via respiratory droplets that come into contact with mucosa of the upper respiratory tract.", "Transmission through contact with a person, bodily fluids, or intermediate objects (fomites) can also occur, such as through contaminated hands and surfaces since influenza viruses can survive for hours on non-porous surfaces.", "If one's hands are contaminated, then touching one's face can cause infection.", "Influenza is usually transmissible from one day before the onset of symptoms to 5–7 days after.", "In healthy adults, the virus is shed for up to 3–5 days.", "In children and the immunocompromised, the virus may be transmissible for several weeks.", "Children ages 2–17 are considered to be the primary and most efficient spreaders of influenza.", "Children who have not had multiple prior exposures to influenza viruses shed the virus at greater quantities and for a longer duration than other children.", "People who are at risk of exposure to influenza include health care workers, social care workers, and those who live with or care for people vulnerable to influenza.", "In long-term care facilities, the flu can spread rapidly after it is introduced.", "A variety of factors likely encourage influenza transmission, including lower temperature, lower absolute and relative humidity, less ultraviolet radiation from the Sun, and crowding.", "Influenza viruses that infect the upper respiratory tract like H1N1 tend to be more mild but more transmissible, whereas those that infect the lower respiratory tract like H5N1 tend to cause more severe illness but are less contagious.", "In humans, influenza viruses first cause infection by infecting epithelial cells in the respiratory tract.", "Illness during infection is primarily the result of lung inflammation and compromise caused by epithelial cell infection and death, combined with inflammation caused by the immune system's response to infection.", "Non-respiratory organs can become involved, but the mechanisms by which influenza is involved in these cases are unknown.", "Severe respiratory illness can be caused by multiple, non-exclusive mechanisms, including obstruction of the airways, loss of alveolar structure, loss of lung epithelial integrity due to epithelial cell infection and death, and degradation of the extracellular matrix that maintains lung structure.", "In particular, alveolar cell infection appears to drive severe symptoms since this results in impaired gas exchange and enables viruses to infect endothelial cells, which produce large quantities of pro-inflammatory cytokines.", "Pneumonia caused by influenza viruses is characterized by high levels of viral replication in the lower respiratory tract, accompanied by a strong pro-inflammatory response called a cytokine storm.", "Infection with H5N1 or H7N9 especially produces high levels of pro-inflammatory cytokines.", "In bacterial infections, early depletion of macrophages during influenza creates a favorable environment in the lungs for bacterial growth since these white blood cells are important in responding to bacterial infection.", "Host mechanisms to encourage tissue repair may inadvertently allow bacterial infection.", "Infection also induces production of systemic glucocorticoids that can reduce inflammation to preserve tissue integrity but allow increased bacterial growth.", "The pathophysiology of influenza is significantly influenced by which receptors influenza viruses bind to during entry into cells.", "Mammalian influenza viruses preferentially bind to sialic acids connected to the rest of the oligosaccharide by an α-2,6 link, most commonly found in various respiratory cells, such as respiratory and retinal epithelial cells.", "AIVs prefer sialic acids with an α-2,3 linkage, which are most common in birds in gastrointestinal epithelial cells and in humans in the lower respiratory tract.", "Furthermore, cleavage of the HA protein into HA, the binding subunit, and HA, the fusion subunit, is performed by different proteases, affecting which cells can be infected.", "For mammalian influenza viruses and low pathogenic AIVs, cleavage is extracellular, which limits infection to cells that have the appropriate proteases, whereas for highly pathogenic AIVs, cleavage is intracellular and performed by ubiquitous proteases, which allows for infection of a greater variety of cells, thereby contributing to more severe disease.", "Cells possess sensors to detect viral RNA, which can then induce interferon production.", "Interferons mediate expression of antiviral proteins and proteins that recruit immune cells to the infection site, and they also notify nearby uninfected cells of infection.", "Some infected cells release pro-inflammatory cytokines that recruit immune cells to the site of infection.", "Immune cells control viral infection by killing infected cells and phagocytizing viral particles and apoptotic cells.", "An exacerbated immune response, however, can harm the host organism through a cytokine storm.", "To counter the immune response, influenza viruses encode various non-structural proteins, including NS1, NEP, PB1-F2, and PA-X, that are involved in curtailing the host immune response by suppressing interferon production and host gene expression.", "B cells, a type of white blood cell, produce antibodies that bind to influenza antigens HA and NA (or HEF) and other proteins to a lesser degree.", "Once bound to these proteins, antibodies block virions from binding to cellular receptors, neutralizing the virus.", "In humans, a sizeable antibody response occurs ~1 week after viral exposure.", "This antibody response is typically robust and long-lasting, especially for ICV and IDV.", "In other words, people exposed to a certain strain in childhood still possess antibodies to that strain at a reasonable level later in life, which can provide some protection to related strains.", "There is, however, an \"original antigenic sin\", in which the first HA subtype a person is exposed to influences the antibody-based immune response to future infections and vaccines.", "Annual vaccination is the primary and most effective way to prevent influenza and influenza-associated complications, especially for high-risk groups.", "Vaccines against the flu are trivalent or quadrivalent, providing protection against an H1N1 strain, an H3N2 strain, and one or two IBV strains corresponding to the two IBV lineages.", "Two types of vaccines are in use: inactivated vaccines that contain \"killed\" (i.e. inactivated) viruses and live attenuated influenza vaccines (LAIVs) that contain weakened viruses.", "There are three types of inactivated vaccines: whole virus, split virus, in which the virus is disrupted by a detergent, and subunit, which only contains the viral antigens HA and NA.", "Most flu vaccines are inactivated and administered via intramuscular injection.", "LAIVs are sprayed into the nasal cavity.", "Vaccination recommendations vary by country.", "Some recommend vaccination for all people above a certain age, such as 6 months, whereas other countries recommendation is limited for high at risk groups, such as pregnant women, young children (excluding newborns), the elderly, people with chronic medical conditions, health care workers, people who come into contact with high-risk people, and people who transmit the virus easily.", "Young infants cannot receive flu vaccines for safety reasons, but they can inherit passive immunity from their mother if inactivated vaccines are administered to the mother during pregnancy.", "Influenza vaccination also helps to reduce the probability of reassortment.", "In general, influenza vaccines are only effective if there is an antigenic match between vaccine strains and circulating strains.", "Additionally, most commercially available flu vaccines are manufactured by propagation of influenza viruses in embryonated chicken eggs, taking 6–8 months.", "Flu seasons are different in the northern and southern hemisphere, so the WHO meets twice a year, one for each hemisphere, to discuss which strains should be included in flu vaccines based on observation from HA inhibition assays.", "Other manufacturing methods include an MDCK cell culture-based inactivated vaccine and a recombinant subunit vaccine manufactured from baculovirus overexpression in insect cells.", "Influenza can be prevented or reduced in severity by post-exposure prophylaxis with the antiviral drugs oseltamivir, which can be taken orally by those at least three months old, and zanamivir, which can be inhaled by those above seven years of age.", "Chemoprophylaxis is most useful for individuals at high-risk of developing complications and those who cannot receive the flu vaccine due to contraindications or lack of effectiveness.", "Post-exposure chemoprophylaxis is only recommended if oseltamivir is taken within 48 hours of contact with a confirmed or suspected influenza case and zanamivir within 36 hours.", "It is recommended that it be offered to people who have yet to receive a vaccine for the current flu season, who have been vaccinated less than two week since contact, if there is a significant mismatch between vaccine and circulating strains, or during an outbreak in a closed setting regardless of vaccination history.", "Hand hygiene is important in reducing the spread of influenza.", "This includes frequent hand washing with soap and water, using alcohol-based hand sanitizers, and not touching one's eyes, nose, and mouth with one's hands.", "Covering one's nose and mouth when coughing or sneezing is important.", "Other methods to limit influenza transmission include staying home when sick, avoiding contact with others until one day after symptoms end, and disinfecting surfaces likely to be contaminated by the virus, such as doorknobs.", "Health education through media and posters is often used to remind people of the aforementioned etiquette and hygiene.", "There is uncertainty about the use of masks since research thus far has not shown a significant reduction in seasonal influenza with mask usage.", "Likewise, the effectiveness of screening at points of entry into countries is not well researched.", "Social distancing measures such as school closures, avoiding contact with infected people via isolation or quarantine, and limiting mass gatherings may reduce transmission, but these measures are often expensive, unpopular, and difficult to implement.", "Consequently, the commonly recommended methods of infection control are respiratory etiquette, hand hygiene, and mask wearing, which are inexpensive and easy to perform.", "Pharmaceutical measures are effective but may not be available in the early stages of an outbreak.", "In health care settings, infected individuals may be cohorted or assigned to individual rooms.", "Protective clothing such as masks, gloves, and gowns is recommended when coming into contact with infected individuals if there is a risk of exposure to infected bodily fluids.", "Keeping patients in negative pressure rooms and avoiding aerosol-producing activities may help, but special air handling and ventilation systems are not considered necessary to prevent the spread of influenza in the air.", "In residential homes, new admissions may need to be closed until the spread of influenza is controlled.", "When discharging patients to care homes, it is important to take care if there is a known influenza outbreak.", "Since influenza viruses circulate in animals such as birds and pigs, prevention of transmission from these animals is important.", "Water treatment, indoor raising of animals, quarantining sick animals, vaccination, and biosecurity are the primary measures used.", "Placing poultry houses and piggeries on high ground away from high-density farms, backyard farms, live poultry markets, and bodies of water helps to minimize contact with wild birds.", "Closure of live poultry markets appears to the most effective measure and has shown to be effective at controlling the spread of H5N1, H7N9, and H9N2.", "Other biosecurity measures include cleaning and disinfecting facilities and vehicles, banning visits to poultry farms, not bringing birds intended for slaughter back to farms, changing clothes, disinfecting foot baths, and treating food and water.", "If live poultry markets are not closed, then \"clean days\" when unsold poultry is removed and facilities are disinfected and \"no carry-over\" policies to eliminate infectious material before new poultry arrive can be used to reduce the spread of influenza viruses.", "If a novel influenza viruses has breached the aforementioned biosecurity measures, then rapid detection to stamp it out via quarantining, decontamination, and culling may be necessary to prevent the virus from becoming endemic.", "Vaccines exist for avian H5, H7, and H9 subtypes that are used in some countries.", "In China, for example, vaccination of domestic birds against H7N9 successfully limited its spread, indicating that vaccination may be an effective strategy if used in combination with other measures to limit transmission.", "In pigs and horses, management of influenza is dependent on vaccination with biosecurity.", "Diagnosis based on symptoms is fairly accurate in otherwise healthy people during seasonal epidemics and should be suspected in cases of pneumonia, acute respiratory distress syndrome (ARDS), sepsis, or if encephalitis, myocarditis, or breaking down of muscle tissue occur.", "Because influenza is similar to other viral respiratory tract illnesses, laboratory diagnosis is necessary for confirmation.", "Common ways of collecting samples for testing include nasal and throat swabs.", "Samples may be taken from the lower respiratory tract if infection has cleared the upper but not lower respiratory tract.", "Influenza testing is recommended for anyone hospitalized with symptoms resembling influenza during flu season or who is connected to an influenza case.", "For severe cases, earlier diagnosis improves patient outcome.", "Diagnostic methods that can identify influenza include viral cultures, antibody- and antigen-detecting tests, and nucleic acid-based tests.", "Viruses can be grown in a culture of mammalian cells or embryonated eggs for 3–10 days to monitor cytopathic effect.", "Final confirmation can then be done via antibody staining, hemadsorption using red blood cells, or immunofluorescence microscopy.", "Shell vial cultures, which can identify infection via immunostaining before a cytopathic effect appears, are more sensitive than traditional cultures with results in 1–3 days.", "Cultures can be used to characterize novel viruses, observe sensitivity to antiviral drugs, and monitor antigenic drift, but they are relatively slow and require specialized skills and equipment.", "Serological assays can be used to detect an antibody response to influenza after natural infection or vaccination.", "Common serological assays include hemagglutination inhibition assays that detect HA-specific antibodies, virus neutralization assays that check whether antibodies have neutralized the virus, and enzyme-linked immunoabsorbant assays.", "These methods tend to be relatively inexpensive and fast but are less reliable than nucleic-acid based tests.", "Direct fluorescent or immunofluorescent antibody (DFA/IFA) tests involve staining respiratory epithelial cells in samples with fluorescently-labeled influenza-specific antibodies, followed by examination under a fluorescent microscope.", "They can differentiate between IAV and IBV but can't subtype IAV.", "Rapid influenza diagnostic tests (RIDTs) are a simple way of obtaining assay results, are low cost, and produce results quickly, at less than 30 minutes, so they are commonly used, but they can't distinguish between IAV and IBV or between IAV subtypes and are not as sensitive as nucleic-acid based tests.", "Nucleic acid-based tests (NATs) amplify and detect viral nucleic acid.", "Most of these tests take a few hours, but rapid molecular assays are as fast as RIDTs.", "Among NATs, reverse transcription polymerase chain reaction (RT-PCR) is the most traditional and considered the gold standard for diagnosing influenza because it is fast and can subtype IAV, but it is relatively expensive and more prone to false-positives than cultures.", "Other NATs that have been used include loop-mediated isothermal amplification-based assays, simple amplification-based assays, and nucleic acid sequence-based amplification.", "Nucleic acid sequencing methods can identify infection by obtaining the nucleic acid sequence of viral samples to identify the virus and antiviral drug resistance.", "The traditional method is Sanger sequencing, but it has been largely replaced by next-generation methods that have greater sequencing speed and throughput.", "Treatment of influenza in cases of mild or moderate illness is supportive and includes anti-fever medications such as acetaminophen and ibuprofen, adequate fluid intake to avoid dehydration, and resting at home.", "Cough drops and throat sprays may be beneficial for sore throat.", "It is recommended to avoid alcohol and tobacco use while sick with the flu.", "Aspirin is not recommended to treat influenza in children due to an elevated risk of developing Reye syndrome.", "Corticosteroids likewise are not recommended except when treating septic shock or an underlying medical condition, such as chronic obstructive pulmonary disease or asthma exacerbation, since they are associated with increased mortality.", "If a secondary bacterial infection occurs, then treatment with antibiotics may be necessary.", "Antiviral drugs are primarily used to treat severely ill patients, especially those with compromised immune systems.", "Antivirals are most effective when started in the first 48 hours after symptoms appear.", "Later administration may still be beneficial for those who have underlying immune defects, those with more severe symptoms, or those who have a higher risk of developing complications if these individuals are still shedding the virus.", "Antiviral treatment is also recommended if a person is hospitalized with suspected influenza instead of waiting for test results to return and if symptoms are worsening.", "Most antiviral drugs against influenza fall into two categories: neuraminidase (NA) inhibitors and M2 inhibitors.", "Baloxavir marboxil is a notable exception, which targets the endonuclease activity of the viral RNA polymerase and can be used as an alternative to NA and M2 inhibitors for IAV and IBV.", "NA inhibitors target the enzymatic activity of NA receptors, mimicking the binding of sialic acid in the active site of NA on IAV and IBV virions so that viral release from infected cells and the rate of viral replication are impaired.", "NA inhibitors include oseltamivir, which is consumed orally in a prodrug form and converted to its active form in the liver, and zanamivir, which is a powder that is inhaled nasally.", "Oseltamivir and zanamivir are effective for prophylaxis and post-exposure prophylaxis, and research overall indicates that NA inhibitors are effective at reducing rates of complications, hospitalization, and mortality and the duration of illness.", "Additionally, the earlier NA inhibitors are provided, the better the outcome, though late administration can still be beneficial in severe cases.", "Other NA inhibitors include laninamivir and peramivir, the latter of which can be used as an alternative to oseltamivir for people who cannot tolerate or absorb it.", "The adamantanes amantadine and rimantadine are orally administered drugs that block the influenza virus's M2 ion channel, preventing viral uncoating.", "These drugs are only functional against IAV but are no longer recommended for use because of widespread resistance to them among IAVs.", "Adamantane resistance first emerged in H3N2 in 2003, becoming worldwide by 2008.", "Oseltamivir resistance is no longer widespread because the 2009 pandemic H1N1 strain (H1N1 pdm09), which is resistant to adamantanes, seemingly replaced resistant strains in circulation.", "Since the 2009 pandemic, oseltamivir resistance has mainly been observed in patients undergoing therapy, especially the immunocompromised and young children.", "Oseltamivir resistance is usually reported in H1N1, but has been reported in H3N2 and IBVs less commonly.", "Because of this, oseltamivir is recommended as the first drug of choice for immunocompetent people, whereas for the immunocompromised, oseltamivir is recommended against H3N2 and IBV and zanamivir against H1N1 pdm09.", "Zanamivir resistance is observed less frequently, and resistance to peramivir and baloxavir marboxil is possible.", "In healthy individuals, influenza infection is usually self-limiting and rarely fatal.", "Symptoms usually last for 2–8 days.", "Influenza can cause people to miss work or school, and it is associated with decreased job performance and, in older adults, reduced independence.", "Fatigue and malaise may last for several weeks after recovery, and healthy adults may experience pulmonary abnormalities that can take several weeks to resolve.", "Complications and mortality primarily occur in high-risk populations and those who are hospitalized.", "Severe disease and mortality are usually attributable to pneumonia from the primary viral infection or a secondary bacterial infection, which can progress to ARDS.", "Other respiratory complications that may occur include sinusitis, bronchitis, bronchiolitis, excess fluid buildup in the lungs, and exacerbation of chronic bronchitis and asthma.", "Middle ear infection and croup may occur, most commonly in children.", "Secondary \"S. aureus\" infection has been observed, primarily in children, to cause toxic shock syndrome after influenza, with hypotension, fever, and reddening and peeling of the skin.", "Complications affecting the cardiovascular system are rare and include pericarditis, fulminant myocarditis with a fast, slow, or irregular heartbeat, and exacerbation of pre-existing cardiovascular disease.", "Inflammation or swelling of muscles accompanied by muscle tissue breaking down occurs rarely, usually in children, which presents as extreme tenderness and muscle pain in the legs and a reluctance to walk for 2–3 days.", "Influenza can affect pregnancy, including causing smaller neonatal size, increased risk of premature birth, and an increased risk of child death shortly before or after birth.", "Neurological complications have been associated with influenza on rare occasions, including aseptic meningitis, encephalitis, disseminated encephalomyelitis, transverse myelitis, and Guillain–Barré syndrome.", "Additionally, febrile seizures and Reye syndrome can occur, most commonly in children.", "Influenza-associated encephalopathy can occur directly from central nervous system infection from the presence of the virus in blood and presents as suddent onset of fever with convulsions, followed by rapid progression to coma.", "An atypical form of encephalitis called encephalitis lethargica, characterized by headache, drowsiness, and coma, may rarely occur sometime after infection.", "In survivors of influenza-associated encephalopathy, neurological defects may occur.", "Primarily in children, in severe cases the immune system may rarely dramatically overproduce white blood cells that release cytokines, causing severe inflammation.", "People who are at least 65 years of age, due to a weakened immune system from aging or a chronic illness, are a high-risk group for developing complications, as are children less than one year of age and children who have not been previously exposed to influenza viruses multiple times.", "Pregnant women are at an elevated risk, which increases by trimester and lasts up to two weeks after childbirth.", "Obesity, in particular a body mass index greater than 35–40, is associated with greater amounts of viral replication, increased severity of secondary bacterial infection, and reduced vaccination efficacy.", "People who have underlying health conditions are also considered at-risk, including those who have congenital or chronic heart problems or lung (e.g. asthma), kidney, liver, blood, neurological, or metabolic (e.g. diabetes) disorders, as are people who are immunocompromised from chemotherapy, asplenia, prolonged steroid treatment, splenic dysfunction, or HIV infection.", "Current or past tobacco use also places a person at risk.", "The role of genetics in influenza is not well researched, but it may be a factor in influenza mortality.", "Influenza is typically characterized by seasonal epidemics and sporadic pandemics.", "Most of the burden of influenza is a result of flu seasons caused by IAV and IBV.", "Among IAV subtypes, H1N1 and H3N2 currently circulate in humans and are responsible for seasonal influenza.", "Cases disproportionately occur in children, but most severe causes are among the elderly, the very young, and the immunocompromised.", "In a typical year, influenza viruses infect 5–15% of the global population, causing 3–5 million cases of severe illness annually and accounting for 290,000–650,000 deaths each year due to respiratory illness.", "5–10% of adults and 20–30% of children contract influenza each year.", "The reported number of influenza cases is usually much lower than the actual number of cases.", "During seasonal epidemics, it is estimated that about 80% of otherwise healthy people who have a cough or sore throat have the flu.", "Approximately 30–40% of people hospitalized for influenza develop pneumonia, and about 5% of all severe pneumonia cases in hospitals are due to influenza, which is also the most common cause of ARDS in adults.", "In children, influenza is one of the two most common causes of ARDS, the other being the respiratory syncytial virus.", "About 3–5% of children each year develop otitis media due to influenza.", "Adults who develop organ failure from influenza and children who have PIM scores and acute renal failure have higher rates of mortality.", "During seasonal influenza, mortality is concentrated in the very young and the elderly, whereas during flu pandemics, young adults are often affected at a high rate.", "In temperate regions, the number of influenza cases varies from season to season.", "Lower vitamin D levels, presumably due to less sunlight, lower humidity, lower temperature, and minor changes in virus proteins caused by antigenic drift contribute to annual epidemics that peak during the winter season.", "In the northern hemisphere, this is from October to May (more narrowly December to April), and in the southern hemisphere, this is from May to October (more narrowly June to September).", "There are therefore two distinct influenza seasons every year in temperate regions, one in the northern hemisphere and one in the southern hemisphere.", "In tropical and subtropical regions, seasonality is more complex and appears to be affected by various climatic factors such as minimum temperature, hours of sunshine, maximum rainfall, and high humidity.", "Influenza may therefore occur year-round in these regions.", "Influenza epidemics in modern times have the tendency to start in the eastern or southern hemisphere, with Asia being a key reservoir of influenza viruses.", "IAV and IBV co-circulate, so the two have the same patterns of transmission.", "The seasonality of ICV, however, is poorly understood.", "ICV infection is most common in children under the age of 2, and by adulthood most people have been exposed to it.", "ICV-associated hospitalization most commonly occurs in children under the age of 3 and is frequently accompanied by co-infection with another virus or a bacterium, which may increase the severity of disease.", "When considering all hospitalizations for respiratory illness among young children, ICV appears to account for only a small percentage of such cases.", "Large outbreaks of ICV infection can occur, so incidence varies significantly.", "Outbreaks of influenza caused by novel influenza viruses are common.", "Depending on the level of pre-existing immunity in the population, novel influenza viruses can spread rapidly and cause pandemics with millions of deaths.", "These pandemics, in contrast to seasonal influenza, are caused by antigenic shifts involving animal influenza viruses.", "To date, all known flu pandemics have been caused by IAVs, and they follow the same pattern of spreading from an origin point to the rest of the world over the course of multiple waves in a year.", "Pandemic strains tend to be associated with higher rates of pneumonia in otherwise healthy individuals.", "Generally after each influenza pandemic, the pandemic strain continues to circulate as the cause of seasonal influenza, replacing prior strains.", "From 1700 to 1889, influenza pandemics occurred about once every 50–60 years.", "Since then, pandemics have occurred about once every 10–50 years, so they may be getting more frequent over time.", "It is impossible to know when an influenza virus first infected humans or when the first influenza pandemic occurred.", "Possibly the first influenza epidemic occurred around 6,000 BC in China, and possible descriptions of influenza exist in Greek writings from the 5th century BC.", "In both 1173–1174 AD and 1387 AD, epidemics occurred across Europe that were named \"influenza\".", "Whether these epidemics and others were caused by influenza is unclear since there was no consistent naming pattern for epidemic respiratory diseases at that time, and \"influenza\" didn't become completely attached to respiratory disease until centuries later.", "Influenza may have been brought to the Americas as early as 1493, when an epidemic disease resembling influenza killed most of the population of the Antilles.", "The first convincing record of an influenza pandemic was chronicled in 1510; it began in East Asia before spreading to North Africa and then Europe.", "Following the pandemic, seasonal influenza occurred, with subsequent pandemics in 1557 and 1580.", "The flu pandemic in 1557 was potentially the first time influenza was connected to miscarriage and death of pregnant women.", "The 1580 flu pandemic originated in Asia during summer, spread to Africa, then Europe, and finally America.", "By the end of the 16th century, influenza was likely beginning to become understood as a specific, recognizable disease with epidemic and endemic forms.", "In 1648, it was discovered that horses also experience influenza.", "Influenza data after 1700 is more informative, so it is easier to identify flu pandemics after this point, each of which incrementally increased understanding of influenza.", "The first flu pandemic of the 18th century started in 1729 in Russia in spring, spreading worldwide over the course of three years with distinct waves, the later ones being more lethal.", "The second flu pandemic of the 18th century was in 1781–1782, starting in China in autumn.", "From this pandemic, influenza became associated with sudden outbreaks of febrile illness.", "The next flu pandemic was from 1830 to 1833, beginning in China in winter.", "This pandemic had a high attack rate, but the mortality rate was low.", "A minor influenza pandemic occurred from 1847 to 1851 at the same time as the third cholera pandemic and was the first flu pandemic to occur with vital statistics being recorded, so influenza mortality was clearly recorded for the first time.", "Highly pathogenic avian influenza was recognized in 1878 and was soon linked to transmission to humans.", "By the time of the 1889 pandemic, which may have been caused by an H2N2 strain, the flu had become an easily recognizable disease.", "Initially, the microbial agent responsible for influenza was incorrently identified in 1892 by R. F. J. Pfeiffer as the bacteria species \"Haemophilus influenzae\", which retains \"influenza\" in its name.", "In the following years, the field of virology began to form as viruses were identified as the cause of many diseases.", "From 1901 to 1903, Italian and Austrian researchers were able to show that avian influenza, then called \"fowl plague\", was caused by a microscopic agent smaller than bacteria by using filters with pores too small for bacteria to pass through.", "The fundamental differences between viruses and bacteria, however, were not yet fully understood.", "From 1918 to 1920, the Spanish flu pandemic became the most devastating influenza pandemic and one of the deadliest pandemics in history.", "The pandemic, probably caused by H1N1, likely began in the USA before spreading worldwide by soldiers during and after the First World War.", "The initial wave in the first half of 1918 was relatively minor and resembled past flu pandemics, but the second wave later that year had a much higher mortality rate, accounting for most deaths.", "A third wave with lower mortality occurred in many places a few months after the second.", "By the end of 1920, it is estimated that about a third to half of all people in the world had been infected, with tens of millions of deaths, disproportionately young adults.", "During the 1918 pandemic, the respiratory route of transmission was clearly identified and influenza was shown to be caused by a \"filter passer\", not a bacterium, but there remained a lack of agreement about influenza's cause for another decade and research on influenza declined.", "After the pandemic, H1N1 circulated in humans in seasonal form up until the next pandemic.", "In 1931, Richard Shope published three papers identifying a virus as the cause of swine influenza, a then newly recognized disease among pigs that was first characterized during the second wave of the 1918 pandemic.", "Shope's research reinvigorated research on human influenza, and many advances in virology, serology, immunology, experimental animal models, vaccinology, and immunotherapy have since arisen from influenza research.", "Just two years after influenza viruses were discovered, in 1933, IAV was identified as the agent responsible for human influenza.", "Subtypes of IAV were discovered throughout the 1930s, and IBV was discovered in 1940.", "During the Second World War, the US government worked on developing inactivated vaccines for influenza, resulting in the first influenza vaccine being licensed in 1945 in the United States.", "ICV was discovered two years later in 1947.", "In 1955, avian influenza was confirmed to be caused by IAV.", "Four influenza pandemics have occurred since WWII, each less severe than the 1918 pandemic.", "The first of these was the Asian flu from 1957 to 1958, caused by an H2N2 strain and beginning in China's Yunnan province.", "The number of deaths probably exceeded one million, mostly among the very young and very old.", "Notably, the 1957 pandemic was the first flu pandemic to occur in the presence of a global surveillance system and laboratories able to study the novel influenza virus.", "After the pandemic, H2N2 was the IAV subtype responsible for seasonal influenza.", "The first antiviral drug against influenza, amantadine, was approved for use in 1966, with additional antiviral drugs being used since the 1990s.", "In 1968, H3N2 was introduced into humans as a result of a reassortment between an avian H3N2 strain and an H2N2 strain that was circulating in humans.", "The novel H3N2 strain first emerged in Hong Kong and spread worldwide, causing the Hong Kong flu pandemic, which resulted in 500,000–2,000,000 deaths.", "This was the first pandemic to spread significantly by air travel.", "H2N2 and H3N2 co-circulated after the pandemic until 1971 when H2N2 waned in prevalence and was completely replaced by H3N2.", "In 1977, H1N1 reemerged in humans, possibly after it was released from a freezer in a laboratory accident, and caused a pseudo-pandemic.", "Whether the 1977 \"pandemic\" deserves to be included in the natural history of flu pandemics is debatable.", "This H1N1 strain was antigenically similar to the H1N1 strains that circulated prior to 1957.", "Since 1977, both H1N1 and H3N2 have circulated in humans as part of seasonal influenza.", "In 1980, the current classification system used to subtype influenza viruses was introduced.", "At some point, IBV diverged into two lineages, named the B/Victoria-like and B/Yamagata-like lineages, both of which have been circulating in humans since 1983.", "In 1996, HPAI H5N1 was detected in Guangdong, China and a year later emerged in poultry in Hong Kong, gradually spreading worldwide from there.", "A small H5N1 outbreak in humans in Hong Kong occurred then, and sporadic human cases have occurred since 1997, carrying a high case fatality rate.", "The most recent flu pandemic was the 2009 swine flu pandemic, which originated in Mexico and resulted in hundreds of thousands of deaths.", "It was caused by a novel H1N1 strain that was a reassortment of human, swine, and avian influenza viruses.", "The 2009 pandemic had the effect of replacing prior H1N1 strains in circulation with the novel strain but not any other influenza viruses.", "Consequently, H1N1, H3N2, and both IBV lineages have been in circulation in seasonal form since the 2009 pandemic.", "In 2011, IDV was discovered in pigs in Oklahoma, USA, and cattle were later identified as the primary reservoir of IDV.", "In the same year, avian H7N9 was detected in China and began to cause human infections in 2013, starting in Shanghai and Anhui and remaining mostly in China.", "HPAI H7N9 emerged sometime in 2016 and has occasionally infected humans incidentally.", "Other AIVs have less commonly infected humans since the 1990s, including H5N6, H6N1, H7N2-4, H7N7, and H10N7-8, and HPAI H subtypes such as H5N1-3, H5N5-6, and H5N8 have begun to spread throughout much of the world since the 2010s.", "Future flu pandemics, which may be caused by an influenza virus of avian origin, are viewed as almost inevitable, and increased globalization has made it easier for novel viruses to spread, so there are continual efforts to prepare for future pandemics and improve the prevention and treatment of influenza.", "The word \"influenza\" comes from the Italian word \"influenza\", from medieval Latin \"influentia\", originally meaning \"visitation\" or \"influence\".", "Terms such as \"influenza di freddo\", meaning \"influence of the cold\", and \"influenza di stelle\", meaning \"influence of the stars\" are attested from the 14th century.", "The latter referred to the disease's cause, which at the time was ascribed by some to unfavorable astrological conditions.", "As early as 1504, \"influenza\" began to mean a \"visitation\" or \"outbreak\" of any disease affecting many people in a single place at once.", "During an outbreak of influenza in 1743 that started in Italy and spread throughout Europe, the word reached the English language and was anglicized in pronunciation.", "Since the mid-1800s, \"influenza\" has also been used to refer to severe colds.", "The shortened form of the word, \"(the) flu\", is first attested in 1839 as \"flue\" with the spelling \"flu\" first attested in 1893.", "Other names that have been used for influenza include \"epidemic catarrh\", \"la grippe\" from French, \"sweating sickness\", and, especially when referring to the 1918 pandemic strain, \"Spanish fever\".", "Influenza research is wide-ranging and includes efforts to understand how influenza viruses enter hosts, the relationship between influenza viruses and bacteria, how influenza symptoms progress, and what make some influenza viruses deadlier than others.", "Non-structural proteins encoded by influenza viruses are periodically discovered and their functions are continually under research.", "Past pandemics, and especially the 1918 pandemic, are the subject of much research to understand flu pandemics.", "As part of pandemic preparedness, the Global Influenza Surveillance and Response System is a global network of laboratories that monitors influenza transmission and epidemiology.", "Additional areas of research include ways to improve the diagnosis, treatment, and prevention of influenza.", "Existing diagnostic methods have a variety of limitations coupled with their advantages.", "For example, NATs have high sensitivity and specificity but are impractical in under-resourced regions due to their high cost, complexity, maintenance, and training required.", "Low-cost, portable RIDTs can rapidly diagnose influenza but have highly variable sensitivity and are unable to subtype IAV.", "As a result of these limitations and others, research into new diagnostic methods revolves around producing new methods that are cost-effective, less labor-intensive, and less complex than existing methods while also being able to differentiate influenza species and IAV subtypes.", "One approach in development are lab-on-a-chips, which are diagnostic devices that make use of a variety of diagnostic tests, such as RT-PCR and serological assays, in microchip form.", "These chips have many potential advantages, including high reaction efficiency, low energy consumption, and low waste generation.", "New antiviral drugs are also in development due to the elimination of adamantines as viable drugs and concerns over oseltamivir resistance.", "These include: NA inhibitors that can be injected intravenously, such as intravenous formulations of zanamivir; favipiravir, which is a polymerase inhibitor used against several RNA viruses; pimodivir, which prevents cap-binding required during viral transcription; and nitazoxanide, which inhibits HA maturation.", "Reducing excess inflammation in the respiratory tract is also subject to much research since this is one of the primary mechanisms of influenza pathology.", "Other forms of therapy in development include monoclonal and polyclonal antibodies that target viral proteins, convalescent plasma, different approaches to modify the host antiviral response, and stem cell-based therapies to repair lung damage.", "Much research on LAIVs focuses on identifying genome sequences that can be deleted to create harmless influenza viruses in vaccines that still confer immunity.", "The high variability and rapid evolution of influenza virus antigens, however, is a major obstacle in developing effective vaccines.", "Furthermore, it is hard to predict which strains will be in circulation during the next flu season, manufacturing a sufficient quantity of flu vaccines for the next season is difficult, LAIVs have limited efficacy, and repeated annual vaccination potentially has diminished efficacy.", "For these reasons, \"broadly-reactive\" or \"universal\" flu vaccines are being researched that can provide protection against many or all influenza viruses.", "Approaches to develop such a vaccine include HA stalk-based methods such as chimeras that have the same stalk but different heads, HA head-based methods such as computationally optimized broadly neutralizing antigens, anti-idiotypic antibodies, and vaccines to elicit immune responses to highly conserved viral proteins.", "mRNA vaccines to provide protection against influenza are also under research.", "Aquatic birds such as ducks, geese, shorebirds, and gulls are the primary reservoir of IAVs.", "In birds, AIVs may be either low pathogenic avian influenza (LPAI) viruses that produce little to no symptoms or highly pathogenic avian influenza (HPAI) viruses that cause severe illness.", "Symptoms of HPAI infection include lack of energy and appetite, decreased egg production, soft-shelled or misshapen eggs, swelling of the head, comb, wattles, and hocks, purple discoloration of wattles, combs, and legs, nasal discharge, coughing, sneezing, incoordination, and diarrhea.", "Birds infected with an HPAI virus may also die suddenly without any signs of infection.", "The distinction between LPAI and HPAI can generally be made based on how lethal an AIV is to chickens.", "At the genetic level, an AIV can be usually be identified as an HPAI virus if it has a multibasic cleavage site in the HA protein, which contains additional residues in the HA gene.", "Most AIVs are LPAI.", "Notable HPAI viruses include HPAI H5N1 and HPAI H7N9.", "HPAI viruses have been a major disease burden in the 21st century, resulting in the death of large numbers of birds.", "In H7N9's case, some circulating strains were originally LPAI but became HPAI by acquiring the HA multibasic cleavage site.", "Avian H9N2 is also of concern because although it is LPAI, it is a common donor of genes to H5N1 and H7N9 during reassortment.", "Migratory birds can spread influenza across long distances.", "An example of this was when an H5N1 strain in 2005 infected birds at Qinghai Lake, China, which is a stopover and breeding site for many migratory birds, subsequently spreading the virus to more than 20 countries across Asia, Europe, and the Middle East.", "AIVs can be transmitted from wild birds to domestic free-range ducks and in turn to poultry through contaminated water, aerosols, and fomites.", "Ducks therefore act as key intermediates between wild and domestic birds.", "Transmission to poultry typically occurs in backyard farming and live animal markets where multiple species interact with each other.", "From there, AIVs can spread to poultry farms in the absence of adequate biosecurity.", "Among poultry, HPAI transmission occurs through aerosols and contaminated feces, cages, feed, and dead animals.", "Back-transmission of HPAI viruses from poultry to wild birds has occurred and is implicated in mass die-offs and intercontinental spread.", "AIVs have occasionally infected humans through aerosols, fomites, and contaminated water.", "Direction transmission from wild birds is rare.", "Instead, most transmission involves domestic poultry, mainly chickens, ducks, and geese but also a variety of other birds such as guinea fowl, partridge, pheasants, and quails.", "The primary risk factor for infection with AIVs is exposure to birds in farms and live poultry markets.", "Typically, infection with an AIV has an incubation period of 3–5 days but can be up to 9 days.", "H5N1 and H7N9 cause severe lower respiratory tract illness, whereas other AIVs such as H9N2 cause a more mild upper respiratory tract illness, commonly with conjunctivitis.", "Limited transmission of avian H2, H5-7, H9, and H10 subtypes from one person to another through respiratory droplets, aerosols, and fomites has occurred, but sustained human-to-human transmission of AIVs has not occurred.", "Before 2013, H5N1 was the most common AIV to infect humans.", "Since then, H7N9 has been responsible for most human cases.", "Influenza in pigs is a respiratory disease similar to influenza in humans and is found worldwide.", "Asymptomatic infections are common.", "Symptoms typically appear 1–3 days after infection and include fever, lethargy, anorexia, weight loss, labored breathing, coughing, sneezing, and nasal discharge.", "In sows, pregnancy may be aborted.", "Complications include secondary infections and potentially fatal bronchopneumonia.", "Pigs become contagious within a day of infection and typically spread the virus for 7–10 days, which can spread rapidly within a herd.", "Pigs usually recover from infection within 3–7 days after symptoms appear.", "Prevention and control measures include inactivated vaccines and culling infected herds.", "The influenza viruses usually responsible for swine flu are IAV subtypes H1N1, H1N2, and H3N2.", "Some IAVs can be transmitted via aerosols from pigs to humans and vice versa.", "Furthermore, pigs, along with bats and quails, are recognized as a mixing vessel of influenza viruses because they have both α-2,3 and α-2,6 sialic acid receptors in their respiratory tract.", "Because of that, both avian and mammalian influenza viruses can infect pigs.", "If co-infection occurs, then reassortment is possible.", "A notable example of this was the reassortment of a swine, avian, and human influenza virus in 2009, resulting in a novel H1N1 strain that caused the 2009 flu pandemic.", "Spillover events from humans to pigs, however, appear to be more common than from pigs to humans.", "Influenza viruses have been found in many other animals, including cattle, horses, dogs, cats, and marine mammals.", "Nearly all IAVs are apparently descended from ancestral viruses in birds.", "The exception are bat influenza-like viruses, which have an uncertain origin.", "These bat viruses have HA and NA subtypes H17, H18, N10, and N11.", "H17N10 and H18N11 are unable to reassort with other IAVs, but they are still able to replicate in other mammals.", "AIVs sometimes crossover into mammals.", "For example, in late 2016 to early 2017, an avian H7N2 strain was found to be infecting cats in New York.", "Equine IAVs include H7N7 and two lineages of H3N8.", "H7N7, however, has not been detected in horses since the late 1970s, so it may have become extinct in horses.", "H3N8 in equines spreads via aerosols and causes respiratory illness.", "Equine H3N8 perferentially binds to α-2,3 sialic acids, so horses are usually considered dead-end hosts, but transmission to dogs and camels has occurred, raising concerns that horses may be mixing vessels for reassortment.", "In canines, the only IAVs in circulation are equine-derived H3N8 and avian-derived H3N2.", "Canine H3N8 has not been observed to reassort with other subtypes.", "H3N2 has a much broader host range and can reassort with H1N1 and H5N1.", "An isolated case of H6N1 likely from a chicken was found infecting a dog, so other AIVs may emerge in canines.", "Other mammals to be infected by IAVs include H7N7 and H4N5 in seals, H1N3 in whales, and H10N4 and H3N2 in minks.", "Various mutations have been identified that are associated with AIVs adapting to mammals.", "Since HA proteins vary in which sialic acids they bind to, mutations in the HA receptor binding site can allow AIVs to infect mammals.", "Other mutations include mutations affecting which sialic acids NA proteins cleave and a mutation in the PB2 polymerase subunit that improves tolerance of lower temperatures in mammalian respiratory tracts and enhances RNP assembly by stabilizing NP and PB2 binding.", "IBV is mainly found in humans but has also been detected in pigs, dogs, horses, and seals.", "Likewise, ICV primarily infects humans but has been observed in pigs, dogs, cattle, and dromedary camels.", "IDV causes an influenza-like illness in pigs but its impact in its natural reservoir, cattle, is relatively unknown.", "It may cause respiratory disease resembling human influenza on its own, or it may be part of a bovine respiratory disease (BRD) complex with other pathogens during co-infection.", "BRD is a concern for the cattle industry, so IDV's possible involvement in BRD has led to research on vaccines for cattle that can provide protection against IDV.", "Two antigenic lineages are in circulation: D/swine/Oklahoma/1334/2011 (D/OK) and D/bovine/Oklahoma/660/2013 (D/660)." ]

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[ "Other complications of infection include acute respiratory distress syndrome, meningitis, encephalitis, and worsening of pre-existing health problems such as asthma and cardiovascular disease.", "In healthy individuals, influenza is typically self-limiting and rarely fatal, but it can be deadly in high-risk groups." ]

[ "The time between exposure to the virus and development of symptoms, called the incubation period, is 1–4 days, most commonly 1–2 days.", "Many infections, however, are asymptomatic.", "The onset of symptoms is sudden, and initial symptoms are predominately non-specific, including fever, chills, headaches, muscle pain or aching, a feeling of discomfort, loss of appetite, lack of energy/fatigue, and confusion.", "These symptoms are usually accompanied by respiratory symptoms such as a dry cough, sore or dry throat, hoarse voice, and a stuffy or runny nose.", "Coughing is the most common symptom.", "Gastrointestinal symptoms may also occur, including nausea, vomiting, diarrhea, and gastroenteritis, especially in children.", "The standard influenza symptoms typically last for 2–8 days.", "A 2021 study suggests influenza can cause long lasting symptoms in a similar way to long COVID.\nSymptomatic infections are usually mild and limited to the upper respiratory tract, but progression to pneumonia is relatively common.", "Pneumonia may be caused by the primary viral infection or by a secondary bacterial infection.", "Primary pneumonia is characterized by rapid progression of fever, cough, labored breathing, and low oxygen levels that cause bluish skin.", "It is especially common among those who have an underlying cardiovascular disease such as rheumatic heart disease.", "Secondary pneumonia typically has a period of improvement in symptoms for 1–3 weeks followed by recurrent fever, sputum production, and fluid buildup in the lungs, but can also occur just a few days after influenza symptoms appear.", "About a third of primary pneumonia cases are followed by secondary pneumonia, which is most frequently caused by the bacteria \"Streptococcus pneumoniae\" and \"Staphylococcus aureus\".", "Influenza viruses comprise four species.", "Each of the four species is the sole member of its own genus, and the four influenza genera comprise four of the seven genera in the family \"Orthomyxoviridae\".", "They are:\n\n\nIAV is responsible for most cases of severe illness as well as seasonal epidemics and occasional pandemics.", "It infects people of all ages but tends to disproportionately cause severe illness in the elderly, the very young, and those who have chronic health issues.", "Birds are the primary reservoir of IAV, especially aquatic birds such as ducks, geese, shorebirds, and gulls, but the virus also circulates among mammals, including pigs, horses, and marine mammals.", "IAV is classified into subtypes based on the viral proteins haemagglutinin (H) and neuraminidase (N).", "As of 2019, 18 H subtypes and 11 N subtypes have been identified.", "Most potential combinations have been reported in birds, but H17-18 and N10-11 have only been found in bats.", "Only H subtypes H1-3 and N subtypes N1-2 are known to have circulated in humans, the current IAV subtypes in circulation being H1N1 and H3N2.", "IAVs can be classified more specifically to also include natural host species, geographical origin, year of isolation, and strain number, such as H1N1/A/duck/Alberta/35/76.", "IBV mainly infects humans but has been identified in seals, horses, dogs, and pigs.", "IBV does not have subtypes like IAV but has two antigenically distinct lineages, termed the B/Victoria/2/1987-like and B/Yamagata/16/1988-like lineages, or simply (B/)Victoria(-like) and (B/)Yamagata(-like).", "Both lineages are in circulation in humans, disproportionately affecting children.", "IBVs contribute to seasonal epidemics alongside IAVs but have never been associated with a pandemic.", "ICV, like IBV, is primarily found in humans, though it also has been detected in pigs, feral dogs, dromedary camels, cattle, and dogs.", "ICV infection primarily affects children and is usually asymptomatic or has mild cold-like symptoms, though more severe symptoms such as gastroenteritis and pneumonia can occur.", "Unlike IAV and IBV, ICV has not been a major focus of research pertaining to antiviral drugs, vaccines, and other measures against influenza.", "ICV is subclassified into six genetic/antigenic lineages.", "IDV has been isolated from pigs and cattle, the latter being the natural reservoir.", "Infection has also been observed in humans, horses, dromedary camels, and small ruminants such as goats and sheep.", "IDV is distantly related to ICV.", "While cattle workers have occasionally tested positive to prior IDV infection, it is not known to cause disease in humans.", "ICV and IDV experience a slower rate of antigenic evolution than IAV and IBV.", "Because of this antigenic stability, relatively few novel lineages emerge.", "Influenza viruses have a negative-sense, single-stranded RNA genome that is segmented.", "The negative sense of the genome means it can be used as a template to synthesize messenger RNA (mRNA).", "IAV and IBV have eight genome segments that encode 10 major proteins.", "ICV and IDV have seven genome segments that encode nine major proteins.", "Three segments encode three subunits of an RNA-dependent RNA polymerase (RdRp) complex: PB1, a transcriptase, PB2, which recognizes 5' caps, and PA (P3 for ICV and IDV), an endonuclease.", "The matrix protein (M1) and membrane protein (M2) share a segment, as do the non-structural protein (NS1) and the nuclear export protein (NEP).", "For IAV and IBV, hemagglutinin (HA) and neuraminidase (NA) are encoded on one segment each, whereas ICV and IDV encode a hemagglutinin-esterase fusion (HEF) protein on one segment that merges the functions of HA and NA.", "The final genome segment encodes the viral nucleoprotein (NP).", "Influenza viruses also encode various accessory proteins, such as PB1-F2 and PA-X, that are expressed through alternative open reading frames and which are important in host defense suppression, virulence, and pathogenicity.", "The virus particle, called a virion, is pleomorphic and varies between being filamentous, bacilliform, or spherical in shape.", "Clinical isolates tend to be pleomorphic, whereas strains adapted to laboratory growth typically produce spherical virions.", "Filamentous virions are about 250 nanometers (nm) by 80 nm, bacilliform 120–250 by 95 nm, and spherical 120 nm in diameter.", "The virion consists of each segment of the genome bound to nucleoproteins in separate ribonucleoprotein (RNP) complexes for each segment, all of which are surrounded by a lipid bilayer membrane called the viral envelope.", "There is a copy of the RdRp, all subunits included, bound to each RNP.", "The envelope is reinforced structurally by matrix proteins on the interior that enclose the RNPs, and the envelope contains HA and NA (or HEF) proteins extending outward from the exterior surface of the envelope.", "HA and HEF proteins have a distinct \"head\" and \"stalk\" structure.", "M2 proteins form proton ion channels through the viral envelope that are required for viral entry and exit.", "IBVs contain a surface protein named NB that is anchored in the envelope, but its function is unknown.", "The viral life cycle begins by binding to a target cell.", "Binding is mediated by the viral HA proteins on the surface of the evelope, which bind to cells that contain sialic acid receptors on the surface of the cell membrane.", "For N1 subtypes with the \"G147R\" mutation and N2 subtypes, the NA protein can initiate entry.", "Prior to binding, NA proteins promote access to target cells by degrading mucous, which helps to remove extracellular decoy receptors that would impede access to target cells.", "After binding, the virus is internalized into the cell by an endosome that contains the virion inside it.", "The endosome is acidified by cellular vATPase to have lower pH, which triggers a conformational change in HA that allows fusion of the viral envelope with the endosomal membrane.", "At the same time, hydrogen ions diffuse into the virion through M2 ion channels, disrupting internal protein-protein interactions to release RNPs into the host cell's cytosol.", "The M1 protein shell surrounding RNPs is degraded, fully uncoating RNPs in the cytosol.", "RNPs are then imported into the nucleus with the help of viral localization signals.", "There, the viral RNA polymerase transcribes mRNA using the genomic negative-sense strand as a template.", "The polymerase snatches 5' caps for viral mRNA from cellular RNA to prime mRNA synthesis and the 3'-end of mRNA is polyadenylated at the end of transcription.", "Once viral mRNA is transcribed, it is exported out of the nucleus and translated by host ribosomes in a cap-dependent manner to synthesize viral proteins.", "RdRp also synthesizes complementary positive-sense strands of the viral genome in a complementary RNP complex which are then used as templates by viral polymerases to synthesize copies of the negative-sense genome.", "During these processes, RdRps of avian influenza viruses (AIVs) function optimally at a higher temperature than mammalian influenza viruses.", "Newly synthesized viral polymerase subunits and NP proteins are imported to the nucleus to further increase the rate of viral replication and form RNPs.", "HA, NA, and M2 proteins are trafficked with the aid of M1 and NEP proteins to the cell membrane through the Golgi apparatus and inserted into the cell's membrane.", "Viral non-structural proteins including NS1, PB1-F2, and PA-X regulate host cellular processes to disable antiviral responses.", "PB1-F2 aso interacts with PB1 to keep polymerases in the nucleus longer.", "M1 and NEP proteins localize to the nucleus during the later stages of infection, bind to viral RNPs and mediate their export to the cytoplasm where they migrate to the cell membrane with the aid of recycled endosomes and are bundled into the segments of the genome.", "Progenic viruses leave the cell by budding from the cell membrane, which is initiated by the accumulation of M1 proteins at the cytoplasmic side of the membrane.", "The viral genome is incorporated inside a viral envelope derived from portions of the cell membrane that have HA, NA, and M2 proteins.", "At the end of budding, HA proteins remain attached to cellular sialic acid until they are cleaved by the sialidase activity of NA proteins.", "The virion is then released from the cell.", "The sialidase activity of NA also cleaves any sialic acid residues from the viral surface, which helps prevent newly assembled viruses from aggregating near the cell surface and improving infectivity.", "Similar to other aspects of influenza replication, optimal NA activity is temperature- and pH-dependent.", "Ultimately, presence of large quantities of viral RNA in the cell triggers apoptosis, i.e. programmed cell death, which is initiated by cellular factors to restrict viral replication.", "Two key processes that influenza viruses evolve through are antigenic drift and antigenic shift.", "Antigenic drift is when an influenza virus's antigens change due to the gradual accumulation of mutations in the antigen's (HA or NA) gene.", "This can occur in response to evolutionary pressure exerted by the host immune response.", "Antigenic drift is especially common for the HA protein, in which just a few amino acid changes in the head region can constitute antigenic drift.", "The result is the production of novel strains that can evade pre-existing antibody-mediated immunity.", "Antigenic drift occurs in all influenza species but is slower in B than A and slowest in C and D. Antigenic drift is a major cause of seasonal influenza, and requires that flu vaccines be updated annually.", "HA is the main component of inactivated vaccines, so surveillance monitors antigenic drift of this antigen among circulating strains.", "Antigenic evolution of influenza viruses of humans appears to be faster than influenza viruses in swine and equines.", "In wild birds, within-subtype antigenic variation appears to be limited but has been observed in poultry.", "Antigenic shift is a sudden, drastic change in an influenza virus's antigen, usually HA.", "During antigenic shift, antigenically different strains that infect the same cell can reassort genome segments with each other, producing hybrid progeny.", "Since all influenza viruses have segmented genomes, all are capable of reassortment.", "Antigenic shift, however, only occurs among influenza viruses of the same genus and most commonly occurs among IAVs.", "In particular, reassortment is very common in AIVs, creating a large diversity of influenza viruses in birds, but is uncommon in human, equine, and canine lineages.", "Pigs, bats, and quails have receptors for both mammalian and avian IAVs, so they are potential \"mixing vessels\" for reassortment.", "If an animal strain reassorts with a human strain, then a novel strain can emerge that is capable of human-to-human transmission.", "This has caused pandemics, but only a limited number have occurred, so it is difficult to predict when the next will happen.", "People who are infected can transmit influenza viruses through breathing, talking, coughing, and sneezing, which spread respiratory droplets and aerosols that contain virus particles into the air.", "A person susceptible to infection can then contract influenza by coming into contact with these particles.", "Respiratory droplets are relatively large and travel less than two meters before falling onto nearby surfaces.", "Aerosols are smaller and remain suspended in the air longer, so they take longer to settle and can travel further than respiratory droplets.", "Inhalation of aerosols can lead to infection, but most transmission is in the area about two meters around an infected person via respiratory droplets that come into contact with mucosa of the upper respiratory tract.", "Transmission through contact with a person, bodily fluids, or intermediate objects (fomites) can also occur, such as through contaminated hands and surfaces since influenza viruses can survive for hours on non-porous surfaces.", "If one's hands are contaminated, then touching one's face can cause infection.", "Influenza is usually transmissible from one day before the onset of symptoms to 5–7 days after.", "In healthy adults, the virus is shed for up to 3–5 days.", "In children and the immunocompromised, the virus may be transmissible for several weeks.", "Children ages 2–17 are considered to be the primary and most efficient spreaders of influenza.", "Children who have not had multiple prior exposures to influenza viruses shed the virus at greater quantities and for a longer duration than other children.", "People who are at risk of exposure to influenza include health care workers, social care workers, and those who live with or care for people vulnerable to influenza.", "In long-term care facilities, the flu can spread rapidly after it is introduced.", "A variety of factors likely encourage influenza transmission, including lower temperature, lower absolute and relative humidity, less ultraviolet radiation from the Sun, and crowding.", "Influenza viruses that infect the upper respiratory tract like H1N1 tend to be more mild but more transmissible, whereas those that infect the lower respiratory tract like H5N1 tend to cause more severe illness but are less contagious.", "In humans, influenza viruses first cause infection by infecting epithelial cells in the respiratory tract.", "Illness during infection is primarily the result of lung inflammation and compromise caused by epithelial cell infection and death, combined with inflammation caused by the immune system's response to infection.", "Non-respiratory organs can become involved, but the mechanisms by which influenza is involved in these cases are unknown.", "Severe respiratory illness can be caused by multiple, non-exclusive mechanisms, including obstruction of the airways, loss of alveolar structure, loss of lung epithelial integrity due to epithelial cell infection and death, and degradation of the extracellular matrix that maintains lung structure.", "In particular, alveolar cell infection appears to drive severe symptoms since this results in impaired gas exchange and enables viruses to infect endothelial cells, which produce large quantities of pro-inflammatory cytokines.", "Pneumonia caused by influenza viruses is characterized by high levels of viral replication in the lower respiratory tract, accompanied by a strong pro-inflammatory response called a cytokine storm.", "Infection with H5N1 or H7N9 especially produces high levels of pro-inflammatory cytokines.", "In bacterial infections, early depletion of macrophages during influenza creates a favorable environment in the lungs for bacterial growth since these white blood cells are important in responding to bacterial infection.", "Host mechanisms to encourage tissue repair may inadvertently allow bacterial infection.", "Infection also induces production of systemic glucocorticoids that can reduce inflammation to preserve tissue integrity but allow increased bacterial growth.", "The pathophysiology of influenza is significantly influenced by which receptors influenza viruses bind to during entry into cells.", "Mammalian influenza viruses preferentially bind to sialic acids connected to the rest of the oligosaccharide by an α-2,6 link, most commonly found in various respiratory cells, such as respiratory and retinal epithelial cells.", "AIVs prefer sialic acids with an α-2,3 linkage, which are most common in birds in gastrointestinal epithelial cells and in humans in the lower respiratory tract.", "Furthermore, cleavage of the HA protein into HA, the binding subunit, and HA, the fusion subunit, is performed by different proteases, affecting which cells can be infected.", "For mammalian influenza viruses and low pathogenic AIVs, cleavage is extracellular, which limits infection to cells that have the appropriate proteases, whereas for highly pathogenic AIVs, cleavage is intracellular and performed by ubiquitous proteases, which allows for infection of a greater variety of cells, thereby contributing to more severe disease.", "Cells possess sensors to detect viral RNA, which can then induce interferon production.", "Interferons mediate expression of antiviral proteins and proteins that recruit immune cells to the infection site, and they also notify nearby uninfected cells of infection.", "Some infected cells release pro-inflammatory cytokines that recruit immune cells to the site of infection.", "Immune cells control viral infection by killing infected cells and phagocytizing viral particles and apoptotic cells.", "An exacerbated immune response, however, can harm the host organism through a cytokine storm.", "To counter the immune response, influenza viruses encode various non-structural proteins, including NS1, NEP, PB1-F2, and PA-X, that are involved in curtailing the host immune response by suppressing interferon production and host gene expression.", "B cells, a type of white blood cell, produce antibodies that bind to influenza antigens HA and NA (or HEF) and other proteins to a lesser degree.", "Once bound to these proteins, antibodies block virions from binding to cellular receptors, neutralizing the virus.", "In humans, a sizeable antibody response occurs ~1 week after viral exposure.", "This antibody response is typically robust and long-lasting, especially for ICV and IDV.", "In other words, people exposed to a certain strain in childhood still possess antibodies to that strain at a reasonable level later in life, which can provide some protection to related strains.", "There is, however, an \"original antigenic sin\", in which the first HA subtype a person is exposed to influences the antibody-based immune response to future infections and vaccines.", "Annual vaccination is the primary and most effective way to prevent influenza and influenza-associated complications, especially for high-risk groups.", "Vaccines against the flu are trivalent or quadrivalent, providing protection against an H1N1 strain, an H3N2 strain, and one or two IBV strains corresponding to the two IBV lineages.", "Two types of vaccines are in use: inactivated vaccines that contain \"killed\" (i.e. inactivated) viruses and live attenuated influenza vaccines (LAIVs) that contain weakened viruses.", "There are three types of inactivated vaccines: whole virus, split virus, in which the virus is disrupted by a detergent, and subunit, which only contains the viral antigens HA and NA.", "Most flu vaccines are inactivated and administered via intramuscular injection.", "LAIVs are sprayed into the nasal cavity.", "Vaccination recommendations vary by country.", "Some recommend vaccination for all people above a certain age, such as 6 months, whereas other countries recommendation is limited for high at risk groups, such as pregnant women, young children (excluding newborns), the elderly, people with chronic medical conditions, health care workers, people who come into contact with high-risk people, and people who transmit the virus easily.", "Young infants cannot receive flu vaccines for safety reasons, but they can inherit passive immunity from their mother if inactivated vaccines are administered to the mother during pregnancy.", "Influenza vaccination also helps to reduce the probability of reassortment.", "In general, influenza vaccines are only effective if there is an antigenic match between vaccine strains and circulating strains.", "Additionally, most commercially available flu vaccines are manufactured by propagation of influenza viruses in embryonated chicken eggs, taking 6–8 months.", "Flu seasons are different in the northern and southern hemisphere, so the WHO meets twice a year, one for each hemisphere, to discuss which strains should be included in flu vaccines based on observation from HA inhibition assays.", "Other manufacturing methods include an MDCK cell culture-based inactivated vaccine and a recombinant subunit vaccine manufactured from baculovirus overexpression in insect cells.", "Influenza can be prevented or reduced in severity by post-exposure prophylaxis with the antiviral drugs oseltamivir, which can be taken orally by those at least three months old, and zanamivir, which can be inhaled by those above seven years of age.", "Chemoprophylaxis is most useful for individuals at high-risk of developing complications and those who cannot receive the flu vaccine due to contraindications or lack of effectiveness.", "Post-exposure chemoprophylaxis is only recommended if oseltamivir is taken within 48 hours of contact with a confirmed or suspected influenza case and zanamivir within 36 hours.", "It is recommended that it be offered to people who have yet to receive a vaccine for the current flu season, who have been vaccinated less than two week since contact, if there is a significant mismatch between vaccine and circulating strains, or during an outbreak in a closed setting regardless of vaccination history.", "Hand hygiene is important in reducing the spread of influenza.", "This includes frequent hand washing with soap and water, using alcohol-based hand sanitizers, and not touching one's eyes, nose, and mouth with one's hands.", "Covering one's nose and mouth when coughing or sneezing is important.", "Other methods to limit influenza transmission include staying home when sick, avoiding contact with others until one day after symptoms end, and disinfecting surfaces likely to be contaminated by the virus, such as doorknobs.", "Health education through media and posters is often used to remind people of the aforementioned etiquette and hygiene.", "There is uncertainty about the use of masks since research thus far has not shown a significant reduction in seasonal influenza with mask usage.", "Likewise, the effectiveness of screening at points of entry into countries is not well researched.", "Social distancing measures such as school closures, avoiding contact with infected people via isolation or quarantine, and limiting mass gatherings may reduce transmission, but these measures are often expensive, unpopular, and difficult to implement.", "Consequently, the commonly recommended methods of infection control are respiratory etiquette, hand hygiene, and mask wearing, which are inexpensive and easy to perform.", "Pharmaceutical measures are effective but may not be available in the early stages of an outbreak.", "In health care settings, infected individuals may be cohorted or assigned to individual rooms.", "Protective clothing such as masks, gloves, and gowns is recommended when coming into contact with infected individuals if there is a risk of exposure to infected bodily fluids.", "Keeping patients in negative pressure rooms and avoiding aerosol-producing activities may help, but special air handling and ventilation systems are not considered necessary to prevent the spread of influenza in the air.", "In residential homes, new admissions may need to be closed until the spread of influenza is controlled.", "When discharging patients to care homes, it is important to take care if there is a known influenza outbreak.", "Since influenza viruses circulate in animals such as birds and pigs, prevention of transmission from these animals is important.", "Water treatment, indoor raising of animals, quarantining sick animals, vaccination, and biosecurity are the primary measures used.", "Placing poultry houses and piggeries on high ground away from high-density farms, backyard farms, live poultry markets, and bodies of water helps to minimize contact with wild birds.", "Closure of live poultry markets appears to the most effective measure and has shown to be effective at controlling the spread of H5N1, H7N9, and H9N2.", "Other biosecurity measures include cleaning and disinfecting facilities and vehicles, banning visits to poultry farms, not bringing birds intended for slaughter back to farms, changing clothes, disinfecting foot baths, and treating food and water.", "If live poultry markets are not closed, then \"clean days\" when unsold poultry is removed and facilities are disinfected and \"no carry-over\" policies to eliminate infectious material before new poultry arrive can be used to reduce the spread of influenza viruses.", "If a novel influenza viruses has breached the aforementioned biosecurity measures, then rapid detection to stamp it out via quarantining, decontamination, and culling may be necessary to prevent the virus from becoming endemic.", "Vaccines exist for avian H5, H7, and H9 subtypes that are used in some countries.", "In China, for example, vaccination of domestic birds against H7N9 successfully limited its spread, indicating that vaccination may be an effective strategy if used in combination with other measures to limit transmission.", "In pigs and horses, management of influenza is dependent on vaccination with biosecurity.", "Diagnosis based on symptoms is fairly accurate in otherwise healthy people during seasonal epidemics and should be suspected in cases of pneumonia, acute respiratory distress syndrome (ARDS), sepsis, or if encephalitis, myocarditis, or breaking down of muscle tissue occur.", "Because influenza is similar to other viral respiratory tract illnesses, laboratory diagnosis is necessary for confirmation.", "Common ways of collecting samples for testing include nasal and throat swabs.", "Samples may be taken from the lower respiratory tract if infection has cleared the upper but not lower respiratory tract.", "Influenza testing is recommended for anyone hospitalized with symptoms resembling influenza during flu season or who is connected to an influenza case.", "For severe cases, earlier diagnosis improves patient outcome.", "Diagnostic methods that can identify influenza include viral cultures, antibody- and antigen-detecting tests, and nucleic acid-based tests.", "Viruses can be grown in a culture of mammalian cells or embryonated eggs for 3–10 days to monitor cytopathic effect.", "Final confirmation can then be done via antibody staining, hemadsorption using red blood cells, or immunofluorescence microscopy.", "Shell vial cultures, which can identify infection via immunostaining before a cytopathic effect appears, are more sensitive than traditional cultures with results in 1–3 days.", "Cultures can be used to characterize novel viruses, observe sensitivity to antiviral drugs, and monitor antigenic drift, but they are relatively slow and require specialized skills and equipment.", "Serological assays can be used to detect an antibody response to influenza after natural infection or vaccination.", "Common serological assays include hemagglutination inhibition assays that detect HA-specific antibodies, virus neutralization assays that check whether antibodies have neutralized the virus, and enzyme-linked immunoabsorbant assays.", "These methods tend to be relatively inexpensive and fast but are less reliable than nucleic-acid based tests.", "Direct fluorescent or immunofluorescent antibody (DFA/IFA) tests involve staining respiratory epithelial cells in samples with fluorescently-labeled influenza-specific antibodies, followed by examination under a fluorescent microscope.", "They can differentiate between IAV and IBV but can't subtype IAV.", "Rapid influenza diagnostic tests (RIDTs) are a simple way of obtaining assay results, are low cost, and produce results quickly, at less than 30 minutes, so they are commonly used, but they can't distinguish between IAV and IBV or between IAV subtypes and are not as sensitive as nucleic-acid based tests.", "Nucleic acid-based tests (NATs) amplify and detect viral nucleic acid.", "Most of these tests take a few hours, but rapid molecular assays are as fast as RIDTs.", "Among NATs, reverse transcription polymerase chain reaction (RT-PCR) is the most traditional and considered the gold standard for diagnosing influenza because it is fast and can subtype IAV, but it is relatively expensive and more prone to false-positives than cultures.", "Other NATs that have been used include loop-mediated isothermal amplification-based assays, simple amplification-based assays, and nucleic acid sequence-based amplification.", "Nucleic acid sequencing methods can identify infection by obtaining the nucleic acid sequence of viral samples to identify the virus and antiviral drug resistance.", "The traditional method is Sanger sequencing, but it has been largely replaced by next-generation methods that have greater sequencing speed and throughput.", "Treatment of influenza in cases of mild or moderate illness is supportive and includes anti-fever medications such as acetaminophen and ibuprofen, adequate fluid intake to avoid dehydration, and resting at home.", "Cough drops and throat sprays may be beneficial for sore throat.", "It is recommended to avoid alcohol and tobacco use while sick with the flu.", "Aspirin is not recommended to treat influenza in children due to an elevated risk of developing Reye syndrome.", "Corticosteroids likewise are not recommended except when treating septic shock or an underlying medical condition, such as chronic obstructive pulmonary disease or asthma exacerbation, since they are associated with increased mortality.", "If a secondary bacterial infection occurs, then treatment with antibiotics may be necessary.", "Antiviral drugs are primarily used to treat severely ill patients, especially those with compromised immune systems.", "Antivirals are most effective when started in the first 48 hours after symptoms appear.", "Later administration may still be beneficial for those who have underlying immune defects, those with more severe symptoms, or those who have a higher risk of developing complications if these individuals are still shedding the virus.", "Antiviral treatment is also recommended if a person is hospitalized with suspected influenza instead of waiting for test results to return and if symptoms are worsening.", "Most antiviral drugs against influenza fall into two categories: neuraminidase (NA) inhibitors and M2 inhibitors.", "Baloxavir marboxil is a notable exception, which targets the endonuclease activity of the viral RNA polymerase and can be used as an alternative to NA and M2 inhibitors for IAV and IBV.", "NA inhibitors target the enzymatic activity of NA receptors, mimicking the binding of sialic acid in the active site of NA on IAV and IBV virions so that viral release from infected cells and the rate of viral replication are impaired.", "NA inhibitors include oseltamivir, which is consumed orally in a prodrug form and converted to its active form in the liver, and zanamivir, which is a powder that is inhaled nasally.", "Oseltamivir and zanamivir are effective for prophylaxis and post-exposure prophylaxis, and research overall indicates that NA inhibitors are effective at reducing rates of complications, hospitalization, and mortality and the duration of illness.", "Additionally, the earlier NA inhibitors are provided, the better the outcome, though late administration can still be beneficial in severe cases.", "Other NA inhibitors include laninamivir and peramivir, the latter of which can be used as an alternative to oseltamivir for people who cannot tolerate or absorb it.", "The adamantanes amantadine and rimantadine are orally administered drugs that block the influenza virus's M2 ion channel, preventing viral uncoating.", "These drugs are only functional against IAV but are no longer recommended for use because of widespread resistance to them among IAVs.", "Adamantane resistance first emerged in H3N2 in 2003, becoming worldwide by 2008.", "Oseltamivir resistance is no longer widespread because the 2009 pandemic H1N1 strain (H1N1 pdm09), which is resistant to adamantanes, seemingly replaced resistant strains in circulation.", "Since the 2009 pandemic, oseltamivir resistance has mainly been observed in patients undergoing therapy, especially the immunocompromised and young children.", "Oseltamivir resistance is usually reported in H1N1, but has been reported in H3N2 and IBVs less commonly.", "Because of this, oseltamivir is recommended as the first drug of choice for immunocompetent people, whereas for the immunocompromised, oseltamivir is recommended against H3N2 and IBV and zanamivir against H1N1 pdm09.", "Zanamivir resistance is observed less frequently, and resistance to peramivir and baloxavir marboxil is possible.", "In healthy individuals, influenza infection is usually self-limiting and rarely fatal.", "Symptoms usually last for 2–8 days.", "Influenza can cause people to miss work or school, and it is associated with decreased job performance and, in older adults, reduced independence.", "Fatigue and malaise may last for several weeks after recovery, and healthy adults may experience pulmonary abnormalities that can take several weeks to resolve.", "Complications and mortality primarily occur in high-risk populations and those who are hospitalized.", "Severe disease and mortality are usually attributable to pneumonia from the primary viral infection or a secondary bacterial infection, which can progress to ARDS.", "Other respiratory complications that may occur include sinusitis, bronchitis, bronchiolitis, excess fluid buildup in the lungs, and exacerbation of chronic bronchitis and asthma.", "Middle ear infection and croup may occur, most commonly in children.", "Secondary \"S. aureus\" infection has been observed, primarily in children, to cause toxic shock syndrome after influenza, with hypotension, fever, and reddening and peeling of the skin.", "Complications affecting the cardiovascular system are rare and include pericarditis, fulminant myocarditis with a fast, slow, or irregular heartbeat, and exacerbation of pre-existing cardiovascular disease.", "Inflammation or swelling of muscles accompanied by muscle tissue breaking down occurs rarely, usually in children, which presents as extreme tenderness and muscle pain in the legs and a reluctance to walk for 2–3 days.", "Influenza can affect pregnancy, including causing smaller neonatal size, increased risk of premature birth, and an increased risk of child death shortly before or after birth.", "Neurological complications have been associated with influenza on rare occasions, including aseptic meningitis, encephalitis, disseminated encephalomyelitis, transverse myelitis, and Guillain–Barré syndrome.", "Additionally, febrile seizures and Reye syndrome can occur, most commonly in children.", "Influenza-associated encephalopathy can occur directly from central nervous system infection from the presence of the virus in blood and presents as suddent onset of fever with convulsions, followed by rapid progression to coma.", "An atypical form of encephalitis called encephalitis lethargica, characterized by headache, drowsiness, and coma, may rarely occur sometime after infection.", "In survivors of influenza-associated encephalopathy, neurological defects may occur.", "Primarily in children, in severe cases the immune system may rarely dramatically overproduce white blood cells that release cytokines, causing severe inflammation.", "People who are at least 65 years of age, due to a weakened immune system from aging or a chronic illness, are a high-risk group for developing complications, as are children less than one year of age and children who have not been previously exposed to influenza viruses multiple times.", "Pregnant women are at an elevated risk, which increases by trimester and lasts up to two weeks after childbirth.", "Obesity, in particular a body mass index greater than 35–40, is associated with greater amounts of viral replication, increased severity of secondary bacterial infection, and reduced vaccination efficacy.", "People who have underlying health conditions are also considered at-risk, including those who have congenital or chronic heart problems or lung (e.g. asthma), kidney, liver, blood, neurological, or metabolic (e.g. diabetes) disorders, as are people who are immunocompromised from chemotherapy, asplenia, prolonged steroid treatment, splenic dysfunction, or HIV infection.", "Current or past tobacco use also places a person at risk.", "The role of genetics in influenza is not well researched, but it may be a factor in influenza mortality.", "Influenza is typically characterized by seasonal epidemics and sporadic pandemics.", "Most of the burden of influenza is a result of flu seasons caused by IAV and IBV.", "Among IAV subtypes, H1N1 and H3N2 currently circulate in humans and are responsible for seasonal influenza.", "Cases disproportionately occur in children, but most severe causes are among the elderly, the very young, and the immunocompromised.", "In a typical year, influenza viruses infect 5–15% of the global population, causing 3–5 million cases of severe illness annually and accounting for 290,000–650,000 deaths each year due to respiratory illness.", "5–10% of adults and 20–30% of children contract influenza each year.", "The reported number of influenza cases is usually much lower than the actual number of cases.", "During seasonal epidemics, it is estimated that about 80% of otherwise healthy people who have a cough or sore throat have the flu.", "Approximately 30–40% of people hospitalized for influenza develop pneumonia, and about 5% of all severe pneumonia cases in hospitals are due to influenza, which is also the most common cause of ARDS in adults.", "In children, influenza is one of the two most common causes of ARDS, the other being the respiratory syncytial virus.", "About 3–5% of children each year develop otitis media due to influenza.", "Adults who develop organ failure from influenza and children who have PIM scores and acute renal failure have higher rates of mortality.", "During seasonal influenza, mortality is concentrated in the very young and the elderly, whereas during flu pandemics, young adults are often affected at a high rate.", "In temperate regions, the number of influenza cases varies from season to season.", "Lower vitamin D levels, presumably due to less sunlight, lower humidity, lower temperature, and minor changes in virus proteins caused by antigenic drift contribute to annual epidemics that peak during the winter season.", "In the northern hemisphere, this is from October to May (more narrowly December to April), and in the southern hemisphere, this is from May to October (more narrowly June to September).", "There are therefore two distinct influenza seasons every year in temperate regions, one in the northern hemisphere and one in the southern hemisphere.", "In tropical and subtropical regions, seasonality is more complex and appears to be affected by various climatic factors such as minimum temperature, hours of sunshine, maximum rainfall, and high humidity.", "Influenza may therefore occur year-round in these regions.", "Influenza epidemics in modern times have the tendency to start in the eastern or southern hemisphere, with Asia being a key reservoir of influenza viruses.", "IAV and IBV co-circulate, so the two have the same patterns of transmission.", "The seasonality of ICV, however, is poorly understood.", "ICV infection is most common in children under the age of 2, and by adulthood most people have been exposed to it.", "ICV-associated hospitalization most commonly occurs in children under the age of 3 and is frequently accompanied by co-infection with another virus or a bacterium, which may increase the severity of disease.", "When considering all hospitalizations for respiratory illness among young children, ICV appears to account for only a small percentage of such cases.", "Large outbreaks of ICV infection can occur, so incidence varies significantly.", "Outbreaks of influenza caused by novel influenza viruses are common.", "Depending on the level of pre-existing immunity in the population, novel influenza viruses can spread rapidly and cause pandemics with millions of deaths.", "These pandemics, in contrast to seasonal influenza, are caused by antigenic shifts involving animal influenza viruses.", "To date, all known flu pandemics have been caused by IAVs, and they follow the same pattern of spreading from an origin point to the rest of the world over the course of multiple waves in a year.", "Pandemic strains tend to be associated with higher rates of pneumonia in otherwise healthy individuals.", "Generally after each influenza pandemic, the pandemic strain continues to circulate as the cause of seasonal influenza, replacing prior strains.", "From 1700 to 1889, influenza pandemics occurred about once every 50–60 years.", "Since then, pandemics have occurred about once every 10–50 years, so they may be getting more frequent over time.", "It is impossible to know when an influenza virus first infected humans or when the first influenza pandemic occurred.", "Possibly the first influenza epidemic occurred around 6,000 BC in China, and possible descriptions of influenza exist in Greek writings from the 5th century BC.", "In both 1173–1174 AD and 1387 AD, epidemics occurred across Europe that were named \"influenza\".", "Whether these epidemics and others were caused by influenza is unclear since there was no consistent naming pattern for epidemic respiratory diseases at that time, and \"influenza\" didn't become completely attached to respiratory disease until centuries later.", "Influenza may have been brought to the Americas as early as 1493, when an epidemic disease resembling influenza killed most of the population of the Antilles.", "The first convincing record of an influenza pandemic was chronicled in 1510; it began in East Asia before spreading to North Africa and then Europe.", "Following the pandemic, seasonal influenza occurred, with subsequent pandemics in 1557 and 1580.", "The flu pandemic in 1557 was potentially the first time influenza was connected to miscarriage and death of pregnant women.", "The 1580 flu pandemic originated in Asia during summer, spread to Africa, then Europe, and finally America.", "By the end of the 16th century, influenza was likely beginning to become understood as a specific, recognizable disease with epidemic and endemic forms.", "In 1648, it was discovered that horses also experience influenza.", "Influenza data after 1700 is more informative, so it is easier to identify flu pandemics after this point, each of which incrementally increased understanding of influenza.", "The first flu pandemic of the 18th century started in 1729 in Russia in spring, spreading worldwide over the course of three years with distinct waves, the later ones being more lethal.", "The second flu pandemic of the 18th century was in 1781–1782, starting in China in autumn.", "From this pandemic, influenza became associated with sudden outbreaks of febrile illness.", "The next flu pandemic was from 1830 to 1833, beginning in China in winter.", "This pandemic had a high attack rate, but the mortality rate was low.", "A minor influenza pandemic occurred from 1847 to 1851 at the same time as the third cholera pandemic and was the first flu pandemic to occur with vital statistics being recorded, so influenza mortality was clearly recorded for the first time.", "Highly pathogenic avian influenza was recognized in 1878 and was soon linked to transmission to humans.", "By the time of the 1889 pandemic, which may have been caused by an H2N2 strain, the flu had become an easily recognizable disease.", "Initially, the microbial agent responsible for influenza was incorrently identified in 1892 by R. F. J. Pfeiffer as the bacteria species \"Haemophilus influenzae\", which retains \"influenza\" in its name.", "In the following years, the field of virology began to form as viruses were identified as the cause of many diseases.", "From 1901 to 1903, Italian and Austrian researchers were able to show that avian influenza, then called \"fowl plague\", was caused by a microscopic agent smaller than bacteria by using filters with pores too small for bacteria to pass through.", "The fundamental differences between viruses and bacteria, however, were not yet fully understood.", "From 1918 to 1920, the Spanish flu pandemic became the most devastating influenza pandemic and one of the deadliest pandemics in history.", "The pandemic, probably caused by H1N1, likely began in the USA before spreading worldwide by soldiers during and after the First World War.", "The initial wave in the first half of 1918 was relatively minor and resembled past flu pandemics, but the second wave later that year had a much higher mortality rate, accounting for most deaths.", "A third wave with lower mortality occurred in many places a few months after the second.", "By the end of 1920, it is estimated that about a third to half of all people in the world had been infected, with tens of millions of deaths, disproportionately young adults.", "During the 1918 pandemic, the respiratory route of transmission was clearly identified and influenza was shown to be caused by a \"filter passer\", not a bacterium, but there remained a lack of agreement about influenza's cause for another decade and research on influenza declined.", "After the pandemic, H1N1 circulated in humans in seasonal form up until the next pandemic.", "In 1931, Richard Shope published three papers identifying a virus as the cause of swine influenza, a then newly recognized disease among pigs that was first characterized during the second wave of the 1918 pandemic.", "Shope's research reinvigorated research on human influenza, and many advances in virology, serology, immunology, experimental animal models, vaccinology, and immunotherapy have since arisen from influenza research.", "Just two years after influenza viruses were discovered, in 1933, IAV was identified as the agent responsible for human influenza.", "Subtypes of IAV were discovered throughout the 1930s, and IBV was discovered in 1940.", "During the Second World War, the US government worked on developing inactivated vaccines for influenza, resulting in the first influenza vaccine being licensed in 1945 in the United States.", "ICV was discovered two years later in 1947.", "In 1955, avian influenza was confirmed to be caused by IAV.", "Four influenza pandemics have occurred since WWII, each less severe than the 1918 pandemic.", "The first of these was the Asian flu from 1957 to 1958, caused by an H2N2 strain and beginning in China's Yunnan province.", "The number of deaths probably exceeded one million, mostly among the very young and very old.", "Notably, the 1957 pandemic was the first flu pandemic to occur in the presence of a global surveillance system and laboratories able to study the novel influenza virus.", "After the pandemic, H2N2 was the IAV subtype responsible for seasonal influenza.", "The first antiviral drug against influenza, amantadine, was approved for use in 1966, with additional antiviral drugs being used since the 1990s.", "In 1968, H3N2 was introduced into humans as a result of a reassortment between an avian H3N2 strain and an H2N2 strain that was circulating in humans.", "The novel H3N2 strain first emerged in Hong Kong and spread worldwide, causing the Hong Kong flu pandemic, which resulted in 500,000–2,000,000 deaths.", "This was the first pandemic to spread significantly by air travel.", "H2N2 and H3N2 co-circulated after the pandemic until 1971 when H2N2 waned in prevalence and was completely replaced by H3N2.", "In 1977, H1N1 reemerged in humans, possibly after it was released from a freezer in a laboratory accident, and caused a pseudo-pandemic.", "Whether the 1977 \"pandemic\" deserves to be included in the natural history of flu pandemics is debatable.", "This H1N1 strain was antigenically similar to the H1N1 strains that circulated prior to 1957.", "Since 1977, both H1N1 and H3N2 have circulated in humans as part of seasonal influenza.", "In 1980, the current classification system used to subtype influenza viruses was introduced.", "At some point, IBV diverged into two lineages, named the B/Victoria-like and B/Yamagata-like lineages, both of which have been circulating in humans since 1983.", "In 1996, HPAI H5N1 was detected in Guangdong, China and a year later emerged in poultry in Hong Kong, gradually spreading worldwide from there.", "A small H5N1 outbreak in humans in Hong Kong occurred then, and sporadic human cases have occurred since 1997, carrying a high case fatality rate.", "The most recent flu pandemic was the 2009 swine flu pandemic, which originated in Mexico and resulted in hundreds of thousands of deaths.", "It was caused by a novel H1N1 strain that was a reassortment of human, swine, and avian influenza viruses.", "The 2009 pandemic had the effect of replacing prior H1N1 strains in circulation with the novel strain but not any other influenza viruses.", "Consequently, H1N1, H3N2, and both IBV lineages have been in circulation in seasonal form since the 2009 pandemic.", "In 2011, IDV was discovered in pigs in Oklahoma, USA, and cattle were later identified as the primary reservoir of IDV.", "In the same year, avian H7N9 was detected in China and began to cause human infections in 2013, starting in Shanghai and Anhui and remaining mostly in China.", "HPAI H7N9 emerged sometime in 2016 and has occasionally infected humans incidentally.", "Other AIVs have less commonly infected humans since the 1990s, including H5N6, H6N1, H7N2-4, H7N7, and H10N7-8, and HPAI H subtypes such as H5N1-3, H5N5-6, and H5N8 have begun to spread throughout much of the world since the 2010s.", "Future flu pandemics, which may be caused by an influenza virus of avian origin, are viewed as almost inevitable, and increased globalization has made it easier for novel viruses to spread, so there are continual efforts to prepare for future pandemics and improve the prevention and treatment of influenza.", "The word \"influenza\" comes from the Italian word \"influenza\", from medieval Latin \"influentia\", originally meaning \"visitation\" or \"influence\".", "Terms such as \"influenza di freddo\", meaning \"influence of the cold\", and \"influenza di stelle\", meaning \"influence of the stars\" are attested from the 14th century.", "The latter referred to the disease's cause, which at the time was ascribed by some to unfavorable astrological conditions.", "As early as 1504, \"influenza\" began to mean a \"visitation\" or \"outbreak\" of any disease affecting many people in a single place at once.", "During an outbreak of influenza in 1743 that started in Italy and spread throughout Europe, the word reached the English language and was anglicized in pronunciation.", "Since the mid-1800s, \"influenza\" has also been used to refer to severe colds.", "The shortened form of the word, \"(the) flu\", is first attested in 1839 as \"flue\" with the spelling \"flu\" first attested in 1893.", "Other names that have been used for influenza include \"epidemic catarrh\", \"la grippe\" from French, \"sweating sickness\", and, especially when referring to the 1918 pandemic strain, \"Spanish fever\".", "Influenza research is wide-ranging and includes efforts to understand how influenza viruses enter hosts, the relationship between influenza viruses and bacteria, how influenza symptoms progress, and what make some influenza viruses deadlier than others.", "Non-structural proteins encoded by influenza viruses are periodically discovered and their functions are continually under research.", "Past pandemics, and especially the 1918 pandemic, are the subject of much research to understand flu pandemics.", "As part of pandemic preparedness, the Global Influenza Surveillance and Response System is a global network of laboratories that monitors influenza transmission and epidemiology.", "Additional areas of research include ways to improve the diagnosis, treatment, and prevention of influenza.", "Existing diagnostic methods have a variety of limitations coupled with their advantages.", "For example, NATs have high sensitivity and specificity but are impractical in under-resourced regions due to their high cost, complexity, maintenance, and training required.", "Low-cost, portable RIDTs can rapidly diagnose influenza but have highly variable sensitivity and are unable to subtype IAV.", "As a result of these limitations and others, research into new diagnostic methods revolves around producing new methods that are cost-effective, less labor-intensive, and less complex than existing methods while also being able to differentiate influenza species and IAV subtypes.", "One approach in development are lab-on-a-chips, which are diagnostic devices that make use of a variety of diagnostic tests, such as RT-PCR and serological assays, in microchip form.", "These chips have many potential advantages, including high reaction efficiency, low energy consumption, and low waste generation.", "New antiviral drugs are also in development due to the elimination of adamantines as viable drugs and concerns over oseltamivir resistance.", "These include: NA inhibitors that can be injected intravenously, such as intravenous formulations of zanamivir; favipiravir, which is a polymerase inhibitor used against several RNA viruses; pimodivir, which prevents cap-binding required during viral transcription; and nitazoxanide, which inhibits HA maturation.", "Reducing excess inflammation in the respiratory tract is also subject to much research since this is one of the primary mechanisms of influenza pathology.", "Other forms of therapy in development include monoclonal and polyclonal antibodies that target viral proteins, convalescent plasma, different approaches to modify the host antiviral response, and stem cell-based therapies to repair lung damage.", "Much research on LAIVs focuses on identifying genome sequences that can be deleted to create harmless influenza viruses in vaccines that still confer immunity.", "The high variability and rapid evolution of influenza virus antigens, however, is a major obstacle in developing effective vaccines.", "Furthermore, it is hard to predict which strains will be in circulation during the next flu season, manufacturing a sufficient quantity of flu vaccines for the next season is difficult, LAIVs have limited efficacy, and repeated annual vaccination potentially has diminished efficacy.", "For these reasons, \"broadly-reactive\" or \"universal\" flu vaccines are being researched that can provide protection against many or all influenza viruses.", "Approaches to develop such a vaccine include HA stalk-based methods such as chimeras that have the same stalk but different heads, HA head-based methods such as computationally optimized broadly neutralizing antigens, anti-idiotypic antibodies, and vaccines to elicit immune responses to highly conserved viral proteins.", "mRNA vaccines to provide protection against influenza are also under research.", "Aquatic birds such as ducks, geese, shorebirds, and gulls are the primary reservoir of IAVs.", "In birds, AIVs may be either low pathogenic avian influenza (LPAI) viruses that produce little to no symptoms or highly pathogenic avian influenza (HPAI) viruses that cause severe illness.", "Symptoms of HPAI infection include lack of energy and appetite, decreased egg production, soft-shelled or misshapen eggs, swelling of the head, comb, wattles, and hocks, purple discoloration of wattles, combs, and legs, nasal discharge, coughing, sneezing, incoordination, and diarrhea.", "Birds infected with an HPAI virus may also die suddenly without any signs of infection.", "The distinction between LPAI and HPAI can generally be made based on how lethal an AIV is to chickens.", "At the genetic level, an AIV can be usually be identified as an HPAI virus if it has a multibasic cleavage site in the HA protein, which contains additional residues in the HA gene.", "Most AIVs are LPAI.", "Notable HPAI viruses include HPAI H5N1 and HPAI H7N9.", "HPAI viruses have been a major disease burden in the 21st century, resulting in the death of large numbers of birds.", "In H7N9's case, some circulating strains were originally LPAI but became HPAI by acquiring the HA multibasic cleavage site.", "Avian H9N2 is also of concern because although it is LPAI, it is a common donor of genes to H5N1 and H7N9 during reassortment.", "Migratory birds can spread influenza across long distances.", "An example of this was when an H5N1 strain in 2005 infected birds at Qinghai Lake, China, which is a stopover and breeding site for many migratory birds, subsequently spreading the virus to more than 20 countries across Asia, Europe, and the Middle East.", "AIVs can be transmitted from wild birds to domestic free-range ducks and in turn to poultry through contaminated water, aerosols, and fomites.", "Ducks therefore act as key intermediates between wild and domestic birds.", "Transmission to poultry typically occurs in backyard farming and live animal markets where multiple species interact with each other.", "From there, AIVs can spread to poultry farms in the absence of adequate biosecurity.", "Among poultry, HPAI transmission occurs through aerosols and contaminated feces, cages, feed, and dead animals.", "Back-transmission of HPAI viruses from poultry to wild birds has occurred and is implicated in mass die-offs and intercontinental spread.", "AIVs have occasionally infected humans through aerosols, fomites, and contaminated water.", "Direction transmission from wild birds is rare.", "Instead, most transmission involves domestic poultry, mainly chickens, ducks, and geese but also a variety of other birds such as guinea fowl, partridge, pheasants, and quails.", "The primary risk factor for infection with AIVs is exposure to birds in farms and live poultry markets.", "Typically, infection with an AIV has an incubation period of 3–5 days but can be up to 9 days.", "H5N1 and H7N9 cause severe lower respiratory tract illness, whereas other AIVs such as H9N2 cause a more mild upper respiratory tract illness, commonly with conjunctivitis.", "Limited transmission of avian H2, H5-7, H9, and H10 subtypes from one person to another through respiratory droplets, aerosols, and fomites has occurred, but sustained human-to-human transmission of AIVs has not occurred.", "Before 2013, H5N1 was the most common AIV to infect humans.", "Since then, H7N9 has been responsible for most human cases.", "Influenza in pigs is a respiratory disease similar to influenza in humans and is found worldwide.", "Asymptomatic infections are common.", "Symptoms typically appear 1–3 days after infection and include fever, lethargy, anorexia, weight loss, labored breathing, coughing, sneezing, and nasal discharge.", "In sows, pregnancy may be aborted.", "Complications include secondary infections and potentially fatal bronchopneumonia.", "Pigs become contagious within a day of infection and typically spread the virus for 7–10 days, which can spread rapidly within a herd.", "Pigs usually recover from infection within 3–7 days after symptoms appear.", "Prevention and control measures include inactivated vaccines and culling infected herds.", "The influenza viruses usually responsible for swine flu are IAV subtypes H1N1, H1N2, and H3N2.", "Some IAVs can be transmitted via aerosols from pigs to humans and vice versa.", "Furthermore, pigs, along with bats and quails, are recognized as a mixing vessel of influenza viruses because they have both α-2,3 and α-2,6 sialic acid receptors in their respiratory tract.", "Because of that, both avian and mammalian influenza viruses can infect pigs.", "If co-infection occurs, then reassortment is possible.", "A notable example of this was the reassortment of a swine, avian, and human influenza virus in 2009, resulting in a novel H1N1 strain that caused the 2009 flu pandemic.", "Spillover events from humans to pigs, however, appear to be more common than from pigs to humans.", "Influenza viruses have been found in many other animals, including cattle, horses, dogs, cats, and marine mammals.", "Nearly all IAVs are apparently descended from ancestral viruses in birds.", "The exception are bat influenza-like viruses, which have an uncertain origin.", "These bat viruses have HA and NA subtypes H17, H18, N10, and N11.", "H17N10 and H18N11 are unable to reassort with other IAVs, but they are still able to replicate in other mammals.", "AIVs sometimes crossover into mammals.", "For example, in late 2016 to early 2017, an avian H7N2 strain was found to be infecting cats in New York.", "Equine IAVs include H7N7 and two lineages of H3N8.", "H7N7, however, has not been detected in horses since the late 1970s, so it may have become extinct in horses.", "H3N8 in equines spreads via aerosols and causes respiratory illness.", "Equine H3N8 perferentially binds to α-2,3 sialic acids, so horses are usually considered dead-end hosts, but transmission to dogs and camels has occurred, raising concerns that horses may be mixing vessels for reassortment.", "In canines, the only IAVs in circulation are equine-derived H3N8 and avian-derived H3N2.", "Canine H3N8 has not been observed to reassort with other subtypes.", "H3N2 has a much broader host range and can reassort with H1N1 and H5N1.", "An isolated case of H6N1 likely from a chicken was found infecting a dog, so other AIVs may emerge in canines.", "Other mammals to be infected by IAVs include H7N7 and H4N5 in seals, H1N3 in whales, and H10N4 and H3N2 in minks.", "Various mutations have been identified that are associated with AIVs adapting to mammals.", "Since HA proteins vary in which sialic acids they bind to, mutations in the HA receptor binding site can allow AIVs to infect mammals.", "Other mutations include mutations affecting which sialic acids NA proteins cleave and a mutation in the PB2 polymerase subunit that improves tolerance of lower temperatures in mammalian respiratory tracts and enhances RNP assembly by stabilizing NP and PB2 binding.", "IBV is mainly found in humans but has also been detected in pigs, dogs, horses, and seals.", "Likewise, ICV primarily infects humans but has been observed in pigs, dogs, cattle, and dromedary camels.", "IDV causes an influenza-like illness in pigs but its impact in its natural reservoir, cattle, is relatively unknown.", "It may cause respiratory disease resembling human influenza on its own, or it may be part of a bovine respiratory disease (BRD) complex with other pathogens during co-infection.", "BRD is a concern for the cattle industry, so IDV's possible involvement in BRD has led to research on vaccines for cattle that can provide protection against IDV.", "Two antigenic lineages are in circulation: D/swine/Oklahoma/1334/2011 (D/OK) and D/bovine/Oklahoma/660/2013 (D/660)." ]

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[ "In a typical year, 5–15% of the population contracts influenza.", "There are 3–5 million severe cases annually, with up to 650,000 respiratory-related deaths globally each year.", "In temperate regions of the world, the number of influenza cases peaks during winter, whereas in the tropics influenza can occur year-round.", "Since the late 1800s, large outbreaks of novel influenza strains that spread globally, called pandemics, have occurred every 10–50 years." ]

[ "The time between exposure to the virus and development of symptoms, called the incubation period, is 1–4 days, most commonly 1–2 days.", "Many infections, however, are asymptomatic.", "The onset of symptoms is sudden, and initial symptoms are predominately non-specific, including fever, chills, headaches, muscle pain or aching, a feeling of discomfort, loss of appetite, lack of energy/fatigue, and confusion.", "These symptoms are usually accompanied by respiratory symptoms such as a dry cough, sore or dry throat, hoarse voice, and a stuffy or runny nose.", "Coughing is the most common symptom.", "Gastrointestinal symptoms may also occur, including nausea, vomiting, diarrhea, and gastroenteritis, especially in children.", "The standard influenza symptoms typically last for 2–8 days.", "A 2021 study suggests influenza can cause long lasting symptoms in a similar way to long COVID.\nSymptomatic infections are usually mild and limited to the upper respiratory tract, but progression to pneumonia is relatively common.", "Pneumonia may be caused by the primary viral infection or by a secondary bacterial infection.", "Primary pneumonia is characterized by rapid progression of fever, cough, labored breathing, and low oxygen levels that cause bluish skin.", "It is especially common among those who have an underlying cardiovascular disease such as rheumatic heart disease.", "Secondary pneumonia typically has a period of improvement in symptoms for 1–3 weeks followed by recurrent fever, sputum production, and fluid buildup in the lungs, but can also occur just a few days after influenza symptoms appear.", "About a third of primary pneumonia cases are followed by secondary pneumonia, which is most frequently caused by the bacteria \"Streptococcus pneumoniae\" and \"Staphylococcus aureus\".", "Influenza viruses comprise four species.", "Each of the four species is the sole member of its own genus, and the four influenza genera comprise four of the seven genera in the family \"Orthomyxoviridae\".", "They are:\n\n\nIAV is responsible for most cases of severe illness as well as seasonal epidemics and occasional pandemics.", "It infects people of all ages but tends to disproportionately cause severe illness in the elderly, the very young, and those who have chronic health issues.", "Birds are the primary reservoir of IAV, especially aquatic birds such as ducks, geese, shorebirds, and gulls, but the virus also circulates among mammals, including pigs, horses, and marine mammals.", "IAV is classified into subtypes based on the viral proteins haemagglutinin (H) and neuraminidase (N).", "As of 2019, 18 H subtypes and 11 N subtypes have been identified.", "Most potential combinations have been reported in birds, but H17-18 and N10-11 have only been found in bats.", "Only H subtypes H1-3 and N subtypes N1-2 are known to have circulated in humans, the current IAV subtypes in circulation being H1N1 and H3N2.", "IAVs can be classified more specifically to also include natural host species, geographical origin, year of isolation, and strain number, such as H1N1/A/duck/Alberta/35/76.", "IBV mainly infects humans but has been identified in seals, horses, dogs, and pigs.", "IBV does not have subtypes like IAV but has two antigenically distinct lineages, termed the B/Victoria/2/1987-like and B/Yamagata/16/1988-like lineages, or simply (B/)Victoria(-like) and (B/)Yamagata(-like).", "Both lineages are in circulation in humans, disproportionately affecting children.", "IBVs contribute to seasonal epidemics alongside IAVs but have never been associated with a pandemic.", "ICV, like IBV, is primarily found in humans, though it also has been detected in pigs, feral dogs, dromedary camels, cattle, and dogs.", "ICV infection primarily affects children and is usually asymptomatic or has mild cold-like symptoms, though more severe symptoms such as gastroenteritis and pneumonia can occur.", "Unlike IAV and IBV, ICV has not been a major focus of research pertaining to antiviral drugs, vaccines, and other measures against influenza.", "ICV is subclassified into six genetic/antigenic lineages.", "IDV has been isolated from pigs and cattle, the latter being the natural reservoir.", "Infection has also been observed in humans, horses, dromedary camels, and small ruminants such as goats and sheep.", "IDV is distantly related to ICV.", "While cattle workers have occasionally tested positive to prior IDV infection, it is not known to cause disease in humans.", "ICV and IDV experience a slower rate of antigenic evolution than IAV and IBV.", "Because of this antigenic stability, relatively few novel lineages emerge.", "Influenza viruses have a negative-sense, single-stranded RNA genome that is segmented.", "The negative sense of the genome means it can be used as a template to synthesize messenger RNA (mRNA).", "IAV and IBV have eight genome segments that encode 10 major proteins.", "ICV and IDV have seven genome segments that encode nine major proteins.", "Three segments encode three subunits of an RNA-dependent RNA polymerase (RdRp) complex: PB1, a transcriptase, PB2, which recognizes 5' caps, and PA (P3 for ICV and IDV), an endonuclease.", "The matrix protein (M1) and membrane protein (M2) share a segment, as do the non-structural protein (NS1) and the nuclear export protein (NEP).", "For IAV and IBV, hemagglutinin (HA) and neuraminidase (NA) are encoded on one segment each, whereas ICV and IDV encode a hemagglutinin-esterase fusion (HEF) protein on one segment that merges the functions of HA and NA.", "The final genome segment encodes the viral nucleoprotein (NP).", "Influenza viruses also encode various accessory proteins, such as PB1-F2 and PA-X, that are expressed through alternative open reading frames and which are important in host defense suppression, virulence, and pathogenicity.", "The virus particle, called a virion, is pleomorphic and varies between being filamentous, bacilliform, or spherical in shape.", "Clinical isolates tend to be pleomorphic, whereas strains adapted to laboratory growth typically produce spherical virions.", "Filamentous virions are about 250 nanometers (nm) by 80 nm, bacilliform 120–250 by 95 nm, and spherical 120 nm in diameter.", "The virion consists of each segment of the genome bound to nucleoproteins in separate ribonucleoprotein (RNP) complexes for each segment, all of which are surrounded by a lipid bilayer membrane called the viral envelope.", "There is a copy of the RdRp, all subunits included, bound to each RNP.", "The envelope is reinforced structurally by matrix proteins on the interior that enclose the RNPs, and the envelope contains HA and NA (or HEF) proteins extending outward from the exterior surface of the envelope.", "HA and HEF proteins have a distinct \"head\" and \"stalk\" structure.", "M2 proteins form proton ion channels through the viral envelope that are required for viral entry and exit.", "IBVs contain a surface protein named NB that is anchored in the envelope, but its function is unknown.", "The viral life cycle begins by binding to a target cell.", "Binding is mediated by the viral HA proteins on the surface of the evelope, which bind to cells that contain sialic acid receptors on the surface of the cell membrane.", "For N1 subtypes with the \"G147R\" mutation and N2 subtypes, the NA protein can initiate entry.", "Prior to binding, NA proteins promote access to target cells by degrading mucous, which helps to remove extracellular decoy receptors that would impede access to target cells.", "After binding, the virus is internalized into the cell by an endosome that contains the virion inside it.", "The endosome is acidified by cellular vATPase to have lower pH, which triggers a conformational change in HA that allows fusion of the viral envelope with the endosomal membrane.", "At the same time, hydrogen ions diffuse into the virion through M2 ion channels, disrupting internal protein-protein interactions to release RNPs into the host cell's cytosol.", "The M1 protein shell surrounding RNPs is degraded, fully uncoating RNPs in the cytosol.", "RNPs are then imported into the nucleus with the help of viral localization signals.", "There, the viral RNA polymerase transcribes mRNA using the genomic negative-sense strand as a template.", "The polymerase snatches 5' caps for viral mRNA from cellular RNA to prime mRNA synthesis and the 3'-end of mRNA is polyadenylated at the end of transcription.", "Once viral mRNA is transcribed, it is exported out of the nucleus and translated by host ribosomes in a cap-dependent manner to synthesize viral proteins.", "RdRp also synthesizes complementary positive-sense strands of the viral genome in a complementary RNP complex which are then used as templates by viral polymerases to synthesize copies of the negative-sense genome.", "During these processes, RdRps of avian influenza viruses (AIVs) function optimally at a higher temperature than mammalian influenza viruses.", "Newly synthesized viral polymerase subunits and NP proteins are imported to the nucleus to further increase the rate of viral replication and form RNPs.", "HA, NA, and M2 proteins are trafficked with the aid of M1 and NEP proteins to the cell membrane through the Golgi apparatus and inserted into the cell's membrane.", "Viral non-structural proteins including NS1, PB1-F2, and PA-X regulate host cellular processes to disable antiviral responses.", "PB1-F2 aso interacts with PB1 to keep polymerases in the nucleus longer.", "M1 and NEP proteins localize to the nucleus during the later stages of infection, bind to viral RNPs and mediate their export to the cytoplasm where they migrate to the cell membrane with the aid of recycled endosomes and are bundled into the segments of the genome.", "Progenic viruses leave the cell by budding from the cell membrane, which is initiated by the accumulation of M1 proteins at the cytoplasmic side of the membrane.", "The viral genome is incorporated inside a viral envelope derived from portions of the cell membrane that have HA, NA, and M2 proteins.", "At the end of budding, HA proteins remain attached to cellular sialic acid until they are cleaved by the sialidase activity of NA proteins.", "The virion is then released from the cell.", "The sialidase activity of NA also cleaves any sialic acid residues from the viral surface, which helps prevent newly assembled viruses from aggregating near the cell surface and improving infectivity.", "Similar to other aspects of influenza replication, optimal NA activity is temperature- and pH-dependent.", "Ultimately, presence of large quantities of viral RNA in the cell triggers apoptosis, i.e. programmed cell death, which is initiated by cellular factors to restrict viral replication.", "Two key processes that influenza viruses evolve through are antigenic drift and antigenic shift.", "Antigenic drift is when an influenza virus's antigens change due to the gradual accumulation of mutations in the antigen's (HA or NA) gene.", "This can occur in response to evolutionary pressure exerted by the host immune response.", "Antigenic drift is especially common for the HA protein, in which just a few amino acid changes in the head region can constitute antigenic drift.", "The result is the production of novel strains that can evade pre-existing antibody-mediated immunity.", "Antigenic drift occurs in all influenza species but is slower in B than A and slowest in C and D. Antigenic drift is a major cause of seasonal influenza, and requires that flu vaccines be updated annually.", "HA is the main component of inactivated vaccines, so surveillance monitors antigenic drift of this antigen among circulating strains.", "Antigenic evolution of influenza viruses of humans appears to be faster than influenza viruses in swine and equines.", "In wild birds, within-subtype antigenic variation appears to be limited but has been observed in poultry.", "Antigenic shift is a sudden, drastic change in an influenza virus's antigen, usually HA.", "During antigenic shift, antigenically different strains that infect the same cell can reassort genome segments with each other, producing hybrid progeny.", "Since all influenza viruses have segmented genomes, all are capable of reassortment.", "Antigenic shift, however, only occurs among influenza viruses of the same genus and most commonly occurs among IAVs.", "In particular, reassortment is very common in AIVs, creating a large diversity of influenza viruses in birds, but is uncommon in human, equine, and canine lineages.", "Pigs, bats, and quails have receptors for both mammalian and avian IAVs, so they are potential \"mixing vessels\" for reassortment.", "If an animal strain reassorts with a human strain, then a novel strain can emerge that is capable of human-to-human transmission.", "This has caused pandemics, but only a limited number have occurred, so it is difficult to predict when the next will happen.", "People who are infected can transmit influenza viruses through breathing, talking, coughing, and sneezing, which spread respiratory droplets and aerosols that contain virus particles into the air.", "A person susceptible to infection can then contract influenza by coming into contact with these particles.", "Respiratory droplets are relatively large and travel less than two meters before falling onto nearby surfaces.", "Aerosols are smaller and remain suspended in the air longer, so they take longer to settle and can travel further than respiratory droplets.", "Inhalation of aerosols can lead to infection, but most transmission is in the area about two meters around an infected person via respiratory droplets that come into contact with mucosa of the upper respiratory tract.", "Transmission through contact with a person, bodily fluids, or intermediate objects (fomites) can also occur, such as through contaminated hands and surfaces since influenza viruses can survive for hours on non-porous surfaces.", "If one's hands are contaminated, then touching one's face can cause infection.", "Influenza is usually transmissible from one day before the onset of symptoms to 5–7 days after.", "In healthy adults, the virus is shed for up to 3–5 days.", "In children and the immunocompromised, the virus may be transmissible for several weeks.", "Children ages 2–17 are considered to be the primary and most efficient spreaders of influenza.", "Children who have not had multiple prior exposures to influenza viruses shed the virus at greater quantities and for a longer duration than other children.", "People who are at risk of exposure to influenza include health care workers, social care workers, and those who live with or care for people vulnerable to influenza.", "In long-term care facilities, the flu can spread rapidly after it is introduced.", "A variety of factors likely encourage influenza transmission, including lower temperature, lower absolute and relative humidity, less ultraviolet radiation from the Sun, and crowding.", "Influenza viruses that infect the upper respiratory tract like H1N1 tend to be more mild but more transmissible, whereas those that infect the lower respiratory tract like H5N1 tend to cause more severe illness but are less contagious.", "In humans, influenza viruses first cause infection by infecting epithelial cells in the respiratory tract.", "Illness during infection is primarily the result of lung inflammation and compromise caused by epithelial cell infection and death, combined with inflammation caused by the immune system's response to infection.", "Non-respiratory organs can become involved, but the mechanisms by which influenza is involved in these cases are unknown.", "Severe respiratory illness can be caused by multiple, non-exclusive mechanisms, including obstruction of the airways, loss of alveolar structure, loss of lung epithelial integrity due to epithelial cell infection and death, and degradation of the extracellular matrix that maintains lung structure.", "In particular, alveolar cell infection appears to drive severe symptoms since this results in impaired gas exchange and enables viruses to infect endothelial cells, which produce large quantities of pro-inflammatory cytokines.", "Pneumonia caused by influenza viruses is characterized by high levels of viral replication in the lower respiratory tract, accompanied by a strong pro-inflammatory response called a cytokine storm.", "Infection with H5N1 or H7N9 especially produces high levels of pro-inflammatory cytokines.", "In bacterial infections, early depletion of macrophages during influenza creates a favorable environment in the lungs for bacterial growth since these white blood cells are important in responding to bacterial infection.", "Host mechanisms to encourage tissue repair may inadvertently allow bacterial infection.", "Infection also induces production of systemic glucocorticoids that can reduce inflammation to preserve tissue integrity but allow increased bacterial growth.", "The pathophysiology of influenza is significantly influenced by which receptors influenza viruses bind to during entry into cells.", "Mammalian influenza viruses preferentially bind to sialic acids connected to the rest of the oligosaccharide by an α-2,6 link, most commonly found in various respiratory cells, such as respiratory and retinal epithelial cells.", "AIVs prefer sialic acids with an α-2,3 linkage, which are most common in birds in gastrointestinal epithelial cells and in humans in the lower respiratory tract.", "Furthermore, cleavage of the HA protein into HA, the binding subunit, and HA, the fusion subunit, is performed by different proteases, affecting which cells can be infected.", "For mammalian influenza viruses and low pathogenic AIVs, cleavage is extracellular, which limits infection to cells that have the appropriate proteases, whereas for highly pathogenic AIVs, cleavage is intracellular and performed by ubiquitous proteases, which allows for infection of a greater variety of cells, thereby contributing to more severe disease.", "Cells possess sensors to detect viral RNA, which can then induce interferon production.", "Interferons mediate expression of antiviral proteins and proteins that recruit immune cells to the infection site, and they also notify nearby uninfected cells of infection.", "Some infected cells release pro-inflammatory cytokines that recruit immune cells to the site of infection.", "Immune cells control viral infection by killing infected cells and phagocytizing viral particles and apoptotic cells.", "An exacerbated immune response, however, can harm the host organism through a cytokine storm.", "To counter the immune response, influenza viruses encode various non-structural proteins, including NS1, NEP, PB1-F2, and PA-X, that are involved in curtailing the host immune response by suppressing interferon production and host gene expression.", "B cells, a type of white blood cell, produce antibodies that bind to influenza antigens HA and NA (or HEF) and other proteins to a lesser degree.", "Once bound to these proteins, antibodies block virions from binding to cellular receptors, neutralizing the virus.", "In humans, a sizeable antibody response occurs ~1 week after viral exposure.", "This antibody response is typically robust and long-lasting, especially for ICV and IDV.", "In other words, people exposed to a certain strain in childhood still possess antibodies to that strain at a reasonable level later in life, which can provide some protection to related strains.", "There is, however, an \"original antigenic sin\", in which the first HA subtype a person is exposed to influences the antibody-based immune response to future infections and vaccines.", "Annual vaccination is the primary and most effective way to prevent influenza and influenza-associated complications, especially for high-risk groups.", "Vaccines against the flu are trivalent or quadrivalent, providing protection against an H1N1 strain, an H3N2 strain, and one or two IBV strains corresponding to the two IBV lineages.", "Two types of vaccines are in use: inactivated vaccines that contain \"killed\" (i.e. inactivated) viruses and live attenuated influenza vaccines (LAIVs) that contain weakened viruses.", "There are three types of inactivated vaccines: whole virus, split virus, in which the virus is disrupted by a detergent, and subunit, which only contains the viral antigens HA and NA.", "Most flu vaccines are inactivated and administered via intramuscular injection.", "LAIVs are sprayed into the nasal cavity.", "Vaccination recommendations vary by country.", "Some recommend vaccination for all people above a certain age, such as 6 months, whereas other countries recommendation is limited for high at risk groups, such as pregnant women, young children (excluding newborns), the elderly, people with chronic medical conditions, health care workers, people who come into contact with high-risk people, and people who transmit the virus easily.", "Young infants cannot receive flu vaccines for safety reasons, but they can inherit passive immunity from their mother if inactivated vaccines are administered to the mother during pregnancy.", "Influenza vaccination also helps to reduce the probability of reassortment.", "In general, influenza vaccines are only effective if there is an antigenic match between vaccine strains and circulating strains.", "Additionally, most commercially available flu vaccines are manufactured by propagation of influenza viruses in embryonated chicken eggs, taking 6–8 months.", "Flu seasons are different in the northern and southern hemisphere, so the WHO meets twice a year, one for each hemisphere, to discuss which strains should be included in flu vaccines based on observation from HA inhibition assays.", "Other manufacturing methods include an MDCK cell culture-based inactivated vaccine and a recombinant subunit vaccine manufactured from baculovirus overexpression in insect cells.", "Influenza can be prevented or reduced in severity by post-exposure prophylaxis with the antiviral drugs oseltamivir, which can be taken orally by those at least three months old, and zanamivir, which can be inhaled by those above seven years of age.", "Chemoprophylaxis is most useful for individuals at high-risk of developing complications and those who cannot receive the flu vaccine due to contraindications or lack of effectiveness.", "Post-exposure chemoprophylaxis is only recommended if oseltamivir is taken within 48 hours of contact with a confirmed or suspected influenza case and zanamivir within 36 hours.", "It is recommended that it be offered to people who have yet to receive a vaccine for the current flu season, who have been vaccinated less than two week since contact, if there is a significant mismatch between vaccine and circulating strains, or during an outbreak in a closed setting regardless of vaccination history.", "Hand hygiene is important in reducing the spread of influenza.", "This includes frequent hand washing with soap and water, using alcohol-based hand sanitizers, and not touching one's eyes, nose, and mouth with one's hands.", "Covering one's nose and mouth when coughing or sneezing is important.", "Other methods to limit influenza transmission include staying home when sick, avoiding contact with others until one day after symptoms end, and disinfecting surfaces likely to be contaminated by the virus, such as doorknobs.", "Health education through media and posters is often used to remind people of the aforementioned etiquette and hygiene.", "There is uncertainty about the use of masks since research thus far has not shown a significant reduction in seasonal influenza with mask usage.", "Likewise, the effectiveness of screening at points of entry into countries is not well researched.", "Social distancing measures such as school closures, avoiding contact with infected people via isolation or quarantine, and limiting mass gatherings may reduce transmission, but these measures are often expensive, unpopular, and difficult to implement.", "Consequently, the commonly recommended methods of infection control are respiratory etiquette, hand hygiene, and mask wearing, which are inexpensive and easy to perform.", "Pharmaceutical measures are effective but may not be available in the early stages of an outbreak.", "In health care settings, infected individuals may be cohorted or assigned to individual rooms.", "Protective clothing such as masks, gloves, and gowns is recommended when coming into contact with infected individuals if there is a risk of exposure to infected bodily fluids.", "Keeping patients in negative pressure rooms and avoiding aerosol-producing activities may help, but special air handling and ventilation systems are not considered necessary to prevent the spread of influenza in the air.", "In residential homes, new admissions may need to be closed until the spread of influenza is controlled.", "When discharging patients to care homes, it is important to take care if there is a known influenza outbreak.", "Since influenza viruses circulate in animals such as birds and pigs, prevention of transmission from these animals is important.", "Water treatment, indoor raising of animals, quarantining sick animals, vaccination, and biosecurity are the primary measures used.", "Placing poultry houses and piggeries on high ground away from high-density farms, backyard farms, live poultry markets, and bodies of water helps to minimize contact with wild birds.", "Closure of live poultry markets appears to the most effective measure and has shown to be effective at controlling the spread of H5N1, H7N9, and H9N2.", "Other biosecurity measures include cleaning and disinfecting facilities and vehicles, banning visits to poultry farms, not bringing birds intended for slaughter back to farms, changing clothes, disinfecting foot baths, and treating food and water.", "If live poultry markets are not closed, then \"clean days\" when unsold poultry is removed and facilities are disinfected and \"no carry-over\" policies to eliminate infectious material before new poultry arrive can be used to reduce the spread of influenza viruses.", "If a novel influenza viruses has breached the aforementioned biosecurity measures, then rapid detection to stamp it out via quarantining, decontamination, and culling may be necessary to prevent the virus from becoming endemic.", "Vaccines exist for avian H5, H7, and H9 subtypes that are used in some countries.", "In China, for example, vaccination of domestic birds against H7N9 successfully limited its spread, indicating that vaccination may be an effective strategy if used in combination with other measures to limit transmission.", "In pigs and horses, management of influenza is dependent on vaccination with biosecurity.", "Diagnosis based on symptoms is fairly accurate in otherwise healthy people during seasonal epidemics and should be suspected in cases of pneumonia, acute respiratory distress syndrome (ARDS), sepsis, or if encephalitis, myocarditis, or breaking down of muscle tissue occur.", "Because influenza is similar to other viral respiratory tract illnesses, laboratory diagnosis is necessary for confirmation.", "Common ways of collecting samples for testing include nasal and throat swabs.", "Samples may be taken from the lower respiratory tract if infection has cleared the upper but not lower respiratory tract.", "Influenza testing is recommended for anyone hospitalized with symptoms resembling influenza during flu season or who is connected to an influenza case.", "For severe cases, earlier diagnosis improves patient outcome.", "Diagnostic methods that can identify influenza include viral cultures, antibody- and antigen-detecting tests, and nucleic acid-based tests.", "Viruses can be grown in a culture of mammalian cells or embryonated eggs for 3–10 days to monitor cytopathic effect.", "Final confirmation can then be done via antibody staining, hemadsorption using red blood cells, or immunofluorescence microscopy.", "Shell vial cultures, which can identify infection via immunostaining before a cytopathic effect appears, are more sensitive than traditional cultures with results in 1–3 days.", "Cultures can be used to characterize novel viruses, observe sensitivity to antiviral drugs, and monitor antigenic drift, but they are relatively slow and require specialized skills and equipment.", "Serological assays can be used to detect an antibody response to influenza after natural infection or vaccination.", "Common serological assays include hemagglutination inhibition assays that detect HA-specific antibodies, virus neutralization assays that check whether antibodies have neutralized the virus, and enzyme-linked immunoabsorbant assays.", "These methods tend to be relatively inexpensive and fast but are less reliable than nucleic-acid based tests.", "Direct fluorescent or immunofluorescent antibody (DFA/IFA) tests involve staining respiratory epithelial cells in samples with fluorescently-labeled influenza-specific antibodies, followed by examination under a fluorescent microscope.", "They can differentiate between IAV and IBV but can't subtype IAV.", "Rapid influenza diagnostic tests (RIDTs) are a simple way of obtaining assay results, are low cost, and produce results quickly, at less than 30 minutes, so they are commonly used, but they can't distinguish between IAV and IBV or between IAV subtypes and are not as sensitive as nucleic-acid based tests.", "Nucleic acid-based tests (NATs) amplify and detect viral nucleic acid.", "Most of these tests take a few hours, but rapid molecular assays are as fast as RIDTs.", "Among NATs, reverse transcription polymerase chain reaction (RT-PCR) is the most traditional and considered the gold standard for diagnosing influenza because it is fast and can subtype IAV, but it is relatively expensive and more prone to false-positives than cultures.", "Other NATs that have been used include loop-mediated isothermal amplification-based assays, simple amplification-based assays, and nucleic acid sequence-based amplification.", "Nucleic acid sequencing methods can identify infection by obtaining the nucleic acid sequence of viral samples to identify the virus and antiviral drug resistance.", "The traditional method is Sanger sequencing, but it has been largely replaced by next-generation methods that have greater sequencing speed and throughput.", "Treatment of influenza in cases of mild or moderate illness is supportive and includes anti-fever medications such as acetaminophen and ibuprofen, adequate fluid intake to avoid dehydration, and resting at home.", "Cough drops and throat sprays may be beneficial for sore throat.", "It is recommended to avoid alcohol and tobacco use while sick with the flu.", "Aspirin is not recommended to treat influenza in children due to an elevated risk of developing Reye syndrome.", "Corticosteroids likewise are not recommended except when treating septic shock or an underlying medical condition, such as chronic obstructive pulmonary disease or asthma exacerbation, since they are associated with increased mortality.", "If a secondary bacterial infection occurs, then treatment with antibiotics may be necessary.", "Antiviral drugs are primarily used to treat severely ill patients, especially those with compromised immune systems.", "Antivirals are most effective when started in the first 48 hours after symptoms appear.", "Later administration may still be beneficial for those who have underlying immune defects, those with more severe symptoms, or those who have a higher risk of developing complications if these individuals are still shedding the virus.", "Antiviral treatment is also recommended if a person is hospitalized with suspected influenza instead of waiting for test results to return and if symptoms are worsening.", "Most antiviral drugs against influenza fall into two categories: neuraminidase (NA) inhibitors and M2 inhibitors.", "Baloxavir marboxil is a notable exception, which targets the endonuclease activity of the viral RNA polymerase and can be used as an alternative to NA and M2 inhibitors for IAV and IBV.", "NA inhibitors target the enzymatic activity of NA receptors, mimicking the binding of sialic acid in the active site of NA on IAV and IBV virions so that viral release from infected cells and the rate of viral replication are impaired.", "NA inhibitors include oseltamivir, which is consumed orally in a prodrug form and converted to its active form in the liver, and zanamivir, which is a powder that is inhaled nasally.", "Oseltamivir and zanamivir are effective for prophylaxis and post-exposure prophylaxis, and research overall indicates that NA inhibitors are effective at reducing rates of complications, hospitalization, and mortality and the duration of illness.", "Additionally, the earlier NA inhibitors are provided, the better the outcome, though late administration can still be beneficial in severe cases.", "Other NA inhibitors include laninamivir and peramivir, the latter of which can be used as an alternative to oseltamivir for people who cannot tolerate or absorb it.", "The adamantanes amantadine and rimantadine are orally administered drugs that block the influenza virus's M2 ion channel, preventing viral uncoating.", "These drugs are only functional against IAV but are no longer recommended for use because of widespread resistance to them among IAVs.", "Adamantane resistance first emerged in H3N2 in 2003, becoming worldwide by 2008.", "Oseltamivir resistance is no longer widespread because the 2009 pandemic H1N1 strain (H1N1 pdm09), which is resistant to adamantanes, seemingly replaced resistant strains in circulation.", "Since the 2009 pandemic, oseltamivir resistance has mainly been observed in patients undergoing therapy, especially the immunocompromised and young children.", "Oseltamivir resistance is usually reported in H1N1, but has been reported in H3N2 and IBVs less commonly.", "Because of this, oseltamivir is recommended as the first drug of choice for immunocompetent people, whereas for the immunocompromised, oseltamivir is recommended against H3N2 and IBV and zanamivir against H1N1 pdm09.", "Zanamivir resistance is observed less frequently, and resistance to peramivir and baloxavir marboxil is possible.", "In healthy individuals, influenza infection is usually self-limiting and rarely fatal.", "Symptoms usually last for 2–8 days.", "Influenza can cause people to miss work or school, and it is associated with decreased job performance and, in older adults, reduced independence.", "Fatigue and malaise may last for several weeks after recovery, and healthy adults may experience pulmonary abnormalities that can take several weeks to resolve.", "Complications and mortality primarily occur in high-risk populations and those who are hospitalized.", "Severe disease and mortality are usually attributable to pneumonia from the primary viral infection or a secondary bacterial infection, which can progress to ARDS.", "Other respiratory complications that may occur include sinusitis, bronchitis, bronchiolitis, excess fluid buildup in the lungs, and exacerbation of chronic bronchitis and asthma.", "Middle ear infection and croup may occur, most commonly in children.", "Secondary \"S. aureus\" infection has been observed, primarily in children, to cause toxic shock syndrome after influenza, with hypotension, fever, and reddening and peeling of the skin.", "Complications affecting the cardiovascular system are rare and include pericarditis, fulminant myocarditis with a fast, slow, or irregular heartbeat, and exacerbation of pre-existing cardiovascular disease.", "Inflammation or swelling of muscles accompanied by muscle tissue breaking down occurs rarely, usually in children, which presents as extreme tenderness and muscle pain in the legs and a reluctance to walk for 2–3 days.", "Influenza can affect pregnancy, including causing smaller neonatal size, increased risk of premature birth, and an increased risk of child death shortly before or after birth.", "Neurological complications have been associated with influenza on rare occasions, including aseptic meningitis, encephalitis, disseminated encephalomyelitis, transverse myelitis, and Guillain–Barré syndrome.", "Additionally, febrile seizures and Reye syndrome can occur, most commonly in children.", "Influenza-associated encephalopathy can occur directly from central nervous system infection from the presence of the virus in blood and presents as suddent onset of fever with convulsions, followed by rapid progression to coma.", "An atypical form of encephalitis called encephalitis lethargica, characterized by headache, drowsiness, and coma, may rarely occur sometime after infection.", "In survivors of influenza-associated encephalopathy, neurological defects may occur.", "Primarily in children, in severe cases the immune system may rarely dramatically overproduce white blood cells that release cytokines, causing severe inflammation.", "People who are at least 65 years of age, due to a weakened immune system from aging or a chronic illness, are a high-risk group for developing complications, as are children less than one year of age and children who have not been previously exposed to influenza viruses multiple times.", "Pregnant women are at an elevated risk, which increases by trimester and lasts up to two weeks after childbirth.", "Obesity, in particular a body mass index greater than 35–40, is associated with greater amounts of viral replication, increased severity of secondary bacterial infection, and reduced vaccination efficacy.", "People who have underlying health conditions are also considered at-risk, including those who have congenital or chronic heart problems or lung (e.g. asthma), kidney, liver, blood, neurological, or metabolic (e.g. diabetes) disorders, as are people who are immunocompromised from chemotherapy, asplenia, prolonged steroid treatment, splenic dysfunction, or HIV infection.", "Current or past tobacco use also places a person at risk.", "The role of genetics in influenza is not well researched, but it may be a factor in influenza mortality.", "Influenza is typically characterized by seasonal epidemics and sporadic pandemics.", "Most of the burden of influenza is a result of flu seasons caused by IAV and IBV.", "Among IAV subtypes, H1N1 and H3N2 currently circulate in humans and are responsible for seasonal influenza.", "Cases disproportionately occur in children, but most severe causes are among the elderly, the very young, and the immunocompromised.", "In a typical year, influenza viruses infect 5–15% of the global population, causing 3–5 million cases of severe illness annually and accounting for 290,000–650,000 deaths each year due to respiratory illness.", "5–10% of adults and 20–30% of children contract influenza each year.", "The reported number of influenza cases is usually much lower than the actual number of cases.", "During seasonal epidemics, it is estimated that about 80% of otherwise healthy people who have a cough or sore throat have the flu.", "Approximately 30–40% of people hospitalized for influenza develop pneumonia, and about 5% of all severe pneumonia cases in hospitals are due to influenza, which is also the most common cause of ARDS in adults.", "In children, influenza is one of the two most common causes of ARDS, the other being the respiratory syncytial virus.", "About 3–5% of children each year develop otitis media due to influenza.", "Adults who develop organ failure from influenza and children who have PIM scores and acute renal failure have higher rates of mortality.", "During seasonal influenza, mortality is concentrated in the very young and the elderly, whereas during flu pandemics, young adults are often affected at a high rate.", "In temperate regions, the number of influenza cases varies from season to season.", "Lower vitamin D levels, presumably due to less sunlight, lower humidity, lower temperature, and minor changes in virus proteins caused by antigenic drift contribute to annual epidemics that peak during the winter season.", "In the northern hemisphere, this is from October to May (more narrowly December to April), and in the southern hemisphere, this is from May to October (more narrowly June to September).", "There are therefore two distinct influenza seasons every year in temperate regions, one in the northern hemisphere and one in the southern hemisphere.", "In tropical and subtropical regions, seasonality is more complex and appears to be affected by various climatic factors such as minimum temperature, hours of sunshine, maximum rainfall, and high humidity.", "Influenza may therefore occur year-round in these regions.", "Influenza epidemics in modern times have the tendency to start in the eastern or southern hemisphere, with Asia being a key reservoir of influenza viruses.", "IAV and IBV co-circulate, so the two have the same patterns of transmission.", "The seasonality of ICV, however, is poorly understood.", "ICV infection is most common in children under the age of 2, and by adulthood most people have been exposed to it.", "ICV-associated hospitalization most commonly occurs in children under the age of 3 and is frequently accompanied by co-infection with another virus or a bacterium, which may increase the severity of disease.", "When considering all hospitalizations for respiratory illness among young children, ICV appears to account for only a small percentage of such cases.", "Large outbreaks of ICV infection can occur, so incidence varies significantly.", "Outbreaks of influenza caused by novel influenza viruses are common.", "Depending on the level of pre-existing immunity in the population, novel influenza viruses can spread rapidly and cause pandemics with millions of deaths.", "These pandemics, in contrast to seasonal influenza, are caused by antigenic shifts involving animal influenza viruses.", "To date, all known flu pandemics have been caused by IAVs, and they follow the same pattern of spreading from an origin point to the rest of the world over the course of multiple waves in a year.", "Pandemic strains tend to be associated with higher rates of pneumonia in otherwise healthy individuals.", "Generally after each influenza pandemic, the pandemic strain continues to circulate as the cause of seasonal influenza, replacing prior strains.", "From 1700 to 1889, influenza pandemics occurred about once every 50–60 years.", "Since then, pandemics have occurred about once every 10–50 years, so they may be getting more frequent over time.", "It is impossible to know when an influenza virus first infected humans or when the first influenza pandemic occurred.", "Possibly the first influenza epidemic occurred around 6,000 BC in China, and possible descriptions of influenza exist in Greek writings from the 5th century BC.", "In both 1173–1174 AD and 1387 AD, epidemics occurred across Europe that were named \"influenza\".", "Whether these epidemics and others were caused by influenza is unclear since there was no consistent naming pattern for epidemic respiratory diseases at that time, and \"influenza\" didn't become completely attached to respiratory disease until centuries later.", "Influenza may have been brought to the Americas as early as 1493, when an epidemic disease resembling influenza killed most of the population of the Antilles.", "The first convincing record of an influenza pandemic was chronicled in 1510; it began in East Asia before spreading to North Africa and then Europe.", "Following the pandemic, seasonal influenza occurred, with subsequent pandemics in 1557 and 1580.", "The flu pandemic in 1557 was potentially the first time influenza was connected to miscarriage and death of pregnant women.", "The 1580 flu pandemic originated in Asia during summer, spread to Africa, then Europe, and finally America.", "By the end of the 16th century, influenza was likely beginning to become understood as a specific, recognizable disease with epidemic and endemic forms.", "In 1648, it was discovered that horses also experience influenza.", "Influenza data after 1700 is more informative, so it is easier to identify flu pandemics after this point, each of which incrementally increased understanding of influenza.", "The first flu pandemic of the 18th century started in 1729 in Russia in spring, spreading worldwide over the course of three years with distinct waves, the later ones being more lethal.", "The second flu pandemic of the 18th century was in 1781–1782, starting in China in autumn.", "From this pandemic, influenza became associated with sudden outbreaks of febrile illness.", "The next flu pandemic was from 1830 to 1833, beginning in China in winter.", "This pandemic had a high attack rate, but the mortality rate was low.", "A minor influenza pandemic occurred from 1847 to 1851 at the same time as the third cholera pandemic and was the first flu pandemic to occur with vital statistics being recorded, so influenza mortality was clearly recorded for the first time.", "Highly pathogenic avian influenza was recognized in 1878 and was soon linked to transmission to humans.", "By the time of the 1889 pandemic, which may have been caused by an H2N2 strain, the flu had become an easily recognizable disease.", "Initially, the microbial agent responsible for influenza was incorrently identified in 1892 by R. F. J. Pfeiffer as the bacteria species \"Haemophilus influenzae\", which retains \"influenza\" in its name.", "In the following years, the field of virology began to form as viruses were identified as the cause of many diseases.", "From 1901 to 1903, Italian and Austrian researchers were able to show that avian influenza, then called \"fowl plague\", was caused by a microscopic agent smaller than bacteria by using filters with pores too small for bacteria to pass through.", "The fundamental differences between viruses and bacteria, however, were not yet fully understood.", "From 1918 to 1920, the Spanish flu pandemic became the most devastating influenza pandemic and one of the deadliest pandemics in history.", "The pandemic, probably caused by H1N1, likely began in the USA before spreading worldwide by soldiers during and after the First World War.", "The initial wave in the first half of 1918 was relatively minor and resembled past flu pandemics, but the second wave later that year had a much higher mortality rate, accounting for most deaths.", "A third wave with lower mortality occurred in many places a few months after the second.", "By the end of 1920, it is estimated that about a third to half of all people in the world had been infected, with tens of millions of deaths, disproportionately young adults.", "During the 1918 pandemic, the respiratory route of transmission was clearly identified and influenza was shown to be caused by a \"filter passer\", not a bacterium, but there remained a lack of agreement about influenza's cause for another decade and research on influenza declined.", "After the pandemic, H1N1 circulated in humans in seasonal form up until the next pandemic.", "In 1931, Richard Shope published three papers identifying a virus as the cause of swine influenza, a then newly recognized disease among pigs that was first characterized during the second wave of the 1918 pandemic.", "Shope's research reinvigorated research on human influenza, and many advances in virology, serology, immunology, experimental animal models, vaccinology, and immunotherapy have since arisen from influenza research.", "Just two years after influenza viruses were discovered, in 1933, IAV was identified as the agent responsible for human influenza.", "Subtypes of IAV were discovered throughout the 1930s, and IBV was discovered in 1940.", "During the Second World War, the US government worked on developing inactivated vaccines for influenza, resulting in the first influenza vaccine being licensed in 1945 in the United States.", "ICV was discovered two years later in 1947.", "In 1955, avian influenza was confirmed to be caused by IAV.", "Four influenza pandemics have occurred since WWII, each less severe than the 1918 pandemic.", "The first of these was the Asian flu from 1957 to 1958, caused by an H2N2 strain and beginning in China's Yunnan province.", "The number of deaths probably exceeded one million, mostly among the very young and very old.", "Notably, the 1957 pandemic was the first flu pandemic to occur in the presence of a global surveillance system and laboratories able to study the novel influenza virus.", "After the pandemic, H2N2 was the IAV subtype responsible for seasonal influenza.", "The first antiviral drug against influenza, amantadine, was approved for use in 1966, with additional antiviral drugs being used since the 1990s.", "In 1968, H3N2 was introduced into humans as a result of a reassortment between an avian H3N2 strain and an H2N2 strain that was circulating in humans.", "The novel H3N2 strain first emerged in Hong Kong and spread worldwide, causing the Hong Kong flu pandemic, which resulted in 500,000–2,000,000 deaths.", "This was the first pandemic to spread significantly by air travel.", "H2N2 and H3N2 co-circulated after the pandemic until 1971 when H2N2 waned in prevalence and was completely replaced by H3N2.", "In 1977, H1N1 reemerged in humans, possibly after it was released from a freezer in a laboratory accident, and caused a pseudo-pandemic.", "Whether the 1977 \"pandemic\" deserves to be included in the natural history of flu pandemics is debatable.", "This H1N1 strain was antigenically similar to the H1N1 strains that circulated prior to 1957.", "Since 1977, both H1N1 and H3N2 have circulated in humans as part of seasonal influenza.", "In 1980, the current classification system used to subtype influenza viruses was introduced.", "At some point, IBV diverged into two lineages, named the B/Victoria-like and B/Yamagata-like lineages, both of which have been circulating in humans since 1983.", "In 1996, HPAI H5N1 was detected in Guangdong, China and a year later emerged in poultry in Hong Kong, gradually spreading worldwide from there.", "A small H5N1 outbreak in humans in Hong Kong occurred then, and sporadic human cases have occurred since 1997, carrying a high case fatality rate.", "The most recent flu pandemic was the 2009 swine flu pandemic, which originated in Mexico and resulted in hundreds of thousands of deaths.", "It was caused by a novel H1N1 strain that was a reassortment of human, swine, and avian influenza viruses.", "The 2009 pandemic had the effect of replacing prior H1N1 strains in circulation with the novel strain but not any other influenza viruses.", "Consequently, H1N1, H3N2, and both IBV lineages have been in circulation in seasonal form since the 2009 pandemic.", "In 2011, IDV was discovered in pigs in Oklahoma, USA, and cattle were later identified as the primary reservoir of IDV.", "In the same year, avian H7N9 was detected in China and began to cause human infections in 2013, starting in Shanghai and Anhui and remaining mostly in China.", "HPAI H7N9 emerged sometime in 2016 and has occasionally infected humans incidentally.", "Other AIVs have less commonly infected humans since the 1990s, including H5N6, H6N1, H7N2-4, H7N7, and H10N7-8, and HPAI H subtypes such as H5N1-3, H5N5-6, and H5N8 have begun to spread throughout much of the world since the 2010s.", "Future flu pandemics, which may be caused by an influenza virus of avian origin, are viewed as almost inevitable, and increased globalization has made it easier for novel viruses to spread, so there are continual efforts to prepare for future pandemics and improve the prevention and treatment of influenza.", "The word \"influenza\" comes from the Italian word \"influenza\", from medieval Latin \"influentia\", originally meaning \"visitation\" or \"influence\".", "Terms such as \"influenza di freddo\", meaning \"influence of the cold\", and \"influenza di stelle\", meaning \"influence of the stars\" are attested from the 14th century.", "The latter referred to the disease's cause, which at the time was ascribed by some to unfavorable astrological conditions.", "As early as 1504, \"influenza\" began to mean a \"visitation\" or \"outbreak\" of any disease affecting many people in a single place at once.", "During an outbreak of influenza in 1743 that started in Italy and spread throughout Europe, the word reached the English language and was anglicized in pronunciation.", "Since the mid-1800s, \"influenza\" has also been used to refer to severe colds.", "The shortened form of the word, \"(the) flu\", is first attested in 1839 as \"flue\" with the spelling \"flu\" first attested in 1893.", "Other names that have been used for influenza include \"epidemic catarrh\", \"la grippe\" from French, \"sweating sickness\", and, especially when referring to the 1918 pandemic strain, \"Spanish fever\".", "Influenza research is wide-ranging and includes efforts to understand how influenza viruses enter hosts, the relationship between influenza viruses and bacteria, how influenza symptoms progress, and what make some influenza viruses deadlier than others.", "Non-structural proteins encoded by influenza viruses are periodically discovered and their functions are continually under research.", "Past pandemics, and especially the 1918 pandemic, are the subject of much research to understand flu pandemics.", "As part of pandemic preparedness, the Global Influenza Surveillance and Response System is a global network of laboratories that monitors influenza transmission and epidemiology.", "Additional areas of research include ways to improve the diagnosis, treatment, and prevention of influenza.", "Existing diagnostic methods have a variety of limitations coupled with their advantages.", "For example, NATs have high sensitivity and specificity but are impractical in under-resourced regions due to their high cost, complexity, maintenance, and training required.", "Low-cost, portable RIDTs can rapidly diagnose influenza but have highly variable sensitivity and are unable to subtype IAV.", "As a result of these limitations and others, research into new diagnostic methods revolves around producing new methods that are cost-effective, less labor-intensive, and less complex than existing methods while also being able to differentiate influenza species and IAV subtypes.", "One approach in development are lab-on-a-chips, which are diagnostic devices that make use of a variety of diagnostic tests, such as RT-PCR and serological assays, in microchip form.", "These chips have many potential advantages, including high reaction efficiency, low energy consumption, and low waste generation.", "New antiviral drugs are also in development due to the elimination of adamantines as viable drugs and concerns over oseltamivir resistance.", "These include: NA inhibitors that can be injected intravenously, such as intravenous formulations of zanamivir; favipiravir, which is a polymerase inhibitor used against several RNA viruses; pimodivir, which prevents cap-binding required during viral transcription; and nitazoxanide, which inhibits HA maturation.", "Reducing excess inflammation in the respiratory tract is also subject to much research since this is one of the primary mechanisms of influenza pathology.", "Other forms of therapy in development include monoclonal and polyclonal antibodies that target viral proteins, convalescent plasma, different approaches to modify the host antiviral response, and stem cell-based therapies to repair lung damage.", "Much research on LAIVs focuses on identifying genome sequences that can be deleted to create harmless influenza viruses in vaccines that still confer immunity.", "The high variability and rapid evolution of influenza virus antigens, however, is a major obstacle in developing effective vaccines.", "Furthermore, it is hard to predict which strains will be in circulation during the next flu season, manufacturing a sufficient quantity of flu vaccines for the next season is difficult, LAIVs have limited efficacy, and repeated annual vaccination potentially has diminished efficacy.", "For these reasons, \"broadly-reactive\" or \"universal\" flu vaccines are being researched that can provide protection against many or all influenza viruses.", "Approaches to develop such a vaccine include HA stalk-based methods such as chimeras that have the same stalk but different heads, HA head-based methods such as computationally optimized broadly neutralizing antigens, anti-idiotypic antibodies, and vaccines to elicit immune responses to highly conserved viral proteins.", "mRNA vaccines to provide protection against influenza are also under research.", "Aquatic birds such as ducks, geese, shorebirds, and gulls are the primary reservoir of IAVs.", "In birds, AIVs may be either low pathogenic avian influenza (LPAI) viruses that produce little to no symptoms or highly pathogenic avian influenza (HPAI) viruses that cause severe illness.", "Symptoms of HPAI infection include lack of energy and appetite, decreased egg production, soft-shelled or misshapen eggs, swelling of the head, comb, wattles, and hocks, purple discoloration of wattles, combs, and legs, nasal discharge, coughing, sneezing, incoordination, and diarrhea.", "Birds infected with an HPAI virus may also die suddenly without any signs of infection.", "The distinction between LPAI and HPAI can generally be made based on how lethal an AIV is to chickens.", "At the genetic level, an AIV can be usually be identified as an HPAI virus if it has a multibasic cleavage site in the HA protein, which contains additional residues in the HA gene.", "Most AIVs are LPAI.", "Notable HPAI viruses include HPAI H5N1 and HPAI H7N9.", "HPAI viruses have been a major disease burden in the 21st century, resulting in the death of large numbers of birds.", "In H7N9's case, some circulating strains were originally LPAI but became HPAI by acquiring the HA multibasic cleavage site.", "Avian H9N2 is also of concern because although it is LPAI, it is a common donor of genes to H5N1 and H7N9 during reassortment.", "Migratory birds can spread influenza across long distances.", "An example of this was when an H5N1 strain in 2005 infected birds at Qinghai Lake, China, which is a stopover and breeding site for many migratory birds, subsequently spreading the virus to more than 20 countries across Asia, Europe, and the Middle East.", "AIVs can be transmitted from wild birds to domestic free-range ducks and in turn to poultry through contaminated water, aerosols, and fomites.", "Ducks therefore act as key intermediates between wild and domestic birds.", "Transmission to poultry typically occurs in backyard farming and live animal markets where multiple species interact with each other.", "From there, AIVs can spread to poultry farms in the absence of adequate biosecurity.", "Among poultry, HPAI transmission occurs through aerosols and contaminated feces, cages, feed, and dead animals.", "Back-transmission of HPAI viruses from poultry to wild birds has occurred and is implicated in mass die-offs and intercontinental spread.", "AIVs have occasionally infected humans through aerosols, fomites, and contaminated water.", "Direction transmission from wild birds is rare.", "Instead, most transmission involves domestic poultry, mainly chickens, ducks, and geese but also a variety of other birds such as guinea fowl, partridge, pheasants, and quails.", "The primary risk factor for infection with AIVs is exposure to birds in farms and live poultry markets.", "Typically, infection with an AIV has an incubation period of 3–5 days but can be up to 9 days.", "H5N1 and H7N9 cause severe lower respiratory tract illness, whereas other AIVs such as H9N2 cause a more mild upper respiratory tract illness, commonly with conjunctivitis.", "Limited transmission of avian H2, H5-7, H9, and H10 subtypes from one person to another through respiratory droplets, aerosols, and fomites has occurred, but sustained human-to-human transmission of AIVs has not occurred.", "Before 2013, H5N1 was the most common AIV to infect humans.", "Since then, H7N9 has been responsible for most human cases.", "Influenza in pigs is a respiratory disease similar to influenza in humans and is found worldwide.", "Asymptomatic infections are common.", "Symptoms typically appear 1–3 days after infection and include fever, lethargy, anorexia, weight loss, labored breathing, coughing, sneezing, and nasal discharge.", "In sows, pregnancy may be aborted.", "Complications include secondary infections and potentially fatal bronchopneumonia.", "Pigs become contagious within a day of infection and typically spread the virus for 7–10 days, which can spread rapidly within a herd.", "Pigs usually recover from infection within 3–7 days after symptoms appear.", "Prevention and control measures include inactivated vaccines and culling infected herds.", "The influenza viruses usually responsible for swine flu are IAV subtypes H1N1, H1N2, and H3N2.", "Some IAVs can be transmitted via aerosols from pigs to humans and vice versa.", "Furthermore, pigs, along with bats and quails, are recognized as a mixing vessel of influenza viruses because they have both α-2,3 and α-2,6 sialic acid receptors in their respiratory tract.", "Because of that, both avian and mammalian influenza viruses can infect pigs.", "If co-infection occurs, then reassortment is possible.", "A notable example of this was the reassortment of a swine, avian, and human influenza virus in 2009, resulting in a novel H1N1 strain that caused the 2009 flu pandemic.", "Spillover events from humans to pigs, however, appear to be more common than from pigs to humans.", "Influenza viruses have been found in many other animals, including cattle, horses, dogs, cats, and marine mammals.", "Nearly all IAVs are apparently descended from ancestral viruses in birds.", "The exception are bat influenza-like viruses, which have an uncertain origin.", "These bat viruses have HA and NA subtypes H17, H18, N10, and N11.", "H17N10 and H18N11 are unable to reassort with other IAVs, but they are still able to replicate in other mammals.", "AIVs sometimes crossover into mammals.", "For example, in late 2016 to early 2017, an avian H7N2 strain was found to be infecting cats in New York.", "Equine IAVs include H7N7 and two lineages of H3N8.", "H7N7, however, has not been detected in horses since the late 1970s, so it may have become extinct in horses.", "H3N8 in equines spreads via aerosols and causes respiratory illness.", "Equine H3N8 perferentially binds to α-2,3 sialic acids, so horses are usually considered dead-end hosts, but transmission to dogs and camels has occurred, raising concerns that horses may be mixing vessels for reassortment.", "In canines, the only IAVs in circulation are equine-derived H3N8 and avian-derived H3N2.", "Canine H3N8 has not been observed to reassort with other subtypes.", "H3N2 has a much broader host range and can reassort with H1N1 and H5N1.", "An isolated case of H6N1 likely from a chicken was found infecting a dog, so other AIVs may emerge in canines.", "Other mammals to be infected by IAVs include H7N7 and H4N5 in seals, H1N3 in whales, and H10N4 and H3N2 in minks.", "Various mutations have been identified that are associated with AIVs adapting to mammals.", "Since HA proteins vary in which sialic acids they bind to, mutations in the HA receptor binding site can allow AIVs to infect mammals.", "Other mutations include mutations affecting which sialic acids NA proteins cleave and a mutation in the PB2 polymerase subunit that improves tolerance of lower temperatures in mammalian respiratory tracts and enhances RNP assembly by stabilizing NP and PB2 binding.", "IBV is mainly found in humans but has also been detected in pigs, dogs, horses, and seals.", "Likewise, ICV primarily infects humans but has been observed in pigs, dogs, cattle, and dromedary camels.", "IDV causes an influenza-like illness in pigs but its impact in its natural reservoir, cattle, is relatively unknown.", "It may cause respiratory disease resembling human influenza on its own, or it may be part of a bovine respiratory disease (BRD) complex with other pathogens during co-infection.", "BRD is a concern for the cattle industry, so IDV's possible involvement in BRD has led to research on vaccines for cattle that can provide protection against IDV.", "Two antigenic lineages are in circulation: D/swine/Oklahoma/1334/2011 (D/OK) and D/bovine/Oklahoma/660/2013 (D/660)." ]

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[ "Influenza, commonly known as \"the flu\", is an infectious disease caused by \"influenza viruses\".", "Five flu pandemics have occurred since 1900: the Spanish flu in 1918–1920, which was the most severe flu pandemic, the Asian flu in 1957, the Hong Kong flu in 1968, the Russian flu in 1977, and the swine flu pandemic in 2009." ]

[ "The time between exposure to the virus and development of symptoms, called the incubation period, is 1–4 days, most commonly 1–2 days.", "Many infections, however, are asymptomatic.", "The onset of symptoms is sudden, and initial symptoms are predominately non-specific, including fever, chills, headaches, muscle pain or aching, a feeling of discomfort, loss of appetite, lack of energy/fatigue, and confusion.", "These symptoms are usually accompanied by respiratory symptoms such as a dry cough, sore or dry throat, hoarse voice, and a stuffy or runny nose.", "Coughing is the most common symptom.", "Gastrointestinal symptoms may also occur, including nausea, vomiting, diarrhea, and gastroenteritis, especially in children.", "The standard influenza symptoms typically last for 2–8 days.", "A 2021 study suggests influenza can cause long lasting symptoms in a similar way to long COVID.\nSymptomatic infections are usually mild and limited to the upper respiratory tract, but progression to pneumonia is relatively common.", "Pneumonia may be caused by the primary viral infection or by a secondary bacterial infection.", "Primary pneumonia is characterized by rapid progression of fever, cough, labored breathing, and low oxygen levels that cause bluish skin.", "It is especially common among those who have an underlying cardiovascular disease such as rheumatic heart disease.", "Secondary pneumonia typically has a period of improvement in symptoms for 1–3 weeks followed by recurrent fever, sputum production, and fluid buildup in the lungs, but can also occur just a few days after influenza symptoms appear.", "About a third of primary pneumonia cases are followed by secondary pneumonia, which is most frequently caused by the bacteria \"Streptococcus pneumoniae\" and \"Staphylococcus aureus\".", "Influenza viruses comprise four species.", "Each of the four species is the sole member of its own genus, and the four influenza genera comprise four of the seven genera in the family \"Orthomyxoviridae\".", "They are:\n\n\nIAV is responsible for most cases of severe illness as well as seasonal epidemics and occasional pandemics.", "It infects people of all ages but tends to disproportionately cause severe illness in the elderly, the very young, and those who have chronic health issues.", "Birds are the primary reservoir of IAV, especially aquatic birds such as ducks, geese, shorebirds, and gulls, but the virus also circulates among mammals, including pigs, horses, and marine mammals.", "IAV is classified into subtypes based on the viral proteins haemagglutinin (H) and neuraminidase (N).", "As of 2019, 18 H subtypes and 11 N subtypes have been identified.", "Most potential combinations have been reported in birds, but H17-18 and N10-11 have only been found in bats.", "Only H subtypes H1-3 and N subtypes N1-2 are known to have circulated in humans, the current IAV subtypes in circulation being H1N1 and H3N2.", "IAVs can be classified more specifically to also include natural host species, geographical origin, year of isolation, and strain number, such as H1N1/A/duck/Alberta/35/76.", "IBV mainly infects humans but has been identified in seals, horses, dogs, and pigs.", "IBV does not have subtypes like IAV but has two antigenically distinct lineages, termed the B/Victoria/2/1987-like and B/Yamagata/16/1988-like lineages, or simply (B/)Victoria(-like) and (B/)Yamagata(-like).", "Both lineages are in circulation in humans, disproportionately affecting children.", "IBVs contribute to seasonal epidemics alongside IAVs but have never been associated with a pandemic.", "ICV, like IBV, is primarily found in humans, though it also has been detected in pigs, feral dogs, dromedary camels, cattle, and dogs.", "ICV infection primarily affects children and is usually asymptomatic or has mild cold-like symptoms, though more severe symptoms such as gastroenteritis and pneumonia can occur.", "Unlike IAV and IBV, ICV has not been a major focus of research pertaining to antiviral drugs, vaccines, and other measures against influenza.", "ICV is subclassified into six genetic/antigenic lineages.", "IDV has been isolated from pigs and cattle, the latter being the natural reservoir.", "Infection has also been observed in humans, horses, dromedary camels, and small ruminants such as goats and sheep.", "IDV is distantly related to ICV.", "While cattle workers have occasionally tested positive to prior IDV infection, it is not known to cause disease in humans.", "ICV and IDV experience a slower rate of antigenic evolution than IAV and IBV.", "Because of this antigenic stability, relatively few novel lineages emerge.", "Influenza viruses have a negative-sense, single-stranded RNA genome that is segmented.", "The negative sense of the genome means it can be used as a template to synthesize messenger RNA (mRNA).", "IAV and IBV have eight genome segments that encode 10 major proteins.", "ICV and IDV have seven genome segments that encode nine major proteins.", "Three segments encode three subunits of an RNA-dependent RNA polymerase (RdRp) complex: PB1, a transcriptase, PB2, which recognizes 5' caps, and PA (P3 for ICV and IDV), an endonuclease.", "The matrix protein (M1) and membrane protein (M2) share a segment, as do the non-structural protein (NS1) and the nuclear export protein (NEP).", "For IAV and IBV, hemagglutinin (HA) and neuraminidase (NA) are encoded on one segment each, whereas ICV and IDV encode a hemagglutinin-esterase fusion (HEF) protein on one segment that merges the functions of HA and NA.", "The final genome segment encodes the viral nucleoprotein (NP).", "Influenza viruses also encode various accessory proteins, such as PB1-F2 and PA-X, that are expressed through alternative open reading frames and which are important in host defense suppression, virulence, and pathogenicity.", "The virus particle, called a virion, is pleomorphic and varies between being filamentous, bacilliform, or spherical in shape.", "Clinical isolates tend to be pleomorphic, whereas strains adapted to laboratory growth typically produce spherical virions.", "Filamentous virions are about 250 nanometers (nm) by 80 nm, bacilliform 120–250 by 95 nm, and spherical 120 nm in diameter.", "The virion consists of each segment of the genome bound to nucleoproteins in separate ribonucleoprotein (RNP) complexes for each segment, all of which are surrounded by a lipid bilayer membrane called the viral envelope.", "There is a copy of the RdRp, all subunits included, bound to each RNP.", "The envelope is reinforced structurally by matrix proteins on the interior that enclose the RNPs, and the envelope contains HA and NA (or HEF) proteins extending outward from the exterior surface of the envelope.", "HA and HEF proteins have a distinct \"head\" and \"stalk\" structure.", "M2 proteins form proton ion channels through the viral envelope that are required for viral entry and exit.", "IBVs contain a surface protein named NB that is anchored in the envelope, but its function is unknown.", "The viral life cycle begins by binding to a target cell.", "Binding is mediated by the viral HA proteins on the surface of the evelope, which bind to cells that contain sialic acid receptors on the surface of the cell membrane.", "For N1 subtypes with the \"G147R\" mutation and N2 subtypes, the NA protein can initiate entry.", "Prior to binding, NA proteins promote access to target cells by degrading mucous, which helps to remove extracellular decoy receptors that would impede access to target cells.", "After binding, the virus is internalized into the cell by an endosome that contains the virion inside it.", "The endosome is acidified by cellular vATPase to have lower pH, which triggers a conformational change in HA that allows fusion of the viral envelope with the endosomal membrane.", "At the same time, hydrogen ions diffuse into the virion through M2 ion channels, disrupting internal protein-protein interactions to release RNPs into the host cell's cytosol.", "The M1 protein shell surrounding RNPs is degraded, fully uncoating RNPs in the cytosol.", "RNPs are then imported into the nucleus with the help of viral localization signals.", "There, the viral RNA polymerase transcribes mRNA using the genomic negative-sense strand as a template.", "The polymerase snatches 5' caps for viral mRNA from cellular RNA to prime mRNA synthesis and the 3'-end of mRNA is polyadenylated at the end of transcription.", "Once viral mRNA is transcribed, it is exported out of the nucleus and translated by host ribosomes in a cap-dependent manner to synthesize viral proteins.", "RdRp also synthesizes complementary positive-sense strands of the viral genome in a complementary RNP complex which are then used as templates by viral polymerases to synthesize copies of the negative-sense genome.", "During these processes, RdRps of avian influenza viruses (AIVs) function optimally at a higher temperature than mammalian influenza viruses.", "Newly synthesized viral polymerase subunits and NP proteins are imported to the nucleus to further increase the rate of viral replication and form RNPs.", "HA, NA, and M2 proteins are trafficked with the aid of M1 and NEP proteins to the cell membrane through the Golgi apparatus and inserted into the cell's membrane.", "Viral non-structural proteins including NS1, PB1-F2, and PA-X regulate host cellular processes to disable antiviral responses.", "PB1-F2 aso interacts with PB1 to keep polymerases in the nucleus longer.", "M1 and NEP proteins localize to the nucleus during the later stages of infection, bind to viral RNPs and mediate their export to the cytoplasm where they migrate to the cell membrane with the aid of recycled endosomes and are bundled into the segments of the genome.", "Progenic viruses leave the cell by budding from the cell membrane, which is initiated by the accumulation of M1 proteins at the cytoplasmic side of the membrane.", "The viral genome is incorporated inside a viral envelope derived from portions of the cell membrane that have HA, NA, and M2 proteins.", "At the end of budding, HA proteins remain attached to cellular sialic acid until they are cleaved by the sialidase activity of NA proteins.", "The virion is then released from the cell.", "The sialidase activity of NA also cleaves any sialic acid residues from the viral surface, which helps prevent newly assembled viruses from aggregating near the cell surface and improving infectivity.", "Similar to other aspects of influenza replication, optimal NA activity is temperature- and pH-dependent.", "Ultimately, presence of large quantities of viral RNA in the cell triggers apoptosis, i.e. programmed cell death, which is initiated by cellular factors to restrict viral replication.", "Two key processes that influenza viruses evolve through are antigenic drift and antigenic shift.", "Antigenic drift is when an influenza virus's antigens change due to the gradual accumulation of mutations in the antigen's (HA or NA) gene.", "This can occur in response to evolutionary pressure exerted by the host immune response.", "Antigenic drift is especially common for the HA protein, in which just a few amino acid changes in the head region can constitute antigenic drift.", "The result is the production of novel strains that can evade pre-existing antibody-mediated immunity.", "Antigenic drift occurs in all influenza species but is slower in B than A and slowest in C and D. Antigenic drift is a major cause of seasonal influenza, and requires that flu vaccines be updated annually.", "HA is the main component of inactivated vaccines, so surveillance monitors antigenic drift of this antigen among circulating strains.", "Antigenic evolution of influenza viruses of humans appears to be faster than influenza viruses in swine and equines.", "In wild birds, within-subtype antigenic variation appears to be limited but has been observed in poultry.", "Antigenic shift is a sudden, drastic change in an influenza virus's antigen, usually HA.", "During antigenic shift, antigenically different strains that infect the same cell can reassort genome segments with each other, producing hybrid progeny.", "Since all influenza viruses have segmented genomes, all are capable of reassortment.", "Antigenic shift, however, only occurs among influenza viruses of the same genus and most commonly occurs among IAVs.", "In particular, reassortment is very common in AIVs, creating a large diversity of influenza viruses in birds, but is uncommon in human, equine, and canine lineages.", "Pigs, bats, and quails have receptors for both mammalian and avian IAVs, so they are potential \"mixing vessels\" for reassortment.", "If an animal strain reassorts with a human strain, then a novel strain can emerge that is capable of human-to-human transmission.", "This has caused pandemics, but only a limited number have occurred, so it is difficult to predict when the next will happen.", "People who are infected can transmit influenza viruses through breathing, talking, coughing, and sneezing, which spread respiratory droplets and aerosols that contain virus particles into the air.", "A person susceptible to infection can then contract influenza by coming into contact with these particles.", "Respiratory droplets are relatively large and travel less than two meters before falling onto nearby surfaces.", "Aerosols are smaller and remain suspended in the air longer, so they take longer to settle and can travel further than respiratory droplets.", "Inhalation of aerosols can lead to infection, but most transmission is in the area about two meters around an infected person via respiratory droplets that come into contact with mucosa of the upper respiratory tract.", "Transmission through contact with a person, bodily fluids, or intermediate objects (fomites) can also occur, such as through contaminated hands and surfaces since influenza viruses can survive for hours on non-porous surfaces.", "If one's hands are contaminated, then touching one's face can cause infection.", "Influenza is usually transmissible from one day before the onset of symptoms to 5–7 days after.", "In healthy adults, the virus is shed for up to 3–5 days.", "In children and the immunocompromised, the virus may be transmissible for several weeks.", "Children ages 2–17 are considered to be the primary and most efficient spreaders of influenza.", "Children who have not had multiple prior exposures to influenza viruses shed the virus at greater quantities and for a longer duration than other children.", "People who are at risk of exposure to influenza include health care workers, social care workers, and those who live with or care for people vulnerable to influenza.", "In long-term care facilities, the flu can spread rapidly after it is introduced.", "A variety of factors likely encourage influenza transmission, including lower temperature, lower absolute and relative humidity, less ultraviolet radiation from the Sun, and crowding.", "Influenza viruses that infect the upper respiratory tract like H1N1 tend to be more mild but more transmissible, whereas those that infect the lower respiratory tract like H5N1 tend to cause more severe illness but are less contagious.", "In humans, influenza viruses first cause infection by infecting epithelial cells in the respiratory tract.", "Illness during infection is primarily the result of lung inflammation and compromise caused by epithelial cell infection and death, combined with inflammation caused by the immune system's response to infection.", "Non-respiratory organs can become involved, but the mechanisms by which influenza is involved in these cases are unknown.", "Severe respiratory illness can be caused by multiple, non-exclusive mechanisms, including obstruction of the airways, loss of alveolar structure, loss of lung epithelial integrity due to epithelial cell infection and death, and degradation of the extracellular matrix that maintains lung structure.", "In particular, alveolar cell infection appears to drive severe symptoms since this results in impaired gas exchange and enables viruses to infect endothelial cells, which produce large quantities of pro-inflammatory cytokines.", "Pneumonia caused by influenza viruses is characterized by high levels of viral replication in the lower respiratory tract, accompanied by a strong pro-inflammatory response called a cytokine storm.", "Infection with H5N1 or H7N9 especially produces high levels of pro-inflammatory cytokines.", "In bacterial infections, early depletion of macrophages during influenza creates a favorable environment in the lungs for bacterial growth since these white blood cells are important in responding to bacterial infection.", "Host mechanisms to encourage tissue repair may inadvertently allow bacterial infection.", "Infection also induces production of systemic glucocorticoids that can reduce inflammation to preserve tissue integrity but allow increased bacterial growth.", "The pathophysiology of influenza is significantly influenced by which receptors influenza viruses bind to during entry into cells.", "Mammalian influenza viruses preferentially bind to sialic acids connected to the rest of the oligosaccharide by an α-2,6 link, most commonly found in various respiratory cells, such as respiratory and retinal epithelial cells.", "AIVs prefer sialic acids with an α-2,3 linkage, which are most common in birds in gastrointestinal epithelial cells and in humans in the lower respiratory tract.", "Furthermore, cleavage of the HA protein into HA, the binding subunit, and HA, the fusion subunit, is performed by different proteases, affecting which cells can be infected.", "For mammalian influenza viruses and low pathogenic AIVs, cleavage is extracellular, which limits infection to cells that have the appropriate proteases, whereas for highly pathogenic AIVs, cleavage is intracellular and performed by ubiquitous proteases, which allows for infection of a greater variety of cells, thereby contributing to more severe disease.", "Cells possess sensors to detect viral RNA, which can then induce interferon production.", "Interferons mediate expression of antiviral proteins and proteins that recruit immune cells to the infection site, and they also notify nearby uninfected cells of infection.", "Some infected cells release pro-inflammatory cytokines that recruit immune cells to the site of infection.", "Immune cells control viral infection by killing infected cells and phagocytizing viral particles and apoptotic cells.", "An exacerbated immune response, however, can harm the host organism through a cytokine storm.", "To counter the immune response, influenza viruses encode various non-structural proteins, including NS1, NEP, PB1-F2, and PA-X, that are involved in curtailing the host immune response by suppressing interferon production and host gene expression.", "B cells, a type of white blood cell, produce antibodies that bind to influenza antigens HA and NA (or HEF) and other proteins to a lesser degree.", "Once bound to these proteins, antibodies block virions from binding to cellular receptors, neutralizing the virus.", "In humans, a sizeable antibody response occurs ~1 week after viral exposure.", "This antibody response is typically robust and long-lasting, especially for ICV and IDV.", "In other words, people exposed to a certain strain in childhood still possess antibodies to that strain at a reasonable level later in life, which can provide some protection to related strains.", "There is, however, an \"original antigenic sin\", in which the first HA subtype a person is exposed to influences the antibody-based immune response to future infections and vaccines.", "Annual vaccination is the primary and most effective way to prevent influenza and influenza-associated complications, especially for high-risk groups.", "Vaccines against the flu are trivalent or quadrivalent, providing protection against an H1N1 strain, an H3N2 strain, and one or two IBV strains corresponding to the two IBV lineages.", "Two types of vaccines are in use: inactivated vaccines that contain \"killed\" (i.e. inactivated) viruses and live attenuated influenza vaccines (LAIVs) that contain weakened viruses.", "There are three types of inactivated vaccines: whole virus, split virus, in which the virus is disrupted by a detergent, and subunit, which only contains the viral antigens HA and NA.", "Most flu vaccines are inactivated and administered via intramuscular injection.", "LAIVs are sprayed into the nasal cavity.", "Vaccination recommendations vary by country.", "Some recommend vaccination for all people above a certain age, such as 6 months, whereas other countries recommendation is limited for high at risk groups, such as pregnant women, young children (excluding newborns), the elderly, people with chronic medical conditions, health care workers, people who come into contact with high-risk people, and people who transmit the virus easily.", "Young infants cannot receive flu vaccines for safety reasons, but they can inherit passive immunity from their mother if inactivated vaccines are administered to the mother during pregnancy.", "Influenza vaccination also helps to reduce the probability of reassortment.", "In general, influenza vaccines are only effective if there is an antigenic match between vaccine strains and circulating strains.", "Additionally, most commercially available flu vaccines are manufactured by propagation of influenza viruses in embryonated chicken eggs, taking 6–8 months.", "Flu seasons are different in the northern and southern hemisphere, so the WHO meets twice a year, one for each hemisphere, to discuss which strains should be included in flu vaccines based on observation from HA inhibition assays.", "Other manufacturing methods include an MDCK cell culture-based inactivated vaccine and a recombinant subunit vaccine manufactured from baculovirus overexpression in insect cells.", "Influenza can be prevented or reduced in severity by post-exposure prophylaxis with the antiviral drugs oseltamivir, which can be taken orally by those at least three months old, and zanamivir, which can be inhaled by those above seven years of age.", "Chemoprophylaxis is most useful for individuals at high-risk of developing complications and those who cannot receive the flu vaccine due to contraindications or lack of effectiveness.", "Post-exposure chemoprophylaxis is only recommended if oseltamivir is taken within 48 hours of contact with a confirmed or suspected influenza case and zanamivir within 36 hours.", "It is recommended that it be offered to people who have yet to receive a vaccine for the current flu season, who have been vaccinated less than two week since contact, if there is a significant mismatch between vaccine and circulating strains, or during an outbreak in a closed setting regardless of vaccination history.", "Hand hygiene is important in reducing the spread of influenza.", "This includes frequent hand washing with soap and water, using alcohol-based hand sanitizers, and not touching one's eyes, nose, and mouth with one's hands.", "Covering one's nose and mouth when coughing or sneezing is important.", "Other methods to limit influenza transmission include staying home when sick, avoiding contact with others until one day after symptoms end, and disinfecting surfaces likely to be contaminated by the virus, such as doorknobs.", "Health education through media and posters is often used to remind people of the aforementioned etiquette and hygiene.", "There is uncertainty about the use of masks since research thus far has not shown a significant reduction in seasonal influenza with mask usage.", "Likewise, the effectiveness of screening at points of entry into countries is not well researched.", "Social distancing measures such as school closures, avoiding contact with infected people via isolation or quarantine, and limiting mass gatherings may reduce transmission, but these measures are often expensive, unpopular, and difficult to implement.", "Consequently, the commonly recommended methods of infection control are respiratory etiquette, hand hygiene, and mask wearing, which are inexpensive and easy to perform.", "Pharmaceutical measures are effective but may not be available in the early stages of an outbreak.", "In health care settings, infected individuals may be cohorted or assigned to individual rooms.", "Protective clothing such as masks, gloves, and gowns is recommended when coming into contact with infected individuals if there is a risk of exposure to infected bodily fluids.", "Keeping patients in negative pressure rooms and avoiding aerosol-producing activities may help, but special air handling and ventilation systems are not considered necessary to prevent the spread of influenza in the air.", "In residential homes, new admissions may need to be closed until the spread of influenza is controlled.", "When discharging patients to care homes, it is important to take care if there is a known influenza outbreak.", "Since influenza viruses circulate in animals such as birds and pigs, prevention of transmission from these animals is important.", "Water treatment, indoor raising of animals, quarantining sick animals, vaccination, and biosecurity are the primary measures used.", "Placing poultry houses and piggeries on high ground away from high-density farms, backyard farms, live poultry markets, and bodies of water helps to minimize contact with wild birds.", "Closure of live poultry markets appears to the most effective measure and has shown to be effective at controlling the spread of H5N1, H7N9, and H9N2.", "Other biosecurity measures include cleaning and disinfecting facilities and vehicles, banning visits to poultry farms, not bringing birds intended for slaughter back to farms, changing clothes, disinfecting foot baths, and treating food and water.", "If live poultry markets are not closed, then \"clean days\" when unsold poultry is removed and facilities are disinfected and \"no carry-over\" policies to eliminate infectious material before new poultry arrive can be used to reduce the spread of influenza viruses.", "If a novel influenza viruses has breached the aforementioned biosecurity measures, then rapid detection to stamp it out via quarantining, decontamination, and culling may be necessary to prevent the virus from becoming endemic.", "Vaccines exist for avian H5, H7, and H9 subtypes that are used in some countries.", "In China, for example, vaccination of domestic birds against H7N9 successfully limited its spread, indicating that vaccination may be an effective strategy if used in combination with other measures to limit transmission.", "In pigs and horses, management of influenza is dependent on vaccination with biosecurity.", "Diagnosis based on symptoms is fairly accurate in otherwise healthy people during seasonal epidemics and should be suspected in cases of pneumonia, acute respiratory distress syndrome (ARDS), sepsis, or if encephalitis, myocarditis, or breaking down of muscle tissue occur.", "Because influenza is similar to other viral respiratory tract illnesses, laboratory diagnosis is necessary for confirmation.", "Common ways of collecting samples for testing include nasal and throat swabs.", "Samples may be taken from the lower respiratory tract if infection has cleared the upper but not lower respiratory tract.", "Influenza testing is recommended for anyone hospitalized with symptoms resembling influenza during flu season or who is connected to an influenza case.", "For severe cases, earlier diagnosis improves patient outcome.", "Diagnostic methods that can identify influenza include viral cultures, antibody- and antigen-detecting tests, and nucleic acid-based tests.", "Viruses can be grown in a culture of mammalian cells or embryonated eggs for 3–10 days to monitor cytopathic effect.", "Final confirmation can then be done via antibody staining, hemadsorption using red blood cells, or immunofluorescence microscopy.", "Shell vial cultures, which can identify infection via immunostaining before a cytopathic effect appears, are more sensitive than traditional cultures with results in 1–3 days.", "Cultures can be used to characterize novel viruses, observe sensitivity to antiviral drugs, and monitor antigenic drift, but they are relatively slow and require specialized skills and equipment.", "Serological assays can be used to detect an antibody response to influenza after natural infection or vaccination.", "Common serological assays include hemagglutination inhibition assays that detect HA-specific antibodies, virus neutralization assays that check whether antibodies have neutralized the virus, and enzyme-linked immunoabsorbant assays.", "These methods tend to be relatively inexpensive and fast but are less reliable than nucleic-acid based tests.", "Direct fluorescent or immunofluorescent antibody (DFA/IFA) tests involve staining respiratory epithelial cells in samples with fluorescently-labeled influenza-specific antibodies, followed by examination under a fluorescent microscope.", "They can differentiate between IAV and IBV but can't subtype IAV.", "Rapid influenza diagnostic tests (RIDTs) are a simple way of obtaining assay results, are low cost, and produce results quickly, at less than 30 minutes, so they are commonly used, but they can't distinguish between IAV and IBV or between IAV subtypes and are not as sensitive as nucleic-acid based tests.", "Nucleic acid-based tests (NATs) amplify and detect viral nucleic acid.", "Most of these tests take a few hours, but rapid molecular assays are as fast as RIDTs.", "Among NATs, reverse transcription polymerase chain reaction (RT-PCR) is the most traditional and considered the gold standard for diagnosing influenza because it is fast and can subtype IAV, but it is relatively expensive and more prone to false-positives than cultures.", "Other NATs that have been used include loop-mediated isothermal amplification-based assays, simple amplification-based assays, and nucleic acid sequence-based amplification.", "Nucleic acid sequencing methods can identify infection by obtaining the nucleic acid sequence of viral samples to identify the virus and antiviral drug resistance.", "The traditional method is Sanger sequencing, but it has been largely replaced by next-generation methods that have greater sequencing speed and throughput.", "Treatment of influenza in cases of mild or moderate illness is supportive and includes anti-fever medications such as acetaminophen and ibuprofen, adequate fluid intake to avoid dehydration, and resting at home.", "Cough drops and throat sprays may be beneficial for sore throat.", "It is recommended to avoid alcohol and tobacco use while sick with the flu.", "Aspirin is not recommended to treat influenza in children due to an elevated risk of developing Reye syndrome.", "Corticosteroids likewise are not recommended except when treating septic shock or an underlying medical condition, such as chronic obstructive pulmonary disease or asthma exacerbation, since they are associated with increased mortality.", "If a secondary bacterial infection occurs, then treatment with antibiotics may be necessary.", "Antiviral drugs are primarily used to treat severely ill patients, especially those with compromised immune systems.", "Antivirals are most effective when started in the first 48 hours after symptoms appear.", "Later administration may still be beneficial for those who have underlying immune defects, those with more severe symptoms, or those who have a higher risk of developing complications if these individuals are still shedding the virus.", "Antiviral treatment is also recommended if a person is hospitalized with suspected influenza instead of waiting for test results to return and if symptoms are worsening.", "Most antiviral drugs against influenza fall into two categories: neuraminidase (NA) inhibitors and M2 inhibitors.", "Baloxavir marboxil is a notable exception, which targets the endonuclease activity of the viral RNA polymerase and can be used as an alternative to NA and M2 inhibitors for IAV and IBV.", "NA inhibitors target the enzymatic activity of NA receptors, mimicking the binding of sialic acid in the active site of NA on IAV and IBV virions so that viral release from infected cells and the rate of viral replication are impaired.", "NA inhibitors include oseltamivir, which is consumed orally in a prodrug form and converted to its active form in the liver, and zanamivir, which is a powder that is inhaled nasally.", "Oseltamivir and zanamivir are effective for prophylaxis and post-exposure prophylaxis, and research overall indicates that NA inhibitors are effective at reducing rates of complications, hospitalization, and mortality and the duration of illness.", "Additionally, the earlier NA inhibitors are provided, the better the outcome, though late administration can still be beneficial in severe cases.", "Other NA inhibitors include laninamivir and peramivir, the latter of which can be used as an alternative to oseltamivir for people who cannot tolerate or absorb it.", "The adamantanes amantadine and rimantadine are orally administered drugs that block the influenza virus's M2 ion channel, preventing viral uncoating.", "These drugs are only functional against IAV but are no longer recommended for use because of widespread resistance to them among IAVs.", "Adamantane resistance first emerged in H3N2 in 2003, becoming worldwide by 2008.", "Oseltamivir resistance is no longer widespread because the 2009 pandemic H1N1 strain (H1N1 pdm09), which is resistant to adamantanes, seemingly replaced resistant strains in circulation.", "Since the 2009 pandemic, oseltamivir resistance has mainly been observed in patients undergoing therapy, especially the immunocompromised and young children.", "Oseltamivir resistance is usually reported in H1N1, but has been reported in H3N2 and IBVs less commonly.", "Because of this, oseltamivir is recommended as the first drug of choice for immunocompetent people, whereas for the immunocompromised, oseltamivir is recommended against H3N2 and IBV and zanamivir against H1N1 pdm09.", "Zanamivir resistance is observed less frequently, and resistance to peramivir and baloxavir marboxil is possible.", "In healthy individuals, influenza infection is usually self-limiting and rarely fatal.", "Symptoms usually last for 2–8 days.", "Influenza can cause people to miss work or school, and it is associated with decreased job performance and, in older adults, reduced independence.", "Fatigue and malaise may last for several weeks after recovery, and healthy adults may experience pulmonary abnormalities that can take several weeks to resolve.", "Complications and mortality primarily occur in high-risk populations and those who are hospitalized.", "Severe disease and mortality are usually attributable to pneumonia from the primary viral infection or a secondary bacterial infection, which can progress to ARDS.", "Other respiratory complications that may occur include sinusitis, bronchitis, bronchiolitis, excess fluid buildup in the lungs, and exacerbation of chronic bronchitis and asthma.", "Middle ear infection and croup may occur, most commonly in children.", "Secondary \"S. aureus\" infection has been observed, primarily in children, to cause toxic shock syndrome after influenza, with hypotension, fever, and reddening and peeling of the skin.", "Complications affecting the cardiovascular system are rare and include pericarditis, fulminant myocarditis with a fast, slow, or irregular heartbeat, and exacerbation of pre-existing cardiovascular disease.", "Inflammation or swelling of muscles accompanied by muscle tissue breaking down occurs rarely, usually in children, which presents as extreme tenderness and muscle pain in the legs and a reluctance to walk for 2–3 days.", "Influenza can affect pregnancy, including causing smaller neonatal size, increased risk of premature birth, and an increased risk of child death shortly before or after birth.", "Neurological complications have been associated with influenza on rare occasions, including aseptic meningitis, encephalitis, disseminated encephalomyelitis, transverse myelitis, and Guillain–Barré syndrome.", "Additionally, febrile seizures and Reye syndrome can occur, most commonly in children.", "Influenza-associated encephalopathy can occur directly from central nervous system infection from the presence of the virus in blood and presents as suddent onset of fever with convulsions, followed by rapid progression to coma.", "An atypical form of encephalitis called encephalitis lethargica, characterized by headache, drowsiness, and coma, may rarely occur sometime after infection.", "In survivors of influenza-associated encephalopathy, neurological defects may occur.", "Primarily in children, in severe cases the immune system may rarely dramatically overproduce white blood cells that release cytokines, causing severe inflammation.", "People who are at least 65 years of age, due to a weakened immune system from aging or a chronic illness, are a high-risk group for developing complications, as are children less than one year of age and children who have not been previously exposed to influenza viruses multiple times.", "Pregnant women are at an elevated risk, which increases by trimester and lasts up to two weeks after childbirth.", "Obesity, in particular a body mass index greater than 35–40, is associated with greater amounts of viral replication, increased severity of secondary bacterial infection, and reduced vaccination efficacy.", "People who have underlying health conditions are also considered at-risk, including those who have congenital or chronic heart problems or lung (e.g. asthma), kidney, liver, blood, neurological, or metabolic (e.g. diabetes) disorders, as are people who are immunocompromised from chemotherapy, asplenia, prolonged steroid treatment, splenic dysfunction, or HIV infection.", "Current or past tobacco use also places a person at risk.", "The role of genetics in influenza is not well researched, but it may be a factor in influenza mortality.", "Influenza is typically characterized by seasonal epidemics and sporadic pandemics.", "Most of the burden of influenza is a result of flu seasons caused by IAV and IBV.", "Among IAV subtypes, H1N1 and H3N2 currently circulate in humans and are responsible for seasonal influenza.", "Cases disproportionately occur in children, but most severe causes are among the elderly, the very young, and the immunocompromised.", "In a typical year, influenza viruses infect 5–15% of the global population, causing 3–5 million cases of severe illness annually and accounting for 290,000–650,000 deaths each year due to respiratory illness.", "5–10% of adults and 20–30% of children contract influenza each year.", "The reported number of influenza cases is usually much lower than the actual number of cases.", "During seasonal epidemics, it is estimated that about 80% of otherwise healthy people who have a cough or sore throat have the flu.", "Approximately 30–40% of people hospitalized for influenza develop pneumonia, and about 5% of all severe pneumonia cases in hospitals are due to influenza, which is also the most common cause of ARDS in adults.", "In children, influenza is one of the two most common causes of ARDS, the other being the respiratory syncytial virus.", "About 3–5% of children each year develop otitis media due to influenza.", "Adults who develop organ failure from influenza and children who have PIM scores and acute renal failure have higher rates of mortality.", "During seasonal influenza, mortality is concentrated in the very young and the elderly, whereas during flu pandemics, young adults are often affected at a high rate.", "In temperate regions, the number of influenza cases varies from season to season.", "Lower vitamin D levels, presumably due to less sunlight, lower humidity, lower temperature, and minor changes in virus proteins caused by antigenic drift contribute to annual epidemics that peak during the winter season.", "In the northern hemisphere, this is from October to May (more narrowly December to April), and in the southern hemisphere, this is from May to October (more narrowly June to September).", "There are therefore two distinct influenza seasons every year in temperate regions, one in the northern hemisphere and one in the southern hemisphere.", "In tropical and subtropical regions, seasonality is more complex and appears to be affected by various climatic factors such as minimum temperature, hours of sunshine, maximum rainfall, and high humidity.", "Influenza may therefore occur year-round in these regions.", "Influenza epidemics in modern times have the tendency to start in the eastern or southern hemisphere, with Asia being a key reservoir of influenza viruses.", "IAV and IBV co-circulate, so the two have the same patterns of transmission.", "The seasonality of ICV, however, is poorly understood.", "ICV infection is most common in children under the age of 2, and by adulthood most people have been exposed to it.", "ICV-associated hospitalization most commonly occurs in children under the age of 3 and is frequently accompanied by co-infection with another virus or a bacterium, which may increase the severity of disease.", "When considering all hospitalizations for respiratory illness among young children, ICV appears to account for only a small percentage of such cases.", "Large outbreaks of ICV infection can occur, so incidence varies significantly.", "Outbreaks of influenza caused by novel influenza viruses are common.", "Depending on the level of pre-existing immunity in the population, novel influenza viruses can spread rapidly and cause pandemics with millions of deaths.", "These pandemics, in contrast to seasonal influenza, are caused by antigenic shifts involving animal influenza viruses.", "To date, all known flu pandemics have been caused by IAVs, and they follow the same pattern of spreading from an origin point to the rest of the world over the course of multiple waves in a year.", "Pandemic strains tend to be associated with higher rates of pneumonia in otherwise healthy individuals.", "Generally after each influenza pandemic, the pandemic strain continues to circulate as the cause of seasonal influenza, replacing prior strains.", "From 1700 to 1889, influenza pandemics occurred about once every 50–60 years.", "Since then, pandemics have occurred about once every 10–50 years, so they may be getting more frequent over time.", "It is impossible to know when an influenza virus first infected humans or when the first influenza pandemic occurred.", "Possibly the first influenza epidemic occurred around 6,000 BC in China, and possible descriptions of influenza exist in Greek writings from the 5th century BC.", "In both 1173–1174 AD and 1387 AD, epidemics occurred across Europe that were named \"influenza\".", "Whether these epidemics and others were caused by influenza is unclear since there was no consistent naming pattern for epidemic respiratory diseases at that time, and \"influenza\" didn't become completely attached to respiratory disease until centuries later.", "Influenza may have been brought to the Americas as early as 1493, when an epidemic disease resembling influenza killed most of the population of the Antilles.", "The first convincing record of an influenza pandemic was chronicled in 1510; it began in East Asia before spreading to North Africa and then Europe.", "Following the pandemic, seasonal influenza occurred, with subsequent pandemics in 1557 and 1580.", "The flu pandemic in 1557 was potentially the first time influenza was connected to miscarriage and death of pregnant women.", "The 1580 flu pandemic originated in Asia during summer, spread to Africa, then Europe, and finally America.", "By the end of the 16th century, influenza was likely beginning to become understood as a specific, recognizable disease with epidemic and endemic forms.", "In 1648, it was discovered that horses also experience influenza.", "Influenza data after 1700 is more informative, so it is easier to identify flu pandemics after this point, each of which incrementally increased understanding of influenza.", "The first flu pandemic of the 18th century started in 1729 in Russia in spring, spreading worldwide over the course of three years with distinct waves, the later ones being more lethal.", "The second flu pandemic of the 18th century was in 1781–1782, starting in China in autumn.", "From this pandemic, influenza became associated with sudden outbreaks of febrile illness.", "The next flu pandemic was from 1830 to 1833, beginning in China in winter.", "This pandemic had a high attack rate, but the mortality rate was low.", "A minor influenza pandemic occurred from 1847 to 1851 at the same time as the third cholera pandemic and was the first flu pandemic to occur with vital statistics being recorded, so influenza mortality was clearly recorded for the first time.", "Highly pathogenic avian influenza was recognized in 1878 and was soon linked to transmission to humans.", "By the time of the 1889 pandemic, which may have been caused by an H2N2 strain, the flu had become an easily recognizable disease.", "Initially, the microbial agent responsible for influenza was incorrently identified in 1892 by R. F. J. Pfeiffer as the bacteria species \"Haemophilus influenzae\", which retains \"influenza\" in its name.", "In the following years, the field of virology began to form as viruses were identified as the cause of many diseases.", "From 1901 to 1903, Italian and Austrian researchers were able to show that avian influenza, then called \"fowl plague\", was caused by a microscopic agent smaller than bacteria by using filters with pores too small for bacteria to pass through.", "The fundamental differences between viruses and bacteria, however, were not yet fully understood.", "From 1918 to 1920, the Spanish flu pandemic became the most devastating influenza pandemic and one of the deadliest pandemics in history.", "The pandemic, probably caused by H1N1, likely began in the USA before spreading worldwide by soldiers during and after the First World War.", "The initial wave in the first half of 1918 was relatively minor and resembled past flu pandemics, but the second wave later that year had a much higher mortality rate, accounting for most deaths.", "A third wave with lower mortality occurred in many places a few months after the second.", "By the end of 1920, it is estimated that about a third to half of all people in the world had been infected, with tens of millions of deaths, disproportionately young adults.", "During the 1918 pandemic, the respiratory route of transmission was clearly identified and influenza was shown to be caused by a \"filter passer\", not a bacterium, but there remained a lack of agreement about influenza's cause for another decade and research on influenza declined.", "After the pandemic, H1N1 circulated in humans in seasonal form up until the next pandemic.", "In 1931, Richard Shope published three papers identifying a virus as the cause of swine influenza, a then newly recognized disease among pigs that was first characterized during the second wave of the 1918 pandemic.", "Shope's research reinvigorated research on human influenza, and many advances in virology, serology, immunology, experimental animal models, vaccinology, and immunotherapy have since arisen from influenza research.", "Just two years after influenza viruses were discovered, in 1933, IAV was identified as the agent responsible for human influenza.", "Subtypes of IAV were discovered throughout the 1930s, and IBV was discovered in 1940.", "During the Second World War, the US government worked on developing inactivated vaccines for influenza, resulting in the first influenza vaccine being licensed in 1945 in the United States.", "ICV was discovered two years later in 1947.", "In 1955, avian influenza was confirmed to be caused by IAV.", "Four influenza pandemics have occurred since WWII, each less severe than the 1918 pandemic.", "The first of these was the Asian flu from 1957 to 1958, caused by an H2N2 strain and beginning in China's Yunnan province.", "The number of deaths probably exceeded one million, mostly among the very young and very old.", "Notably, the 1957 pandemic was the first flu pandemic to occur in the presence of a global surveillance system and laboratories able to study the novel influenza virus.", "After the pandemic, H2N2 was the IAV subtype responsible for seasonal influenza.", "The first antiviral drug against influenza, amantadine, was approved for use in 1966, with additional antiviral drugs being used since the 1990s.", "In 1968, H3N2 was introduced into humans as a result of a reassortment between an avian H3N2 strain and an H2N2 strain that was circulating in humans.", "The novel H3N2 strain first emerged in Hong Kong and spread worldwide, causing the Hong Kong flu pandemic, which resulted in 500,000–2,000,000 deaths.", "This was the first pandemic to spread significantly by air travel.", "H2N2 and H3N2 co-circulated after the pandemic until 1971 when H2N2 waned in prevalence and was completely replaced by H3N2.", "In 1977, H1N1 reemerged in humans, possibly after it was released from a freezer in a laboratory accident, and caused a pseudo-pandemic.", "Whether the 1977 \"pandemic\" deserves to be included in the natural history of flu pandemics is debatable.", "This H1N1 strain was antigenically similar to the H1N1 strains that circulated prior to 1957.", "Since 1977, both H1N1 and H3N2 have circulated in humans as part of seasonal influenza.", "In 1980, the current classification system used to subtype influenza viruses was introduced.", "At some point, IBV diverged into two lineages, named the B/Victoria-like and B/Yamagata-like lineages, both of which have been circulating in humans since 1983.", "In 1996, HPAI H5N1 was detected in Guangdong, China and a year later emerged in poultry in Hong Kong, gradually spreading worldwide from there.", "A small H5N1 outbreak in humans in Hong Kong occurred then, and sporadic human cases have occurred since 1997, carrying a high case fatality rate.", "The most recent flu pandemic was the 2009 swine flu pandemic, which originated in Mexico and resulted in hundreds of thousands of deaths.", "It was caused by a novel H1N1 strain that was a reassortment of human, swine, and avian influenza viruses.", "The 2009 pandemic had the effect of replacing prior H1N1 strains in circulation with the novel strain but not any other influenza viruses.", "Consequently, H1N1, H3N2, and both IBV lineages have been in circulation in seasonal form since the 2009 pandemic.", "In 2011, IDV was discovered in pigs in Oklahoma, USA, and cattle were later identified as the primary reservoir of IDV.", "In the same year, avian H7N9 was detected in China and began to cause human infections in 2013, starting in Shanghai and Anhui and remaining mostly in China.", "HPAI H7N9 emerged sometime in 2016 and has occasionally infected humans incidentally.", "Other AIVs have less commonly infected humans since the 1990s, including H5N6, H6N1, H7N2-4, H7N7, and H10N7-8, and HPAI H subtypes such as H5N1-3, H5N5-6, and H5N8 have begun to spread throughout much of the world since the 2010s.", "Future flu pandemics, which may be caused by an influenza virus of avian origin, are viewed as almost inevitable, and increased globalization has made it easier for novel viruses to spread, so there are continual efforts to prepare for future pandemics and improve the prevention and treatment of influenza.", "The word \"influenza\" comes from the Italian word \"influenza\", from medieval Latin \"influentia\", originally meaning \"visitation\" or \"influence\".", "Terms such as \"influenza di freddo\", meaning \"influence of the cold\", and \"influenza di stelle\", meaning \"influence of the stars\" are attested from the 14th century.", "The latter referred to the disease's cause, which at the time was ascribed by some to unfavorable astrological conditions.", "As early as 1504, \"influenza\" began to mean a \"visitation\" or \"outbreak\" of any disease affecting many people in a single place at once.", "During an outbreak of influenza in 1743 that started in Italy and spread throughout Europe, the word reached the English language and was anglicized in pronunciation.", "Since the mid-1800s, \"influenza\" has also been used to refer to severe colds.", "The shortened form of the word, \"(the) flu\", is first attested in 1839 as \"flue\" with the spelling \"flu\" first attested in 1893.", "Other names that have been used for influenza include \"epidemic catarrh\", \"la grippe\" from French, \"sweating sickness\", and, especially when referring to the 1918 pandemic strain, \"Spanish fever\".", "Influenza research is wide-ranging and includes efforts to understand how influenza viruses enter hosts, the relationship between influenza viruses and bacteria, how influenza symptoms progress, and what make some influenza viruses deadlier than others.", "Non-structural proteins encoded by influenza viruses are periodically discovered and their functions are continually under research.", "Past pandemics, and especially the 1918 pandemic, are the subject of much research to understand flu pandemics.", "As part of pandemic preparedness, the Global Influenza Surveillance and Response System is a global network of laboratories that monitors influenza transmission and epidemiology.", "Additional areas of research include ways to improve the diagnosis, treatment, and prevention of influenza.", "Existing diagnostic methods have a variety of limitations coupled with their advantages.", "For example, NATs have high sensitivity and specificity but are impractical in under-resourced regions due to their high cost, complexity, maintenance, and training required.", "Low-cost, portable RIDTs can rapidly diagnose influenza but have highly variable sensitivity and are unable to subtype IAV.", "As a result of these limitations and others, research into new diagnostic methods revolves around producing new methods that are cost-effective, less labor-intensive, and less complex than existing methods while also being able to differentiate influenza species and IAV subtypes.", "One approach in development are lab-on-a-chips, which are diagnostic devices that make use of a variety of diagnostic tests, such as RT-PCR and serological assays, in microchip form.", "These chips have many potential advantages, including high reaction efficiency, low energy consumption, and low waste generation.", "New antiviral drugs are also in development due to the elimination of adamantines as viable drugs and concerns over oseltamivir resistance.", "These include: NA inhibitors that can be injected intravenously, such as intravenous formulations of zanamivir; favipiravir, which is a polymerase inhibitor used against several RNA viruses; pimodivir, which prevents cap-binding required during viral transcription; and nitazoxanide, which inhibits HA maturation.", "Reducing excess inflammation in the respiratory tract is also subject to much research since this is one of the primary mechanisms of influenza pathology.", "Other forms of therapy in development include monoclonal and polyclonal antibodies that target viral proteins, convalescent plasma, different approaches to modify the host antiviral response, and stem cell-based therapies to repair lung damage.", "Much research on LAIVs focuses on identifying genome sequences that can be deleted to create harmless influenza viruses in vaccines that still confer immunity.", "The high variability and rapid evolution of influenza virus antigens, however, is a major obstacle in developing effective vaccines.", "Furthermore, it is hard to predict which strains will be in circulation during the next flu season, manufacturing a sufficient quantity of flu vaccines for the next season is difficult, LAIVs have limited efficacy, and repeated annual vaccination potentially has diminished efficacy.", "For these reasons, \"broadly-reactive\" or \"universal\" flu vaccines are being researched that can provide protection against many or all influenza viruses.", "Approaches to develop such a vaccine include HA stalk-based methods such as chimeras that have the same stalk but different heads, HA head-based methods such as computationally optimized broadly neutralizing antigens, anti-idiotypic antibodies, and vaccines to elicit immune responses to highly conserved viral proteins.", "mRNA vaccines to provide protection against influenza are also under research.", "Aquatic birds such as ducks, geese, shorebirds, and gulls are the primary reservoir of IAVs.", "In birds, AIVs may be either low pathogenic avian influenza (LPAI) viruses that produce little to no symptoms or highly pathogenic avian influenza (HPAI) viruses that cause severe illness.", "Symptoms of HPAI infection include lack of energy and appetite, decreased egg production, soft-shelled or misshapen eggs, swelling of the head, comb, wattles, and hocks, purple discoloration of wattles, combs, and legs, nasal discharge, coughing, sneezing, incoordination, and diarrhea.", "Birds infected with an HPAI virus may also die suddenly without any signs of infection.", "The distinction between LPAI and HPAI can generally be made based on how lethal an AIV is to chickens.", "At the genetic level, an AIV can be usually be identified as an HPAI virus if it has a multibasic cleavage site in the HA protein, which contains additional residues in the HA gene.", "Most AIVs are LPAI.", "Notable HPAI viruses include HPAI H5N1 and HPAI H7N9.", "HPAI viruses have been a major disease burden in the 21st century, resulting in the death of large numbers of birds.", "In H7N9's case, some circulating strains were originally LPAI but became HPAI by acquiring the HA multibasic cleavage site.", "Avian H9N2 is also of concern because although it is LPAI, it is a common donor of genes to H5N1 and H7N9 during reassortment.", "Migratory birds can spread influenza across long distances.", "An example of this was when an H5N1 strain in 2005 infected birds at Qinghai Lake, China, which is a stopover and breeding site for many migratory birds, subsequently spreading the virus to more than 20 countries across Asia, Europe, and the Middle East.", "AIVs can be transmitted from wild birds to domestic free-range ducks and in turn to poultry through contaminated water, aerosols, and fomites.", "Ducks therefore act as key intermediates between wild and domestic birds.", "Transmission to poultry typically occurs in backyard farming and live animal markets where multiple species interact with each other.", "From there, AIVs can spread to poultry farms in the absence of adequate biosecurity.", "Among poultry, HPAI transmission occurs through aerosols and contaminated feces, cages, feed, and dead animals.", "Back-transmission of HPAI viruses from poultry to wild birds has occurred and is implicated in mass die-offs and intercontinental spread.", "AIVs have occasionally infected humans through aerosols, fomites, and contaminated water.", "Direction transmission from wild birds is rare.", "Instead, most transmission involves domestic poultry, mainly chickens, ducks, and geese but also a variety of other birds such as guinea fowl, partridge, pheasants, and quails.", "The primary risk factor for infection with AIVs is exposure to birds in farms and live poultry markets.", "Typically, infection with an AIV has an incubation period of 3–5 days but can be up to 9 days.", "H5N1 and H7N9 cause severe lower respiratory tract illness, whereas other AIVs such as H9N2 cause a more mild upper respiratory tract illness, commonly with conjunctivitis.", "Limited transmission of avian H2, H5-7, H9, and H10 subtypes from one person to another through respiratory droplets, aerosols, and fomites has occurred, but sustained human-to-human transmission of AIVs has not occurred.", "Before 2013, H5N1 was the most common AIV to infect humans.", "Since then, H7N9 has been responsible for most human cases.", "Influenza in pigs is a respiratory disease similar to influenza in humans and is found worldwide.", "Asymptomatic infections are common.", "Symptoms typically appear 1–3 days after infection and include fever, lethargy, anorexia, weight loss, labored breathing, coughing, sneezing, and nasal discharge.", "In sows, pregnancy may be aborted.", "Complications include secondary infections and potentially fatal bronchopneumonia.", "Pigs become contagious within a day of infection and typically spread the virus for 7–10 days, which can spread rapidly within a herd.", "Pigs usually recover from infection within 3–7 days after symptoms appear.", "Prevention and control measures include inactivated vaccines and culling infected herds.", "The influenza viruses usually responsible for swine flu are IAV subtypes H1N1, H1N2, and H3N2.", "Some IAVs can be transmitted via aerosols from pigs to humans and vice versa.", "Furthermore, pigs, along with bats and quails, are recognized as a mixing vessel of influenza viruses because they have both α-2,3 and α-2,6 sialic acid receptors in their respiratory tract.", "Because of that, both avian and mammalian influenza viruses can infect pigs.", "If co-infection occurs, then reassortment is possible.", "A notable example of this was the reassortment of a swine, avian, and human influenza virus in 2009, resulting in a novel H1N1 strain that caused the 2009 flu pandemic.", "Spillover events from humans to pigs, however, appear to be more common than from pigs to humans.", "Influenza viruses have been found in many other animals, including cattle, horses, dogs, cats, and marine mammals.", "Nearly all IAVs are apparently descended from ancestral viruses in birds.", "The exception are bat influenza-like viruses, which have an uncertain origin.", "These bat viruses have HA and NA subtypes H17, H18, N10, and N11.", "H17N10 and H18N11 are unable to reassort with other IAVs, but they are still able to replicate in other mammals.", "AIVs sometimes crossover into mammals.", "For example, in late 2016 to early 2017, an avian H7N2 strain was found to be infecting cats in New York.", "Equine IAVs include H7N7 and two lineages of H3N8.", "H7N7, however, has not been detected in horses since the late 1970s, so it may have become extinct in horses.", "H3N8 in equines spreads via aerosols and causes respiratory illness.", "Equine H3N8 perferentially binds to α-2,3 sialic acids, so horses are usually considered dead-end hosts, but transmission to dogs and camels has occurred, raising concerns that horses may be mixing vessels for reassortment.", "In canines, the only IAVs in circulation are equine-derived H3N8 and avian-derived H3N2.", "Canine H3N8 has not been observed to reassort with other subtypes.", "H3N2 has a much broader host range and can reassort with H1N1 and H5N1.", "An isolated case of H6N1 likely from a chicken was found infecting a dog, so other AIVs may emerge in canines.", "Other mammals to be infected by IAVs include H7N7 and H4N5 in seals, H1N3 in whales, and H10N4 and H3N2 in minks.", "Various mutations have been identified that are associated with AIVs adapting to mammals.", "Since HA proteins vary in which sialic acids they bind to, mutations in the HA receptor binding site can allow AIVs to infect mammals.", "Other mutations include mutations affecting which sialic acids NA proteins cleave and a mutation in the PB2 polymerase subunit that improves tolerance of lower temperatures in mammalian respiratory tracts and enhances RNP assembly by stabilizing NP and PB2 binding.", "IBV is mainly found in humans but has also been detected in pigs, dogs, horses, and seals.", "Likewise, ICV primarily infects humans but has been observed in pigs, dogs, cattle, and dromedary camels.", "IDV causes an influenza-like illness in pigs but its impact in its natural reservoir, cattle, is relatively unknown.", "It may cause respiratory disease resembling human influenza on its own, or it may be part of a bovine respiratory disease (BRD) complex with other pathogens during co-infection.", "BRD is a concern for the cattle industry, so IDV's possible involvement in BRD has led to research on vaccines for cattle that can provide protection against IDV.", "Two antigenic lineages are in circulation: D/swine/Oklahoma/1334/2011 (D/OK) and D/bovine/Oklahoma/660/2013 (D/660)." ]

[ 363, 364, 365, 366, 367, 368, 369, 370, 371, 372, 373, 374, 375, 376, 377, 378, 379, 380, 381, 382, 383 ]

[ "Annual vaccination can help to provide protection against influenza." ]

[ "Locus was commissioned by IBM to produce a version of the AIX UNIX based operating system for the PS/2 and System/370 ranges.", "The single-system image capabilities of LOCUS were incorporated under the name of AIX TCF (transparent computing facility).", "Locus was commissioned by Intel to produce a multiprocessor version of OSF/1 for the Intel Paragon a massively parallel NORMA (No Remote Memory Access) system.", "The system was known as OSF/1 AD, where AD stood for \"Advanced Development\".", "To allow inter processor process migration and communication between the individual nodes of the Paragon system they re-worked the TCF technology from LOCUS as Transparent Network Computing, or TNC, inventing the concept of the VPROC (virtual process) an analogy of the VNODE (virtual inode) from the SunOS virtual file system.", "Locus was commissioned by Tandem Computers to include their TNC technology in a highly available single-system image clustering system based on SCO UnixWare, UnixWare NonStop Clusters.", "During the course of the project Locus was acquired by Platinum Technology Inc, who transferred the team working on NonStop Clusters to Tandem.", "Tandem were later bought by Compaq.", "The UnixWare product was acquired from SCO by Caldera Systems/Caldera International, who discontinued commercialization of the NonStop Clusters product in favor of the simpler Reliant HA system.", "Compaq then decided to release the NonStop Clusters code as open source software, porting it to Linux as the OpenSSI project.", "Merge was a system developed by Locus in late 1984 for the AT&T 6300+ computer, which allowed DOS (and hence DOS applications) to be run under the native UNIX SVR2 operating system.", "The 6300+ used an Intel 80286 processor and included special-purpose circuitry to allow virtualization of the 8086 instruction set used by DOS.", "Merge was later modified to use the virtual 8086 mode provided by Intel 80386 processors.", "It was sold for Microport SVR3 and later SCO Unix and UnixWare.", "In the late 1980, the main commercial competitor of Merge was VP/IX developed by Interactive Systems Corporation and Phoenix Technologies.", "Around 1994, Merge included an innovative socket API that used Intel ring 2 for virtualization.", "Although this was the fastest network access of any Windows virtualization system then on the market, it did not increase sales enough to make Locus independent.", "This socket API was designed and developed by Real Time, Inc. of Santa Barbara.", "Locus eventually joined the Microsoft WISE\nprogram which gave them access to Windows source code, which allowed later versions of Merge to run Windows \"Shrink wrapped\" applications without a copy of Windows.", "PC-Interface was a popular Lan-based Cross-Platform Integration Toolkit for Unix, providing MS-DOS/Windows/Macintosh and Unix integration using Unix as the file system.", "It supported AIX, Santa Cruz Operation Inc, UnixWare and Motorola 9000 and many other Unixes and came with one Mac and one MS-DOS/Windows client." ]

[ 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 ]

[ "Locus was notable for commercializing single-system image software and producing the Merge package which allowed the use of DOS and Windows 3.1 software on Unix systems.", "Locus was acquired by Platinum Technology Inc in 1995." ]

[ "Locus was commissioned by IBM to produce a version of the AIX UNIX based operating system for the PS/2 and System/370 ranges.", "The single-system image capabilities of LOCUS were incorporated under the name of AIX TCF (transparent computing facility).", "Locus was commissioned by Intel to produce a multiprocessor version of OSF/1 for the Intel Paragon a massively parallel NORMA (No Remote Memory Access) system.", "The system was known as OSF/1 AD, where AD stood for \"Advanced Development\".", "To allow inter processor process migration and communication between the individual nodes of the Paragon system they re-worked the TCF technology from LOCUS as Transparent Network Computing, or TNC, inventing the concept of the VPROC (virtual process) an analogy of the VNODE (virtual inode) from the SunOS virtual file system.", "Locus was commissioned by Tandem Computers to include their TNC technology in a highly available single-system image clustering system based on SCO UnixWare, UnixWare NonStop Clusters.", "During the course of the project Locus was acquired by Platinum Technology Inc, who transferred the team working on NonStop Clusters to Tandem.", "Tandem were later bought by Compaq.", "The UnixWare product was acquired from SCO by Caldera Systems/Caldera International, who discontinued commercialization of the NonStop Clusters product in favor of the simpler Reliant HA system.", "Compaq then decided to release the NonStop Clusters code as open source software, porting it to Linux as the OpenSSI project.", "Merge was a system developed by Locus in late 1984 for the AT&T 6300+ computer, which allowed DOS (and hence DOS applications) to be run under the native UNIX SVR2 operating system.", "The 6300+ used an Intel 80286 processor and included special-purpose circuitry to allow virtualization of the 8086 instruction set used by DOS.", "Merge was later modified to use the virtual 8086 mode provided by Intel 80386 processors.", "It was sold for Microport SVR3 and later SCO Unix and UnixWare.", "In the late 1980, the main commercial competitor of Merge was VP/IX developed by Interactive Systems Corporation and Phoenix Technologies.", "Around 1994, Merge included an innovative socket API that used Intel ring 2 for virtualization.", "Although this was the fastest network access of any Windows virtualization system then on the market, it did not increase sales enough to make Locus independent.", "This socket API was designed and developed by Real Time, Inc. of Santa Barbara.", "Locus eventually joined the Microsoft WISE\nprogram which gave them access to Windows source code, which allowed later versions of Merge to run Windows \"Shrink wrapped\" applications without a copy of Windows.", "PC-Interface was a popular Lan-based Cross-Platform Integration Toolkit for Unix, providing MS-DOS/Windows/Macintosh and Unix integration using Unix as the file system.", "It supported AIX, Santa Cruz Operation Inc, UnixWare and Motorola 9000 and many other Unixes and came with one Mac and one MS-DOS/Windows client." ]

[ 5, 6, 7, 8, 9 ]

[ "Locus was acquired by Platinum Technology Inc in 1995." ]

[ "The settlement took its name from Hagg, an archaic word which meant 'broken ground in a bog,' and from the Levett family, an Anglo-Norman family prominent in Yorkshire for centuries.", "The River Don valley, in which the settlement was situated, was a site given to limestone formations which lent themselves to early mining for building purposes.", "The area in which Levitt Hagg is located was known as Conisbrough Cliffs and was composed of two quarries: Near Cliff, which had been exhausted by 1791; and \"Far Cliff\" which included the long-gone early industrial hamlet of Levitt Hagg.", "Limestone from the quarries at Levitt Hagg, which had a vertical height of 75 feet, has been widely used in building in the South Yorkshire area since medieval times.", "The soft dolomite limestone from the banks of the Don east of Conisbrough made ideal building material, which yielded profits for some.", "An account book from the mid-eighteenth century records the expenses of quarrying limestone at the site, which belonged at that time to the Battie-Wrightson family of Cusworth.", "As well as quarrying operations, barges to be used on the canals were also built on the bank by the village, the first one being completed in 1886.", "Boat building was abandoned in 1901.", "The only surviving evidence of industrial activity are abandoned lime kilns, the upper portions of which are still visible.", "Today Levitt Hagg is the site of an abandoned quarry and landfill site, providing refuge for four species of bats, including whiskered, long-eared, Daubenton's and Natterer's.", "(The bats and their habitat are protected by law.)", "The village of Levitt Hagg began to grow around 1815 when the company of Lockwood, Blagden and Kemp constructed six cottages, known locally as 'White Row.'", "Four more houses had been constructed before 1851 when, according to the 1851 census, the dwellings were occupied by 60 people.", "During 1875, six more houses were constructed.", "Each one contained a living room, two bedrooms, an attic and a kitchen.", "At this time the village population was nearly 100, and in 1878 a small Mission Hall cum Reading Room was built on a site given by Cusworth Hall Estate owner William Battie-Wrightson.\nDuring 1925, the County Medical Officer made a report on the sanitary conditions at Levitt Hagg, and his findings were that many of the houses were in a state of disrepair, water had to be obtained from wells and drainage was discharged into the river and whenever the river overflowed the houses were prone to flooding.", "The insanitary conditions and the badly polluted state of the river led to all the Levitt Hagg houses being condemned as unfit for occupation and by 1957 the area had been cleared.", "The Levitt Hagg landfill site is run by Waste Recycling Group who have restored 2 acres to calcareous grassland and installed equipment to supply gas from the site to the grid." ]

[ 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 ]

[ "Levitt Hagg (sometimes spelled Levit Hagg or Levett Hagg ) is an abandoned hamlet in South Yorkshire, located approximately two miles southwest of Doncaster and near Conisbrough Castle.", "Limestone began to be quarried at the site in ancient times." ]

[ "Although the brain and spinal cord are surrounded by tough membranes, enclosed in the bones of the skull and spinal vertebrae, and chemically isolated by the blood–brain barrier, they are very susceptible if compromised.", "Nerves tend to lie deep under the skin but can still become exposed to damage.", "Individual neurons, the neural circuits, and nerves into which they form are susceptible to electrochemical and structural disruption.", "Neuroregeneration may occur in the peripheral nervous system and thus overcome or work around injuries to some extents, but it is thought to be rare in the brain and spinal cord.", "The specific causes of neurological problems vary, but can include genetic disorders, congenital abnormalities or disorders, infections, lifestyle or environmental health problems including malnutrition, brain damage, spinal cord injury, nerve injury or gluten sensitivity (with or without intestinal damage or digestive symptoms).", "Metal poisoning, where metals accumulate in the human body and disrupt biological processes, has been reported to induce neurological problems, at least in the case of lead.", "The neurological problem may start in another body system that interacts with the nervous system.", "For example, cerebrovascular disease involves brain injury due to problems with the blood vessels (cardiovascular system) supplying the brain; autoimmune disorders involve damage caused by the body's own immune system; lysosomal storage diseases such as Niemann–Pick disease can lead to neurological deterioration.", "The National Institute for Health and Care Excellence recommends considering the evaluation of an underlying coeliac disease in people with unexplained neurological symptoms, particularly peripheral neuropathy or ataxia.", "In a substantial minority of cases of neurological symptoms, no neural cause can be identified using current testing procedures, and such \"idiopathic\" conditions can invite different theories about what is occurring.", "Generally speaking, a substantial number of neurological disorders may have originated from a previous clinically not recognized viral infection.", "For example, it is thought that infection with the Hepatitis E virus, which is often initially asymptomatic may provoke neurological disorders, but there are many other examples as well.", "Numerous examples have been described of neurological disorders that are associated with mutated DNA repair genes (for reviews see).", "Inadequate repair of DNA damages can lead directly to cell death and neuron depletion as well as disruptions in the pattern of epigenetic alterations required for normal neuronal function.", "Neurological disorders can be categorized according to the primary location affected, the primary type of dysfunction involved, or the primary type of cause.", "The broadest division is between central nervous system disorders and peripheral nervous system disorders.", "The Merck Manual lists brain, spinal cord and nerve disorders in the following overlapping categories:\n\n\n\n\n\n\n\n\n\n\n\n\nMany of the diseases and disorders listed above have neurosurgical treatments available (e.g. Tourette's syndrome, Parkinson's disease, essential tremor and obsessive compulsive disorder).", "Neurological disorders in non-human animals are treated by veterinarians.", "A neurological examination can, to some extent, assess the impact of neurological damage and disease on brain function in terms of behavior, memory or cognition.", "Behavioral neurology specializes in this area.", "In addition, clinical neuropsychology uses neuropsychological assessment to precisely identify and track problems in mental functioning, usually after some sort of brain injury or neurological impairment.", "Alternatively, a condition might first be detected through the presence of abnormalities in mental functioning, and further assessment may indicate an underlying neurological disorder.", "There are sometimes unclear boundaries in the distinction between disorders treated within neurology, and mental disorders treated within the other medical specialty of psychiatry, or other mental health professions such as clinical psychology.", "In practice, cases may present as one type but be assessed as more appropriate to the other.", "Neuropsychiatry deals with mental disorders arising from specific identified diseases of the nervous system.", "One area that can be contested is in cases of idiopathic neurological symptoms - conditions where the cause cannot be established.", "It can be decided in some cases, perhaps by exclusion of any accepted diagnosis, that higher-level brain/mental activity is causing symptoms, rather than the symptoms originating in the area of the nervous system from which they may appear to originate.", "Classic examples are \"functional\" seizures, sensory numbness, \"functional\" limb weakness and functional neurological deficit (\"functional\" in this context is usually contrasted with the old term \"organic disease\").", "Such cases may be contentiously interpreted as being \"psychological\" rather than \"neurological\".", "Some cases may be classified as mental disorders, for example as conversion disorder, if the symptoms appear to be causally linked to emotional states or responses to social stress or social contexts.", "On the other hand, dissociation refers to partial or complete disruption of the integration of a person's conscious functioning, such that a person may feel detached from one's emotions, body and/or immediate surroundings.", "At one extreme this may be diagnosed as depersonalization disorder.", "There are also conditions viewed as neurological where a person appears to consciously register neurological stimuli that cannot possibly be coming from the part of the nervous system to which they would normally be attributed, such as phantom pain or synesthesia, or where limbs act without conscious direction, as in alien hand syndrome.", "Theories and assumptions about consciousness, free will, moral responsibility and social stigma can play a part in this, whether from the perspective of the clinician or the patient.", "Conditions that are classed as mental disorders, or learning disabilities and forms of intellectual disability, are not themselves usually dealt with as neurological disorders.", "Biological psychiatry seeks to understand mental disorders in terms of their basis in the nervous system, however.", "In clinical practice, mental disorders are usually indicated by a mental state examination, or other type of structured interview or questionnaire process.", "At the present time, neuroimaging (brain scans) alone cannot accurately diagnose a mental disorder or tell the risk of developing one; however, it can be used to rule out other medical conditions such as a brain tumor.", "In research, neuroimaging and other neurological tests can show correlations between reported and observed mental difficulties and certain aspects of neural function or differences in brain structure.", "In general, numerous fields intersect to try to understand the basic processes involved in mental functioning, many of which are brought together in cognitive science.", "The distinction between neurological and mental disorders can be a matter of some debate, either in regard to specific facts about the cause of a condition or in regard to the general understanding of brain and mind.", "Moreover, the definition of disorder in medicine or psychology is sometimes contested in terms of what is considered abnormal, dysfunctional, harmful or unnatural in neurological, evolutionary, psychometric or social terms." ]

[ 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 ]

[ "A neurological disorder is any disorder of the nervous system.", "Structural, biochemical or electrical abnormalities in the brain, spinal cord or other nerves can result in a range of symptoms.", "There are many recognized neurological disorders, some relatively common, but many rare." ]

[ "Although the brain and spinal cord are surrounded by tough membranes, enclosed in the bones of the skull and spinal vertebrae, and chemically isolated by the blood–brain barrier, they are very susceptible if compromised.", "Nerves tend to lie deep under the skin but can still become exposed to damage.", "Individual neurons, the neural circuits, and nerves into which they form are susceptible to electrochemical and structural disruption.", "Neuroregeneration may occur in the peripheral nervous system and thus overcome or work around injuries to some extents, but it is thought to be rare in the brain and spinal cord.", "The specific causes of neurological problems vary, but can include genetic disorders, congenital abnormalities or disorders, infections, lifestyle or environmental health problems including malnutrition, brain damage, spinal cord injury, nerve injury or gluten sensitivity (with or without intestinal damage or digestive symptoms).", "Metal poisoning, where metals accumulate in the human body and disrupt biological processes, has been reported to induce neurological problems, at least in the case of lead.", "The neurological problem may start in another body system that interacts with the nervous system.", "For example, cerebrovascular disease involves brain injury due to problems with the blood vessels (cardiovascular system) supplying the brain; autoimmune disorders involve damage caused by the body's own immune system; lysosomal storage diseases such as Niemann–Pick disease can lead to neurological deterioration.", "The National Institute for Health and Care Excellence recommends considering the evaluation of an underlying coeliac disease in people with unexplained neurological symptoms, particularly peripheral neuropathy or ataxia.", "In a substantial minority of cases of neurological symptoms, no neural cause can be identified using current testing procedures, and such \"idiopathic\" conditions can invite different theories about what is occurring.", "Generally speaking, a substantial number of neurological disorders may have originated from a previous clinically not recognized viral infection.", "For example, it is thought that infection with the Hepatitis E virus, which is often initially asymptomatic may provoke neurological disorders, but there are many other examples as well.", "Numerous examples have been described of neurological disorders that are associated with mutated DNA repair genes (for reviews see).", "Inadequate repair of DNA damages can lead directly to cell death and neuron depletion as well as disruptions in the pattern of epigenetic alterations required for normal neuronal function.", "Neurological disorders can be categorized according to the primary location affected, the primary type of dysfunction involved, or the primary type of cause.", "The broadest division is between central nervous system disorders and peripheral nervous system disorders.", "The Merck Manual lists brain, spinal cord and nerve disorders in the following overlapping categories:\n\n\n\n\n\n\n\n\n\n\n\n\nMany of the diseases and disorders listed above have neurosurgical treatments available (e.g. Tourette's syndrome, Parkinson's disease, essential tremor and obsessive compulsive disorder).", "Neurological disorders in non-human animals are treated by veterinarians.", "A neurological examination can, to some extent, assess the impact of neurological damage and disease on brain function in terms of behavior, memory or cognition.", "Behavioral neurology specializes in this area.", "In addition, clinical neuropsychology uses neuropsychological assessment to precisely identify and track problems in mental functioning, usually after some sort of brain injury or neurological impairment.", "Alternatively, a condition might first be detected through the presence of abnormalities in mental functioning, and further assessment may indicate an underlying neurological disorder.", "There are sometimes unclear boundaries in the distinction between disorders treated within neurology, and mental disorders treated within the other medical specialty of psychiatry, or other mental health professions such as clinical psychology.", "In practice, cases may present as one type but be assessed as more appropriate to the other.", "Neuropsychiatry deals with mental disorders arising from specific identified diseases of the nervous system.", "One area that can be contested is in cases of idiopathic neurological symptoms - conditions where the cause cannot be established.", "It can be decided in some cases, perhaps by exclusion of any accepted diagnosis, that higher-level brain/mental activity is causing symptoms, rather than the symptoms originating in the area of the nervous system from which they may appear to originate.", "Classic examples are \"functional\" seizures, sensory numbness, \"functional\" limb weakness and functional neurological deficit (\"functional\" in this context is usually contrasted with the old term \"organic disease\").", "Such cases may be contentiously interpreted as being \"psychological\" rather than \"neurological\".", "Some cases may be classified as mental disorders, for example as conversion disorder, if the symptoms appear to be causally linked to emotional states or responses to social stress or social contexts.", "On the other hand, dissociation refers to partial or complete disruption of the integration of a person's conscious functioning, such that a person may feel detached from one's emotions, body and/or immediate surroundings.", "At one extreme this may be diagnosed as depersonalization disorder.", "There are also conditions viewed as neurological where a person appears to consciously register neurological stimuli that cannot possibly be coming from the part of the nervous system to which they would normally be attributed, such as phantom pain or synesthesia, or where limbs act without conscious direction, as in alien hand syndrome.", "Theories and assumptions about consciousness, free will, moral responsibility and social stigma can play a part in this, whether from the perspective of the clinician or the patient.", "Conditions that are classed as mental disorders, or learning disabilities and forms of intellectual disability, are not themselves usually dealt with as neurological disorders.", "Biological psychiatry seeks to understand mental disorders in terms of their basis in the nervous system, however.", "In clinical practice, mental disorders are usually indicated by a mental state examination, or other type of structured interview or questionnaire process.", "At the present time, neuroimaging (brain scans) alone cannot accurately diagnose a mental disorder or tell the risk of developing one; however, it can be used to rule out other medical conditions such as a brain tumor.", "In research, neuroimaging and other neurological tests can show correlations between reported and observed mental difficulties and certain aspects of neural function or differences in brain structure.", "In general, numerous fields intersect to try to understand the basic processes involved in mental functioning, many of which are brought together in cognitive science.", "The distinction between neurological and mental disorders can be a matter of some debate, either in regard to specific facts about the cause of a condition or in regard to the general understanding of brain and mind.", "Moreover, the definition of disorder in medicine or psychology is sometimes contested in terms of what is considered abnormal, dysfunctional, harmful or unnatural in neurological, evolutionary, psychometric or social terms." ]

[ 14, 15, 16, 17 ]

[ "A neurological disorder is any disorder of the nervous system." ]

[ "Although the brain and spinal cord are surrounded by tough membranes, enclosed in the bones of the skull and spinal vertebrae, and chemically isolated by the blood–brain barrier, they are very susceptible if compromised.", "Nerves tend to lie deep under the skin but can still become exposed to damage.", "Individual neurons, the neural circuits, and nerves into which they form are susceptible to electrochemical and structural disruption.", "Neuroregeneration may occur in the peripheral nervous system and thus overcome or work around injuries to some extents, but it is thought to be rare in the brain and spinal cord.", "The specific causes of neurological problems vary, but can include genetic disorders, congenital abnormalities or disorders, infections, lifestyle or environmental health problems including malnutrition, brain damage, spinal cord injury, nerve injury or gluten sensitivity (with or without intestinal damage or digestive symptoms).", "Metal poisoning, where metals accumulate in the human body and disrupt biological processes, has been reported to induce neurological problems, at least in the case of lead.", "The neurological problem may start in another body system that interacts with the nervous system.", "For example, cerebrovascular disease involves brain injury due to problems with the blood vessels (cardiovascular system) supplying the brain; autoimmune disorders involve damage caused by the body's own immune system; lysosomal storage diseases such as Niemann–Pick disease can lead to neurological deterioration.", "The National Institute for Health and Care Excellence recommends considering the evaluation of an underlying coeliac disease in people with unexplained neurological symptoms, particularly peripheral neuropathy or ataxia.", "In a substantial minority of cases of neurological symptoms, no neural cause can be identified using current testing procedures, and such \"idiopathic\" conditions can invite different theories about what is occurring.", "Generally speaking, a substantial number of neurological disorders may have originated from a previous clinically not recognized viral infection.", "For example, it is thought that infection with the Hepatitis E virus, which is often initially asymptomatic may provoke neurological disorders, but there are many other examples as well.", "Numerous examples have been described of neurological disorders that are associated with mutated DNA repair genes (for reviews see).", "Inadequate repair of DNA damages can lead directly to cell death and neuron depletion as well as disruptions in the pattern of epigenetic alterations required for normal neuronal function.", "Neurological disorders can be categorized according to the primary location affected, the primary type of dysfunction involved, or the primary type of cause.", "The broadest division is between central nervous system disorders and peripheral nervous system disorders.", "The Merck Manual lists brain, spinal cord and nerve disorders in the following overlapping categories:\n\n\n\n\n\n\n\n\n\n\n\n\nMany of the diseases and disorders listed above have neurosurgical treatments available (e.g. Tourette's syndrome, Parkinson's disease, essential tremor and obsessive compulsive disorder).", "Neurological disorders in non-human animals are treated by veterinarians.", "A neurological examination can, to some extent, assess the impact of neurological damage and disease on brain function in terms of behavior, memory or cognition.", "Behavioral neurology specializes in this area.", "In addition, clinical neuropsychology uses neuropsychological assessment to precisely identify and track problems in mental functioning, usually after some sort of brain injury or neurological impairment.", "Alternatively, a condition might first be detected through the presence of abnormalities in mental functioning, and further assessment may indicate an underlying neurological disorder.", "There are sometimes unclear boundaries in the distinction between disorders treated within neurology, and mental disorders treated within the other medical specialty of psychiatry, or other mental health professions such as clinical psychology.", "In practice, cases may present as one type but be assessed as more appropriate to the other.", "Neuropsychiatry deals with mental disorders arising from specific identified diseases of the nervous system.", "One area that can be contested is in cases of idiopathic neurological symptoms - conditions where the cause cannot be established.", "It can be decided in some cases, perhaps by exclusion of any accepted diagnosis, that higher-level brain/mental activity is causing symptoms, rather than the symptoms originating in the area of the nervous system from which they may appear to originate.", "Classic examples are \"functional\" seizures, sensory numbness, \"functional\" limb weakness and functional neurological deficit (\"functional\" in this context is usually contrasted with the old term \"organic disease\").", "Such cases may be contentiously interpreted as being \"psychological\" rather than \"neurological\".", "Some cases may be classified as mental disorders, for example as conversion disorder, if the symptoms appear to be causally linked to emotional states or responses to social stress or social contexts.", "On the other hand, dissociation refers to partial or complete disruption of the integration of a person's conscious functioning, such that a person may feel detached from one's emotions, body and/or immediate surroundings.", "At one extreme this may be diagnosed as depersonalization disorder.", "There are also conditions viewed as neurological where a person appears to consciously register neurological stimuli that cannot possibly be coming from the part of the nervous system to which they would normally be attributed, such as phantom pain or synesthesia, or where limbs act without conscious direction, as in alien hand syndrome.", "Theories and assumptions about consciousness, free will, moral responsibility and social stigma can play a part in this, whether from the perspective of the clinician or the patient.", "Conditions that are classed as mental disorders, or learning disabilities and forms of intellectual disability, are not themselves usually dealt with as neurological disorders.", "Biological psychiatry seeks to understand mental disorders in terms of their basis in the nervous system, however.", "In clinical practice, mental disorders are usually indicated by a mental state examination, or other type of structured interview or questionnaire process.", "At the present time, neuroimaging (brain scans) alone cannot accurately diagnose a mental disorder or tell the risk of developing one; however, it can be used to rule out other medical conditions such as a brain tumor.", "In research, neuroimaging and other neurological tests can show correlations between reported and observed mental difficulties and certain aspects of neural function or differences in brain structure.", "In general, numerous fields intersect to try to understand the basic processes involved in mental functioning, many of which are brought together in cognitive science.", "The distinction between neurological and mental disorders can be a matter of some debate, either in regard to specific facts about the cause of a condition or in regard to the general understanding of brain and mind.", "Moreover, the definition of disorder in medicine or psychology is sometimes contested in terms of what is considered abnormal, dysfunctional, harmful or unnatural in neurological, evolutionary, psychometric or social terms." ]

[ 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 ]

[ "They may be assessed by neurological examination, and studied and treated within the specialities of neurology and clinical neuropsychology." ]

[ "Jagannathan was born into a Dalit family in 1926.", "She encountered social injustice and poverty in her daily life as she observed her mother Nagammal who toiled hard and had to continue working even as she was in the advanced stages of pregnancy.", "Despite being from a poor family, she managed to get a university education and was soon involved with the Gandhian Sarvodaya Movement.", "It was through Sarvodaya that she met Sankaralingam, who would later become her husband.", "Sankaralingam hailed from a wealthy family, but discontinued his college education in 1930 in response to Gandhi's call for non-co-operation movement and civil disobedience.", "Krishnammal shared a stage with Mahatma Gandhi and met with Martin Luther King Jr. Sankaralinga later joined the Quit India Movement in 1942 and spent years in jail before India gained its independence in 1947.", "Having decided only to marry in independent India Sankaralingam and Krishnammal married in 1950.", "She would later lead the Salt Satyagraha march in Vedaranyam, this time not in protest, but to commemorate the platinum jubilee of the event in 2006.", "Sankaralingam and Krishnammal believed that one of the key requirements for achieving a Gandhian society is by empowering the rural poor through redistribution of land to the landless.", "For two years between 1950 and 1952 Sankaralingam was with Vinoba Bhave in Northern India on his Bhoodan (land-gift) Padayatra (pilgrimage on foot), the march appealing to landlords to give one sixth of their land to the landless.", "Meanwhile, Krishnammal completed her teacher-training course in Madras (now renamed Chennai).", "When Sankaralingam returned to Tamil Nadu to start the Bhoodhan movement the couple, until 1968, worked for land redistribution through Vinoba Bhave's Gramdan movement (Village Gift, the next phase of the land-gift movement), and through Satyagraha (non-violent resistance).", "Sankaralingam was imprisoned many times for this work.", "Between 1953 and 1967, the couple played an active role in the Bhoodhan movement spearheaded by Vinoba Bhave, through which about of land were distributed to thousands of landless poor across several Indian states.", "After the burning of 42 Dalits including women and children in the Kilvenmani massacre in Nagapattinam district following a wage-dispute with the landlord in 1968, the couple started to work in Thanjavur District in Tamil Nadu to concentrate on land reform issues.", "It was this incident that would inspire the couple, Krishnammal and Sankaralaingam to start the organisation LAFTI.", "Jagannathan founded Land for Tillers' Freedom in 1981 with her husband.", "The purpose of the organisation was to bring \"the landlords and landless poor to the negotiating table, obtain loans to enable the landless to buy land at reasonable price and then to help them work it cooperatively, so that the loans could be repaid\".", "Although the initial response was lukewarm with banks unwilling to lend and the high rates of stamp duty, Jagannathan managed to go on with the cause.", "By 2007, through LAFTI, she had transferred to about 13,000 families.", "Through LAFTI, she also conducted workshops to allow people, during the nonagricultural season, to support themselves through entrepreneurial efforts like mat weaving, tailoring, plumbing, carpentry, masonry, computer education and electronics.", "LAFTI would gain such popularity that later even the Government of India would implement LAFTI's approach to increase the peaceful transfer of land.", "In 1992 Jagannathan started working on issues concerned with prawn farms along the coast of Tamil Nadu.", "This time the problems were not from the local landlords, but from large industries from cities such as Chennai, Mumbai, Kolkata, Delhi and Hyderabad which occupied large areas of land for aquaculture along the coast, which not only threw the landless labourers out of employment but also converted fertile and cultivable land into salty deserts after a few years when the prawn companies moved on.", "The prawn farms also caused heavy seepage of seawater into the groundwater in the neighbourhood, thus the local people were deprived of clean drinking water resources.", "The result is that even more small farmers sell their meagre land-holdings to multinational prawn companies and move to the cities, filling urban slums.", "To address prawn farm issue the Jagannathans organised the whole of LAFTI's village movement to raise awareness among the people to oppose the prawn farms.", "Since 1993, the villagers have offered Satygraha (non-violent resistance), through rallies, fasts, and demonstrations in protest of establishing the prawn farms.", "They have been beaten up by hired goons, their houses have been burnt, and LAFTI workers have been imprisoned, because of false accusations of looting and arson.", "Undeterred by this, Jagannathan filed a 'public interest petition' in the Indian Supreme Court, which in turn asked NEERI (National Environmental Engineering Institute of India) to investigate the matter.", "NEERI's investigation report highlighted the environmental cost of the prawn farms to the nation and recommended all prawn farms within 500 meters of the coast to be banned.", "In December 1996 the Supreme Court issued a ruling against intensive shrimp farming in cultivable lands within 500 meters of the coastal area.", "It is said that because of the prawn farmers' local political influence, the Supreme Court judgement was not implemented on the ground.", "The legal battle around the prawn farms is still not resolved and the Jagannathans continue their struggle to establish non-exploitative, eco-friendly communities in the coastal areas of Tamil Nadu.", "Jagannathan also works towards upliftment of women in Dalits and poor.", "She believes in mobilising women's cause by peaceful means.", "Jagannathan, either independently or together with her husband, has established a total of seven non-governmental institutions for the poor.", "In addition to this she has also played an active role in wider public life.", "She has been a Senate member of the Gandhigram Trust and University and of Madurai University.", "She was also a member of a number of local and state social welfare committees and a member of the National Committee on Education, the Land Reform Committee and the Planning Committee.", "These activities have gained for the Jagannathans a high profile in India and they have won many awards: the Swami Pranavananda Peace Award (1987); the Jamnalal Bajaj Award (1988) and Padma Shri in 1989.", "In 1996 the couple received the Bhagavan Mahaveer Award \"for propagating non-violence.\"", "In 1999 Krishnammal was awarded a Summit Foundation Award (Switzerland), and in 2008 she was awarded 'Opus Prize' by the University of Seattle.", "She also received the Right Livelihood Award along with her husband \"for two long lifetimes of work dedicated to realising in practice the Gandhian vision of social justice and sustainable human development, for which they have been referred to as 'India's soul'\".", "She is lovingly called as \"Amma\" (Mother in Tamil) by her followers.", "She plans to use the award money for her projects rather than for herself.", "Inspired by Amma's contribution of enabling more than 11000 poor and landless women to become landowners, a M.Phil research dissertation is dedicated to Amma.", "The dissertation is titled as \"Aspects of Agrarian History of Tamilakam:Region, Women and Technology during 16th and 17th centuries AD\", submitted to Department of History, University of Hyderabad in 2009." ]

[ 0, 1, 2, 3, 4, 5, 6, 7 ]

[ "She and her husband, Sankaralingam Jagannathan (1912 – 12 February 2013), protested against social injustice and they are Gandhian activists." ]

[ "Jagannathan was born into a Dalit family in 1926.", "She encountered social injustice and poverty in her daily life as she observed her mother Nagammal who toiled hard and had to continue working even as she was in the advanced stages of pregnancy.", "Despite being from a poor family, she managed to get a university education and was soon involved with the Gandhian Sarvodaya Movement.", "It was through Sarvodaya that she met Sankaralingam, who would later become her husband.", "Sankaralingam hailed from a wealthy family, but discontinued his college education in 1930 in response to Gandhi's call for non-co-operation movement and civil disobedience.", "Krishnammal shared a stage with Mahatma Gandhi and met with Martin Luther King Jr. Sankaralinga later joined the Quit India Movement in 1942 and spent years in jail before India gained its independence in 1947.", "Having decided only to marry in independent India Sankaralingam and Krishnammal married in 1950.", "She would later lead the Salt Satyagraha march in Vedaranyam, this time not in protest, but to commemorate the platinum jubilee of the event in 2006.", "Sankaralingam and Krishnammal believed that one of the key requirements for achieving a Gandhian society is by empowering the rural poor through redistribution of land to the landless.", "For two years between 1950 and 1952 Sankaralingam was with Vinoba Bhave in Northern India on his Bhoodan (land-gift) Padayatra (pilgrimage on foot), the march appealing to landlords to give one sixth of their land to the landless.", "Meanwhile, Krishnammal completed her teacher-training course in Madras (now renamed Chennai).", "When Sankaralingam returned to Tamil Nadu to start the Bhoodhan movement the couple, until 1968, worked for land redistribution through Vinoba Bhave's Gramdan movement (Village Gift, the next phase of the land-gift movement), and through Satyagraha (non-violent resistance).", "Sankaralingam was imprisoned many times for this work.", "Between 1953 and 1967, the couple played an active role in the Bhoodhan movement spearheaded by Vinoba Bhave, through which about of land were distributed to thousands of landless poor across several Indian states.", "After the burning of 42 Dalits including women and children in the Kilvenmani massacre in Nagapattinam district following a wage-dispute with the landlord in 1968, the couple started to work in Thanjavur District in Tamil Nadu to concentrate on land reform issues.", "It was this incident that would inspire the couple, Krishnammal and Sankaralaingam to start the organisation LAFTI.", "Jagannathan founded Land for Tillers' Freedom in 1981 with her husband.", "The purpose of the organisation was to bring \"the landlords and landless poor to the negotiating table, obtain loans to enable the landless to buy land at reasonable price and then to help them work it cooperatively, so that the loans could be repaid\".", "Although the initial response was lukewarm with banks unwilling to lend and the high rates of stamp duty, Jagannathan managed to go on with the cause.", "By 2007, through LAFTI, she had transferred to about 13,000 families.", "Through LAFTI, she also conducted workshops to allow people, during the nonagricultural season, to support themselves through entrepreneurial efforts like mat weaving, tailoring, plumbing, carpentry, masonry, computer education and electronics.", "LAFTI would gain such popularity that later even the Government of India would implement LAFTI's approach to increase the peaceful transfer of land.", "In 1992 Jagannathan started working on issues concerned with prawn farms along the coast of Tamil Nadu.", "This time the problems were not from the local landlords, but from large industries from cities such as Chennai, Mumbai, Kolkata, Delhi and Hyderabad which occupied large areas of land for aquaculture along the coast, which not only threw the landless labourers out of employment but also converted fertile and cultivable land into salty deserts after a few years when the prawn companies moved on.", "The prawn farms also caused heavy seepage of seawater into the groundwater in the neighbourhood, thus the local people were deprived of clean drinking water resources.", "The result is that even more small farmers sell their meagre land-holdings to multinational prawn companies and move to the cities, filling urban slums.", "To address prawn farm issue the Jagannathans organised the whole of LAFTI's village movement to raise awareness among the people to oppose the prawn farms.", "Since 1993, the villagers have offered Satygraha (non-violent resistance), through rallies, fasts, and demonstrations in protest of establishing the prawn farms.", "They have been beaten up by hired goons, their houses have been burnt, and LAFTI workers have been imprisoned, because of false accusations of looting and arson.", "Undeterred by this, Jagannathan filed a 'public interest petition' in the Indian Supreme Court, which in turn asked NEERI (National Environmental Engineering Institute of India) to investigate the matter.", "NEERI's investigation report highlighted the environmental cost of the prawn farms to the nation and recommended all prawn farms within 500 meters of the coast to be banned.", "In December 1996 the Supreme Court issued a ruling against intensive shrimp farming in cultivable lands within 500 meters of the coastal area.", "It is said that because of the prawn farmers' local political influence, the Supreme Court judgement was not implemented on the ground.", "The legal battle around the prawn farms is still not resolved and the Jagannathans continue their struggle to establish non-exploitative, eco-friendly communities in the coastal areas of Tamil Nadu.", "Jagannathan also works towards upliftment of women in Dalits and poor.", "She believes in mobilising women's cause by peaceful means.", "Jagannathan, either independently or together with her husband, has established a total of seven non-governmental institutions for the poor.", "In addition to this she has also played an active role in wider public life.", "She has been a Senate member of the Gandhigram Trust and University and of Madurai University.", "She was also a member of a number of local and state social welfare committees and a member of the National Committee on Education, the Land Reform Committee and the Planning Committee.", "These activities have gained for the Jagannathans a high profile in India and they have won many awards: the Swami Pranavananda Peace Award (1987); the Jamnalal Bajaj Award (1988) and Padma Shri in 1989.", "In 1996 the couple received the Bhagavan Mahaveer Award \"for propagating non-violence.\"", "In 1999 Krishnammal was awarded a Summit Foundation Award (Switzerland), and in 2008 she was awarded 'Opus Prize' by the University of Seattle.", "She also received the Right Livelihood Award along with her husband \"for two long lifetimes of work dedicated to realising in practice the Gandhian vision of social justice and sustainable human development, for which they have been referred to as 'India's soul'\".", "She is lovingly called as \"Amma\" (Mother in Tamil) by her followers.", "She plans to use the award money for her projects rather than for herself.", "Inspired by Amma's contribution of enabling more than 11000 poor and landless women to become landowners, a M.Phil research dissertation is dedicated to Amma.", "The dissertation is titled as \"Aspects of Agrarian History of Tamilakam:Region, Women and Technology during 16th and 17th centuries AD\", submitted to Department of History, University of Hyderabad in 2009." ]

[ 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 ]

[ "Her work includes upliftment of the landless, and the poor; she has sometimes fought against governments as well as big industries." ]

[ "Jagannathan was born into a Dalit family in 1926.", "She encountered social injustice and poverty in her daily life as she observed her mother Nagammal who toiled hard and had to continue working even as she was in the advanced stages of pregnancy.", "Despite being from a poor family, she managed to get a university education and was soon involved with the Gandhian Sarvodaya Movement.", "It was through Sarvodaya that she met Sankaralingam, who would later become her husband.", "Sankaralingam hailed from a wealthy family, but discontinued his college education in 1930 in response to Gandhi's call for non-co-operation movement and civil disobedience.", "Krishnammal shared a stage with Mahatma Gandhi and met with Martin Luther King Jr. Sankaralinga later joined the Quit India Movement in 1942 and spent years in jail before India gained its independence in 1947.", "Having decided only to marry in independent India Sankaralingam and Krishnammal married in 1950.", "She would later lead the Salt Satyagraha march in Vedaranyam, this time not in protest, but to commemorate the platinum jubilee of the event in 2006.", "Sankaralingam and Krishnammal believed that one of the key requirements for achieving a Gandhian society is by empowering the rural poor through redistribution of land to the landless.", "For two years between 1950 and 1952 Sankaralingam was with Vinoba Bhave in Northern India on his Bhoodan (land-gift) Padayatra (pilgrimage on foot), the march appealing to landlords to give one sixth of their land to the landless.", "Meanwhile, Krishnammal completed her teacher-training course in Madras (now renamed Chennai).", "When Sankaralingam returned to Tamil Nadu to start the Bhoodhan movement the couple, until 1968, worked for land redistribution through Vinoba Bhave's Gramdan movement (Village Gift, the next phase of the land-gift movement), and through Satyagraha (non-violent resistance).", "Sankaralingam was imprisoned many times for this work.", "Between 1953 and 1967, the couple played an active role in the Bhoodhan movement spearheaded by Vinoba Bhave, through which about of land were distributed to thousands of landless poor across several Indian states.", "After the burning of 42 Dalits including women and children in the Kilvenmani massacre in Nagapattinam district following a wage-dispute with the landlord in 1968, the couple started to work in Thanjavur District in Tamil Nadu to concentrate on land reform issues.", "It was this incident that would inspire the couple, Krishnammal and Sankaralaingam to start the organisation LAFTI.", "Jagannathan founded Land for Tillers' Freedom in 1981 with her husband.", "The purpose of the organisation was to bring \"the landlords and landless poor to the negotiating table, obtain loans to enable the landless to buy land at reasonable price and then to help them work it cooperatively, so that the loans could be repaid\".", "Although the initial response was lukewarm with banks unwilling to lend and the high rates of stamp duty, Jagannathan managed to go on with the cause.", "By 2007, through LAFTI, she had transferred to about 13,000 families.", "Through LAFTI, she also conducted workshops to allow people, during the nonagricultural season, to support themselves through entrepreneurial efforts like mat weaving, tailoring, plumbing, carpentry, masonry, computer education and electronics.", "LAFTI would gain such popularity that later even the Government of India would implement LAFTI's approach to increase the peaceful transfer of land.", "In 1992 Jagannathan started working on issues concerned with prawn farms along the coast of Tamil Nadu.", "This time the problems were not from the local landlords, but from large industries from cities such as Chennai, Mumbai, Kolkata, Delhi and Hyderabad which occupied large areas of land for aquaculture along the coast, which not only threw the landless labourers out of employment but also converted fertile and cultivable land into salty deserts after a few years when the prawn companies moved on.", "The prawn farms also caused heavy seepage of seawater into the groundwater in the neighbourhood, thus the local people were deprived of clean drinking water resources.", "The result is that even more small farmers sell their meagre land-holdings to multinational prawn companies and move to the cities, filling urban slums.", "To address prawn farm issue the Jagannathans organised the whole of LAFTI's village movement to raise awareness among the people to oppose the prawn farms.", "Since 1993, the villagers have offered Satygraha (non-violent resistance), through rallies, fasts, and demonstrations in protest of establishing the prawn farms.", "They have been beaten up by hired goons, their houses have been burnt, and LAFTI workers have been imprisoned, because of false accusations of looting and arson.", "Undeterred by this, Jagannathan filed a 'public interest petition' in the Indian Supreme Court, which in turn asked NEERI (National Environmental Engineering Institute of India) to investigate the matter.", "NEERI's investigation report highlighted the environmental cost of the prawn farms to the nation and recommended all prawn farms within 500 meters of the coast to be banned.", "In December 1996 the Supreme Court issued a ruling against intensive shrimp farming in cultivable lands within 500 meters of the coastal area.", "It is said that because of the prawn farmers' local political influence, the Supreme Court judgement was not implemented on the ground.", "The legal battle around the prawn farms is still not resolved and the Jagannathans continue their struggle to establish non-exploitative, eco-friendly communities in the coastal areas of Tamil Nadu.", "Jagannathan also works towards upliftment of women in Dalits and poor.", "She believes in mobilising women's cause by peaceful means.", "Jagannathan, either independently or together with her husband, has established a total of seven non-governmental institutions for the poor.", "In addition to this she has also played an active role in wider public life.", "She has been a Senate member of the Gandhigram Trust and University and of Madurai University.", "She was also a member of a number of local and state social welfare committees and a member of the National Committee on Education, the Land Reform Committee and the Planning Committee.", "These activities have gained for the Jagannathans a high profile in India and they have won many awards: the Swami Pranavananda Peace Award (1987); the Jamnalal Bajaj Award (1988) and Padma Shri in 1989.", "In 1996 the couple received the Bhagavan Mahaveer Award \"for propagating non-violence.\"", "In 1999 Krishnammal was awarded a Summit Foundation Award (Switzerland), and in 2008 she was awarded 'Opus Prize' by the University of Seattle.", "She also received the Right Livelihood Award along with her husband \"for two long lifetimes of work dedicated to realising in practice the Gandhian vision of social justice and sustainable human development, for which they have been referred to as 'India's soul'\".", "She is lovingly called as \"Amma\" (Mother in Tamil) by her followers.", "She plans to use the award money for her projects rather than for herself.", "Inspired by Amma's contribution of enabling more than 11000 poor and landless women to become landowners, a M.Phil research dissertation is dedicated to Amma.", "The dissertation is titled as \"Aspects of Agrarian History of Tamilakam:Region, Women and Technology during 16th and 17th centuries AD\", submitted to Department of History, University of Hyderabad in 2009." ]

[ 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47 ]

[ "In 2008 she received the Right Livelihood Award, which she shared with her husband." ]

[ "In Japan, a traditional reed mat is the tatami (畳).", "Tatami are covered with a weft-faced weave of (common rush), on a warp of hemp or weaker cotton.", "There are four warps per weft shed, two at each end (or sometimes two per shed, one at each end, to cut costs).", "The (core) is traditionally made from sewn-together rice straw, but contemporary tatami sometimes have compressed wood chip boards or extruded polystyrene foam in their cores, instead or as well.", "The long sides are usually with brocade or plain cloth, although some tatami have no edging.", "In the Philippines, woven reed mats are called banig.", "They are used as sleeping mats or floor mats, and were also historically used as sails.", "They come in many different weaving styles and typically have colorful geometric patterns unique to the ethnic group that created them.", "They are made from buri palm leaves, pandan leaves, rattan, or various kinds of native reeds known by local names like \"tikog\", \"sesed\" (\"Fimbristykis miliacea\"), \"rono\", or \"bamban\".", "In Thailand and Cambodia, the mats are produced by plaiting reeds, strips of palm leaf, or some other easily available local plant.", "The supple mats made by this process of weaving without a loom are widely used in Thai homes.", "These mats are also now being made into shopping bags, place mats, and decorative wall hangings.", "One popular kind of Thai mat is made from a kind of reed known as Kachud, which grows in the southern marshes.", "After the reeds are harvested, they are steeped in mud, which toughens them and prevents them from becoming brittle.", "They are then dried in the sun for a time and pounded flat, after which they are ready to be dyed and woven into mats of various sizes and patterns.", "Other mats are produced in different parts of Thailand, most notably in the eastern province of Chanthaburi.", "Durable as well as attractive, they are plaited entirely by hand with an intricacy that makes the best resemble finely woven fabrics.", "In India, reed mats (called paay in Tamil or chatai in Hindi) are used as cooling and eco-friendly floor coverings." ]

[ 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 ]

[ "Reed mats are handmade mats of plaited reed or other plant material." ]

[ "Born into a mining family in 1940 and educated at Westoe Secondary Modern, Olley began his working life 1955 as a painter and decorator before going into the mining industry in which he spent eleven years at Whitburn Colliery until the pit closed 1968.", "Leaving the industry he joined Plessey Telecoms by which time he was developing his artistic talents with the hope of becoming a professional magazine illustrator supplementing his income by selling his paintings at the Sunday Painters Exhibition on Bayswater Road, London.", "By 1972 he had two exhibitions under his belt.", "It was in the second of these that the now world-famous painting \"Westoe Netty\" was first exhibited.", "There was an outcry of indecency from an alderman who attempted to have the show closed down.", "By the time the council had met and discussed the problem the exhibition was finished but the publicity that it had generated catapulted Olley's career forward allowing him to leave the telecoms industry in 1974 and become a full-time professional painter selling his work with like- minded artists on the Armstrong Bridge, Newcastle every Sunday.", "Between 1972 and 1978 he completed many commissions producing work for both Tyne Tees and BBC, a theatre company and a number of murals.", "By now he had moved into the field of ceramics and cold cast bronze figurines which, along with drawings and paintings made up one hundred works in total for his first one-man exhibition \"The Heart and Humour of the North East” Robert Olley Sculpture Castings Ltd. was formed 1979 to produce a range of small cold cast bronze mining figures from his factory in Washington.", "The 1984/5 coal strike was a disaster for the business and as orders dried up he closed the factory and relocated to South Shields where he opened \"The Gambling Man Gallery\" that became a popular attraction of the town's Catherine Cookson Trail.", "In the following years he worked on some large projects like sculptures of John Simpson Kirkpatrick, the towns WW1 Hero of Gallipoli and Stan Laurel for Persimmon Homes sited in Dockwray Square North Shields and unveiled by MP Mr Neville Trotter.", "The sculpture of John Simpson Kirkpatrick was erected In 1988, in Ocean Road, not far from the town’s museum.", "The 2.5m tall bronze coloured sculpture, mounted on a large concrete base, was unveiled by the Mayor, Councillor Albert Tate.", "In 1995, the towns MP Dr. David Clark opened \"Old, New, Borrowed and Blue\" Olleys' first exhibition for seventeen years.", "After the success of the exhibition he spent time in Spain working on new material and gaining fresh inspiration.", "In 1996, NEXUS, the Tyne and Wear Transport Executive sponsored \"Robert Olley at Work.\"", "The exhibition was opened by its Director General Mr. Mike Parker.", "As artist in residence Olley spent four weeks working in the gallery of The Customs House, South Shields where he painted the 16 ft x 4 ft mural \"Famous Faces\" depicting North East personalities from the world of sport, TV, music, business and the church peering from the windows of a metro carriage.", "It is now displayed at Monument metro station, Newcastle.\n2000.", "\"This, that and some of the other\" a display of some fifty paintings mostly documenting everyday street life at the beginning of the new century.", "The largest painting displayed, \"Off the Way\" (Three miners lifting a coal truck back onto the track) is featured on the front cover of the 2002 publication \"Shafts of Light\" Mining Art in the Great Northern Coalfield.", "The exhibition was opened by actor, comedian and radio presenter Mike Elliott.", "Later that year South Shield's twin town Noisy –Le –Sec, France invited him to show his work in the Centre Gerard- Philipe.", "The exhibition was opened by Mm.", "Claude Roger Secretary General of the Comite De Jumilage De Noisy-Le-Sec.", "Although it didn't have a theme was exceptionally well received by the French and especially by the many parties of school children that attended as part of the project.", "He was astonished at the amount of interest that the pupils showed in the mining subjects and spent much of the time answering their questions.", "There is now a permanent display of his mining sculpture that is exhibited around the schools in the area around Paris.", "Having briefly returned to the subject of coal mining the Hutchinson Gallery, Bishop Auckland in 2002 invited Olley to exhibit.", "\"Toil, Sweat, Water and Dust\" was opened by the late Mr David Guy, President, DMA & NUM North East Area.", "Olley said he was returning to his roots as Durham was the heart of the mining industry for more than a century.", "Both his great grandfathers Robert Smith, an illiterate miner, born in Coundon and Peter Greenwell a publican lived in Croxdale, managing several public houses in the area including the Britannia Inn in the City.", "To celebrate forty years of Town Twinning Noisy-Le-Sec commissioned Olley to design a mural to commemorate the occasion.", "The 4x3 metre panel depicting the links with South Shields, Arganda del Rey (Spain) and Djeol (Mauritania) was unveiled by Madam le Maire, Nicol RIVOIRE in 2003.", "In June, after completing the twin town mural he visited an exhibition of Marc Chagall in Paris.", "Inspired by Chagall's abstract works on the fables of Jean de la Fontaine, he started a new work with a changed subject, medium and style.", "The subject was the fables of Aesop, the medium, gouache and the style semi-abstract.", "Olley visited Greece, the birthplace of Aesop and researched almost six hundred fables, produced many rough sketches and in the space of twelve weeks completed forty works to be exhibited.", "The Exhibition, \"Olley on Aesop\" was opened by Member of Parliament for South Shields, David Miliband.", "The following December the exhibition went to the McGuiness Gallery, Bishop Auckland.", "After the Aesop exhibitions, he turned his attention to the French fabulist La Fontaine.", "Twenty new works were produced for exhibitions in both the twin towns of Noisy-Le-Sec and Epinay-Sur-Seine.", "Opened officially the mayors of both towns Mm Rivoire and Mr Herve Chevreau respectively.", "South Tyneside District Hospital commissioned Olley in 2005 to produce a mural for the children's waiting area of the radiography department and a large painting for the adult area.", "For the mural he reverted to the style of the Aesop fables with bright colours and many animals.", "This mural work continued in 2006 with a commission from the Primary Care Trust for the new health centre situated in Flagg Court.", "The theme of the 4 x 1.5-metre bas relief wall metallic finish panel was health, care and water from Celtic times to the present incorporating the history of the borough, titled, \"Salus Curatio et Aqua.\"", "Sited in the reception area it was unveiled by the towns MP Mr David Miliband who officially opened the centre in July 2007.", "In 2008, he travelled to Chengdu, Sichuan Province, China to work in the foundry that he contracted to cast the life sized bronze sculpture of Stan Laurel (his second Laurel sculpture) commissioned by Wear Valley District Council.", "The statue that had survived the earth quake that devastated the foundry and surrounding of Sichuan in May finally arrived in the UK after a 5.000-mile journey was unveiled 4 September that year by Nancy Wardell, Stan's niece to the applause of \"Sons of the Desert\" the international Laurel and Hardy appreciation society.", "Stan on his black marble plinth stands on Theatre Corner, Bishop Auckland Town Centre, the site of the Eden Theatre owned at one time by his father.", "In June 2010, Bob Olley opened his latest exhibition \"Mining to Abstraction\".", "According to Olley, techniques for this exhibition have been gleaned from Egyptian, Assyrian, Mongolian, Chinese and Mexican art.", "He also drew inspiration from the Hindu culture, its art, sculpture and vibrant colours.", "The main exhibition was based on the Kama Sutra and erotic statues that adorn the temples of Khajuraho and executed in the rich colours of the Indian continent.", "This new body of work is in sharp contrast to his earlier mining paintings and drawings that formed part of this retrospective and celebratory exhibition.", "Olley has four children, Daryl, Dene, Graeme, and Kim and 12 Grandchildren,Damonon, Sean, Sam, Neve, Lewis, Emily, Jessika, Lucy, Daryl, Harry and Josephine." ]

[ 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54 ]

[ "Robert \"Bob\" Olley (born 16 January 1940) is an artist and sculptor best known for his mining subjects, humorous drawings and paintings of everyday life, especially his iconic painting and internationally acclaimed \"Westoe Netty\"." ]

[ "It is April 3 and Phil's birthday coincides with the launch of the new Apple iPad.", "Being an early adopter and a technophile, Phil wants to wake up early to get in line for the product at the local Apple store.", "Claire wants him to have a relaxing birthday so she takes it upon herself to wake up early and go buy the product.", "She does wake up early, but quickly falls back to sleep on the couch; it is not until the family wakes up and is making breakfast that she manages to sneak out of the house to get in line.", "However, the local store has sold out by the time she gets there, so she returns empty-handed.", "After being confronted by Phil, she makes it her mission to get one for the rest of the day.", "Phil decides to go to the batting cages to cool off and mistakenly believes a child's birthday party is for him – only adding to his unhappiness, so he eats a 'Game changer', (a pancake with bacon and golden syrup) to cheer himself up.", "Jay has purchased a chess set for Phil.", "Jay decides to challenge Manny not knowing that Manny is a good player.", "Gloria, not wanting Jay to be a sore loser, tells Manny to throw the game.", "When Jay keeps trying to get Manny to try a child's version of chess, Manny is insulted and challenges Jay to a rematch.", "Manny states that if he wins, he gets Jay's watch and beats Jay in four moves.", "Gloria tells Jay she is also an excellent player but lets Jay think he is better.", "Jay – believing he is winning – decides to call the game because he does not want an unhappy wife while Gloria reveals that she would have beaten him in two moves.", "She says to the camera \"I'm an excellent chess player, but a better wife\".", "The night before Phil's birthday, Cameron and Mitchell hear a man's voice coming from Lily's room.", "They believe that it might be a burglar.", "They then discover that there was no burglar; just a signal accidentally received from a neighboring house by the baby monitor.", "The next day, Mitchell asks Jay to help him toughen up so that if it actually happens in the future, he can take more appropriate action while Cameron keeps listening to conversations from the baby monitor.", "He discovers that a misunderstanding may cause a divorce and decides to tell the wife the truth before anything bad happens.", "Meanwhile, Claire comes home without an iPad.", "However, Luke manages to convince a man online that his father was dying and his last wish was an iPad – so the man brought a second iPad over and gave it to Luke to give to Phil.", "That night, during the party, she brings out the iPad to a delighted Phil.", "In the end, Mitchell and Cameron listen to the couple talk about how Cameron must be an angel, but Cameron quickly turns it off when the couple realizes that he may have been a creepy pervert.", "The episode was written by Joe Lawson & Alex Herschlag, Joe Lawson's third writing credit and Alex's first writing credit.", "It was directed by Kevin Sullivan.", "The episode includes guest stars Kevin Fry-Bowers as the security guard at the Apple Store, Jason Antoon as Clark, Whitney Claire Kaufman as Sarah, Tyrel Jackson Williams as Little Phil, Harrison White as the postman and Zak Boggan as the kid outside the batting cage.", "Although the iPad was prominently featured, Apple Inc. did not pay for product placement within this episode.", "In its original American broadcast, \"Game Changer\" came second in its timeslot after \"American Idol\" being viewed by 9.34 million viewers and an 18-49 Nielsen Rating of 3.8 rating and an 11% share beating last week's 3.7.", "The show was the 4th most viewed show of the night.", "The episode ranked 20 in the weekly viewership ranking sixth for ABC and ranked 8 in the 18-49 Nielsen Rating ranking 3rd on ABC in the rating.", "The episode received positive reviews.", "Robert Canning of \"IGN\" gave the episode an 8 saying it was \"impressive\" and \"though \"Game Changer\" lacked creativity when it came to storylines, the likeability of these characters kept the tone fun and made the episode enjoyable.", "\"\nLesley Savage of \"Entertainment Weekly\" gave the episode positive review saying: \"It’s the little things that make this show so clever.\".", "Donna Bowman from \"The A.V. Club\" gave the episode an A−, saying \"Even though there were funny moments in the other two stories, Phil's journey from excitement to near-catatonic resignation (\"honey, it's okay, I don't feel things anymore,\" he reassures Claire) to euphoric rebirth was brilliantly played\"\nJoel Keller of \"The TV Squad\" criticized the episode for product placement of the iPad saying \"Look, I'm not an Apple hater; I love my iPod Touch, and one day I may convert from being a PC guy to a Mac guy.", "But this company has enough buzz from tech media types who get the vapors every time Jobs dons his black mock turtleneck to introduce a new product, and it's not like they don't already have a monstrous advertising budget.", "Do they really need to infect our favorite shows, too?\"" ]

[ 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 ]

[ "Meanwhile, Mitchell wants to toughen up and Cameron hears a neighbor's marital difficulties over the baby monitor.", "Cameron tries to help his neighbors not to get a divorce and is pleased when he succeeds.", "Jay faces off with Manny and Gloria over chess." ]

[ "It is April 3 and Phil's birthday coincides with the launch of the new Apple iPad.", "Being an early adopter and a technophile, Phil wants to wake up early to get in line for the product at the local Apple store.", "Claire wants him to have a relaxing birthday so she takes it upon herself to wake up early and go buy the product.", "She does wake up early, but quickly falls back to sleep on the couch; it is not until the family wakes up and is making breakfast that she manages to sneak out of the house to get in line.", "However, the local store has sold out by the time she gets there, so she returns empty-handed.", "After being confronted by Phil, she makes it her mission to get one for the rest of the day.", "Phil decides to go to the batting cages to cool off and mistakenly believes a child's birthday party is for him – only adding to his unhappiness, so he eats a 'Game changer', (a pancake with bacon and golden syrup) to cheer himself up.", "Jay has purchased a chess set for Phil.", "Jay decides to challenge Manny not knowing that Manny is a good player.", "Gloria, not wanting Jay to be a sore loser, tells Manny to throw the game.", "When Jay keeps trying to get Manny to try a child's version of chess, Manny is insulted and challenges Jay to a rematch.", "Manny states that if he wins, he gets Jay's watch and beats Jay in four moves.", "Gloria tells Jay she is also an excellent player but lets Jay think he is better.", "Jay – believing he is winning – decides to call the game because he does not want an unhappy wife while Gloria reveals that she would have beaten him in two moves.", "She says to the camera \"I'm an excellent chess player, but a better wife\".", "The night before Phil's birthday, Cameron and Mitchell hear a man's voice coming from Lily's room.", "They believe that it might be a burglar.", "They then discover that there was no burglar; just a signal accidentally received from a neighboring house by the baby monitor.", "The next day, Mitchell asks Jay to help him toughen up so that if it actually happens in the future, he can take more appropriate action while Cameron keeps listening to conversations from the baby monitor.", "He discovers that a misunderstanding may cause a divorce and decides to tell the wife the truth before anything bad happens.", "Meanwhile, Claire comes home without an iPad.", "However, Luke manages to convince a man online that his father was dying and his last wish was an iPad – so the man brought a second iPad over and gave it to Luke to give to Phil.", "That night, during the party, she brings out the iPad to a delighted Phil.", "In the end, Mitchell and Cameron listen to the couple talk about how Cameron must be an angel, but Cameron quickly turns it off when the couple realizes that he may have been a creepy pervert.", "The episode was written by Joe Lawson & Alex Herschlag, Joe Lawson's third writing credit and Alex's first writing credit.", "It was directed by Kevin Sullivan.", "The episode includes guest stars Kevin Fry-Bowers as the security guard at the Apple Store, Jason Antoon as Clark, Whitney Claire Kaufman as Sarah, Tyrel Jackson Williams as Little Phil, Harrison White as the postman and Zak Boggan as the kid outside the batting cage.", "Although the iPad was prominently featured, Apple Inc. did not pay for product placement within this episode.", "In its original American broadcast, \"Game Changer\" came second in its timeslot after \"American Idol\" being viewed by 9.34 million viewers and an 18-49 Nielsen Rating of 3.8 rating and an 11% share beating last week's 3.7.", "The show was the 4th most viewed show of the night.", "The episode ranked 20 in the weekly viewership ranking sixth for ABC and ranked 8 in the 18-49 Nielsen Rating ranking 3rd on ABC in the rating.", "The episode received positive reviews.", "Robert Canning of \"IGN\" gave the episode an 8 saying it was \"impressive\" and \"though \"Game Changer\" lacked creativity when it came to storylines, the likeability of these characters kept the tone fun and made the episode enjoyable.", "\"\nLesley Savage of \"Entertainment Weekly\" gave the episode positive review saying: \"It’s the little things that make this show so clever.\".", "Donna Bowman from \"The A.V. Club\" gave the episode an A−, saying \"Even though there were funny moments in the other two stories, Phil's journey from excitement to near-catatonic resignation (\"honey, it's okay, I don't feel things anymore,\" he reassures Claire) to euphoric rebirth was brilliantly played\"\nJoel Keller of \"The TV Squad\" criticized the episode for product placement of the iPad saying \"Look, I'm not an Apple hater; I love my iPod Touch, and one day I may convert from being a PC guy to a Mac guy.", "But this company has enough buzz from tech media types who get the vapors every time Jobs dons his black mock turtleneck to introduce a new product, and it's not like they don't already have a monstrous advertising budget.", "Do they really need to infect our favorite shows, too?\"" ]

[ 24, 25, 26, 27 ]

[ "The episode's teleplay was written by Joe Lawson & Alex Herschlag from a story by Vanessa McCarthy & Joe Lawson.", "It was directed by Kevin Sullivan." ]

[ "It is April 3 and Phil's birthday coincides with the launch of the new Apple iPad.", "Being an early adopter and a technophile, Phil wants to wake up early to get in line for the product at the local Apple store.", "Claire wants him to have a relaxing birthday so she takes it upon herself to wake up early and go buy the product.", "She does wake up early, but quickly falls back to sleep on the couch; it is not until the family wakes up and is making breakfast that she manages to sneak out of the house to get in line.", "However, the local store has sold out by the time she gets there, so she returns empty-handed.", "After being confronted by Phil, she makes it her mission to get one for the rest of the day.", "Phil decides to go to the batting cages to cool off and mistakenly believes a child's birthday party is for him – only adding to his unhappiness, so he eats a 'Game changer', (a pancake with bacon and golden syrup) to cheer himself up.", "Jay has purchased a chess set for Phil.", "Jay decides to challenge Manny not knowing that Manny is a good player.", "Gloria, not wanting Jay to be a sore loser, tells Manny to throw the game.", "When Jay keeps trying to get Manny to try a child's version of chess, Manny is insulted and challenges Jay to a rematch.", "Manny states that if he wins, he gets Jay's watch and beats Jay in four moves.", "Gloria tells Jay she is also an excellent player but lets Jay think he is better.", "Jay – believing he is winning – decides to call the game because he does not want an unhappy wife while Gloria reveals that she would have beaten him in two moves.", "She says to the camera \"I'm an excellent chess player, but a better wife\".", "The night before Phil's birthday, Cameron and Mitchell hear a man's voice coming from Lily's room.", "They believe that it might be a burglar.", "They then discover that there was no burglar; just a signal accidentally received from a neighboring house by the baby monitor.", "The next day, Mitchell asks Jay to help him toughen up so that if it actually happens in the future, he can take more appropriate action while Cameron keeps listening to conversations from the baby monitor.", "He discovers that a misunderstanding may cause a divorce and decides to tell the wife the truth before anything bad happens.", "Meanwhile, Claire comes home without an iPad.", "However, Luke manages to convince a man online that his father was dying and his last wish was an iPad – so the man brought a second iPad over and gave it to Luke to give to Phil.", "That night, during the party, she brings out the iPad to a delighted Phil.", "In the end, Mitchell and Cameron listen to the couple talk about how Cameron must be an angel, but Cameron quickly turns it off when the couple realizes that he may have been a creepy pervert.", "The episode was written by Joe Lawson & Alex Herschlag, Joe Lawson's third writing credit and Alex's first writing credit.", "It was directed by Kevin Sullivan.", "The episode includes guest stars Kevin Fry-Bowers as the security guard at the Apple Store, Jason Antoon as Clark, Whitney Claire Kaufman as Sarah, Tyrel Jackson Williams as Little Phil, Harrison White as the postman and Zak Boggan as the kid outside the batting cage.", "Although the iPad was prominently featured, Apple Inc. did not pay for product placement within this episode.", "In its original American broadcast, \"Game Changer\" came second in its timeslot after \"American Idol\" being viewed by 9.34 million viewers and an 18-49 Nielsen Rating of 3.8 rating and an 11% share beating last week's 3.7.", "The show was the 4th most viewed show of the night.", "The episode ranked 20 in the weekly viewership ranking sixth for ABC and ranked 8 in the 18-49 Nielsen Rating ranking 3rd on ABC in the rating.", "The episode received positive reviews.", "Robert Canning of \"IGN\" gave the episode an 8 saying it was \"impressive\" and \"though \"Game Changer\" lacked creativity when it came to storylines, the likeability of these characters kept the tone fun and made the episode enjoyable.", "\"\nLesley Savage of \"Entertainment Weekly\" gave the episode positive review saying: \"It’s the little things that make this show so clever.\".", "Donna Bowman from \"The A.V. Club\" gave the episode an A−, saying \"Even though there were funny moments in the other two stories, Phil's journey from excitement to near-catatonic resignation (\"honey, it's okay, I don't feel things anymore,\" he reassures Claire) to euphoric rebirth was brilliantly played\"\nJoel Keller of \"The TV Squad\" criticized the episode for product placement of the iPad saying \"Look, I'm not an Apple hater; I love my iPod Touch, and one day I may convert from being a PC guy to a Mac guy.", "But this company has enough buzz from tech media types who get the vapors every time Jobs dons his black mock turtleneck to introduce a new product, and it's not like they don't already have a monstrous advertising budget.", "Do they really need to infect our favorite shows, too?\"" ]

[ 28, 29, 30, 31, 32, 33, 34, 35, 36 ]

[ "\"Game Changer\" received positive reviews but was criticized for excessively promoting the iPad.", "The episode received an 18-49 Nielsen Rating of 3.8/7." ]

[ "It is April 3 and Phil's birthday coincides with the launch of the new Apple iPad.", "Being an early adopter and a technophile, Phil wants to wake up early to get in line for the product at the local Apple store.", "Claire wants him to have a relaxing birthday so she takes it upon herself to wake up early and go buy the product.", "She does wake up early, but quickly falls back to sleep on the couch; it is not until the family wakes up and is making breakfast that she manages to sneak out of the house to get in line.", "However, the local store has sold out by the time she gets there, so she returns empty-handed.", "After being confronted by Phil, she makes it her mission to get one for the rest of the day.", "Phil decides to go to the batting cages to cool off and mistakenly believes a child's birthday party is for him – only adding to his unhappiness, so he eats a 'Game changer', (a pancake with bacon and golden syrup) to cheer himself up.", "Jay has purchased a chess set for Phil.", "Jay decides to challenge Manny not knowing that Manny is a good player.", "Gloria, not wanting Jay to be a sore loser, tells Manny to throw the game.", "When Jay keeps trying to get Manny to try a child's version of chess, Manny is insulted and challenges Jay to a rematch.", "Manny states that if he wins, he gets Jay's watch and beats Jay in four moves.", "Gloria tells Jay she is also an excellent player but lets Jay think he is better.", "Jay – believing he is winning – decides to call the game because he does not want an unhappy wife while Gloria reveals that she would have beaten him in two moves.", "She says to the camera \"I'm an excellent chess player, but a better wife\".", "The night before Phil's birthday, Cameron and Mitchell hear a man's voice coming from Lily's room.", "They believe that it might be a burglar.", "They then discover that there was no burglar; just a signal accidentally received from a neighboring house by the baby monitor.", "The next day, Mitchell asks Jay to help him toughen up so that if it actually happens in the future, he can take more appropriate action while Cameron keeps listening to conversations from the baby monitor.", "He discovers that a misunderstanding may cause a divorce and decides to tell the wife the truth before anything bad happens.", "Meanwhile, Claire comes home without an iPad.", "However, Luke manages to convince a man online that his father was dying and his last wish was an iPad – so the man brought a second iPad over and gave it to Luke to give to Phil.", "That night, during the party, she brings out the iPad to a delighted Phil.", "In the end, Mitchell and Cameron listen to the couple talk about how Cameron must be an angel, but Cameron quickly turns it off when the couple realizes that he may have been a creepy pervert.", "The episode was written by Joe Lawson & Alex Herschlag, Joe Lawson's third writing credit and Alex's first writing credit.", "It was directed by Kevin Sullivan.", "The episode includes guest stars Kevin Fry-Bowers as the security guard at the Apple Store, Jason Antoon as Clark, Whitney Claire Kaufman as Sarah, Tyrel Jackson Williams as Little Phil, Harrison White as the postman and Zak Boggan as the kid outside the batting cage.", "Although the iPad was prominently featured, Apple Inc. did not pay for product placement within this episode.", "In its original American broadcast, \"Game Changer\" came second in its timeslot after \"American Idol\" being viewed by 9.34 million viewers and an 18-49 Nielsen Rating of 3.8 rating and an 11% share beating last week's 3.7.", "The show was the 4th most viewed show of the night.", "The episode ranked 20 in the weekly viewership ranking sixth for ABC and ranked 8 in the 18-49 Nielsen Rating ranking 3rd on ABC in the rating.", "The episode received positive reviews.", "Robert Canning of \"IGN\" gave the episode an 8 saying it was \"impressive\" and \"though \"Game Changer\" lacked creativity when it came to storylines, the likeability of these characters kept the tone fun and made the episode enjoyable.", "\"\nLesley Savage of \"Entertainment Weekly\" gave the episode positive review saying: \"It’s the little things that make this show so clever.\".", "Donna Bowman from \"The A.V. Club\" gave the episode an A−, saying \"Even though there were funny moments in the other two stories, Phil's journey from excitement to near-catatonic resignation (\"honey, it's okay, I don't feel things anymore,\" he reassures Claire) to euphoric rebirth was brilliantly played\"\nJoel Keller of \"The TV Squad\" criticized the episode for product placement of the iPad saying \"Look, I'm not an Apple hater; I love my iPod Touch, and one day I may convert from being a PC guy to a Mac guy.", "But this company has enough buzz from tech media types who get the vapors every time Jobs dons his black mock turtleneck to introduce a new product, and it's not like they don't already have a monstrous advertising budget.", "Do they really need to infect our favorite shows, too?\"" ]

[ 28, 29, 30 ]

[ "The episode received an 18-49 Nielsen Rating of 3.8/7." ]

[ "It is April 3 and Phil's birthday coincides with the launch of the new Apple iPad.", "Being an early adopter and a technophile, Phil wants to wake up early to get in line for the product at the local Apple store.", "Claire wants him to have a relaxing birthday so she takes it upon herself to wake up early and go buy the product.", "She does wake up early, but quickly falls back to sleep on the couch; it is not until the family wakes up and is making breakfast that she manages to sneak out of the house to get in line.", "However, the local store has sold out by the time she gets there, so she returns empty-handed.", "After being confronted by Phil, she makes it her mission to get one for the rest of the day.", "Phil decides to go to the batting cages to cool off and mistakenly believes a child's birthday party is for him – only adding to his unhappiness, so he eats a 'Game changer', (a pancake with bacon and golden syrup) to cheer himself up.", "Jay has purchased a chess set for Phil.", "Jay decides to challenge Manny not knowing that Manny is a good player.", "Gloria, not wanting Jay to be a sore loser, tells Manny to throw the game.", "When Jay keeps trying to get Manny to try a child's version of chess, Manny is insulted and challenges Jay to a rematch.", "Manny states that if he wins, he gets Jay's watch and beats Jay in four moves.", "Gloria tells Jay she is also an excellent player but lets Jay think he is better.", "Jay – believing he is winning – decides to call the game because he does not want an unhappy wife while Gloria reveals that she would have beaten him in two moves.", "She says to the camera \"I'm an excellent chess player, but a better wife\".", "The night before Phil's birthday, Cameron and Mitchell hear a man's voice coming from Lily's room.", "They believe that it might be a burglar.", "They then discover that there was no burglar; just a signal accidentally received from a neighboring house by the baby monitor.", "The next day, Mitchell asks Jay to help him toughen up so that if it actually happens in the future, he can take more appropriate action while Cameron keeps listening to conversations from the baby monitor.", "He discovers that a misunderstanding may cause a divorce and decides to tell the wife the truth before anything bad happens.", "Meanwhile, Claire comes home without an iPad.", "However, Luke manages to convince a man online that his father was dying and his last wish was an iPad – so the man brought a second iPad over and gave it to Luke to give to Phil.", "That night, during the party, she brings out the iPad to a delighted Phil.", "In the end, Mitchell and Cameron listen to the couple talk about how Cameron must be an angel, but Cameron quickly turns it off when the couple realizes that he may have been a creepy pervert.", "The episode was written by Joe Lawson & Alex Herschlag, Joe Lawson's third writing credit and Alex's first writing credit.", "It was directed by Kevin Sullivan.", "The episode includes guest stars Kevin Fry-Bowers as the security guard at the Apple Store, Jason Antoon as Clark, Whitney Claire Kaufman as Sarah, Tyrel Jackson Williams as Little Phil, Harrison White as the postman and Zak Boggan as the kid outside the batting cage.", "Although the iPad was prominently featured, Apple Inc. did not pay for product placement within this episode.", "In its original American broadcast, \"Game Changer\" came second in its timeslot after \"American Idol\" being viewed by 9.34 million viewers and an 18-49 Nielsen Rating of 3.8 rating and an 11% share beating last week's 3.7.", "The show was the 4th most viewed show of the night.", "The episode ranked 20 in the weekly viewership ranking sixth for ABC and ranked 8 in the 18-49 Nielsen Rating ranking 3rd on ABC in the rating.", "The episode received positive reviews.", "Robert Canning of \"IGN\" gave the episode an 8 saying it was \"impressive\" and \"though \"Game Changer\" lacked creativity when it came to storylines, the likeability of these characters kept the tone fun and made the episode enjoyable.", "\"\nLesley Savage of \"Entertainment Weekly\" gave the episode positive review saying: \"It’s the little things that make this show so clever.\".", "Donna Bowman from \"The A.V. Club\" gave the episode an A−, saying \"Even though there were funny moments in the other two stories, Phil's journey from excitement to near-catatonic resignation (\"honey, it's okay, I don't feel things anymore,\" he reassures Claire) to euphoric rebirth was brilliantly played\"\nJoel Keller of \"The TV Squad\" criticized the episode for product placement of the iPad saying \"Look, I'm not an Apple hater; I love my iPod Touch, and one day I may convert from being a PC guy to a Mac guy.", "But this company has enough buzz from tech media types who get the vapors every time Jobs dons his black mock turtleneck to introduce a new product, and it's not like they don't already have a monstrous advertising budget.", "Do they really need to infect our favorite shows, too?\"" ]

[ 31, 32, 33, 34, 35, 36 ]

[ "\"Game Changer\" received positive reviews but was criticized for excessively promoting the iPad." ]

[ "\"L' Autrichienne\", which is Jucifer's fourth album, was recorded in July 2007 at Bakery Studios by Andy Baker.", "It was released in 2008, two years after the release of the band's previous album, \"If Thine Enemy Hunger\", by Relapse Records; on March 18 in the United States and on March 24 internationally.", "To support the album, Jucifer embarked on their first tour through Europe.", "After the European tour they toured over the Northeastern United States and Canada.", "According to Greg Prato from Allmusic, there are so many different styles found in \"L'Autrichienne\" that it would be possible to fool the average listener into thinking each track was made by a different band; it shows influences ranging from indie rock to sludge metal.", "In the album there are songs with a style close to Black Sabbath's, such as \"Blackpowder\", hardcore punk tracks like \"Thermidor\", Melvins-esque metal slow pieces such as \"Deficit\", and doom metal songs such as \"The Mountain\" and \"Procession a la Guillotine\"; even quiet balladry can be found in the album.", "Amber Valetine uses many vocal techniques in the record.", "It's a concept album about the French Revolution.", "Although the album includes songs about many events of the period, and its lyrics reflect voices of major figures ranging from the peasantry to the deposed King and Queen and their court, the title refers to Marie Antoinette, who was nicknamed \"l'Autrichienne\" (French: \"the Austrian\") due to her Austrian origin.", "The name seems on its surface merely descriptive, but in context of the Revolution was used derisively, as it is a homonym of \"l'autre chienne\"", "[\"the other bitch\"].", "The band chose this title for its historical relevance and double entendre meaning.", "Guitarist/vocalist Valentine had been intrigued with this period of history, and Marie Antoinette's poor treatment by peers and historians, since receiving a historical paper doll book including Antoinette at the age of six.", "During the intervening 30 years, Valentine read voraciously about the time period and was inspired to write most of the double album's worth of songs (the remainder written by drummer and co-founding member Edgar Livengood).", "The album's liner notes feature a historical commentary to each song, written by Valentine and based on her lifelong research about the French Revolution.", "\"L' Autrichienne\" was given a 4.5 out of 5 in AllMusic and an 8.0 of 10 in Pitchfork Media.", "Both praised the musical variety which can be appreciated in the album.", "Gazelle Amber Valentine's work as a singer in this album has been compared to young PJ Harvey's as well as Courtney Love's.", "Her ability to shift from one vocal technique to another has been praised specially by Greg Prato from Allmusic, who asserts only very talented vocalists are able to do what she does.", "Music by Jucifer.", "Lyrics written by Amber Valentine." ]

[ 0, 1, 2, 3 ]

[ "L'Autrichienne is the fourth album by the American metal band Jucifer.", "It was first released on March 18, 2008." ]

[ "\"L' Autrichienne\", which is Jucifer's fourth album, was recorded in July 2007 at Bakery Studios by Andy Baker.", "It was released in 2008, two years after the release of the band's previous album, \"If Thine Enemy Hunger\", by Relapse Records; on March 18 in the United States and on March 24 internationally.", "To support the album, Jucifer embarked on their first tour through Europe.", "After the European tour they toured over the Northeastern United States and Canada.", "According to Greg Prato from Allmusic, there are so many different styles found in \"L'Autrichienne\" that it would be possible to fool the average listener into thinking each track was made by a different band; it shows influences ranging from indie rock to sludge metal.", "In the album there are songs with a style close to Black Sabbath's, such as \"Blackpowder\", hardcore punk tracks like \"Thermidor\", Melvins-esque metal slow pieces such as \"Deficit\", and doom metal songs such as \"The Mountain\" and \"Procession a la Guillotine\"; even quiet balladry can be found in the album.", "Amber Valetine uses many vocal techniques in the record.", "It's a concept album about the French Revolution.", "Although the album includes songs about many events of the period, and its lyrics reflect voices of major figures ranging from the peasantry to the deposed King and Queen and their court, the title refers to Marie Antoinette, who was nicknamed \"l'Autrichienne\" (French: \"the Austrian\") due to her Austrian origin.", "The name seems on its surface merely descriptive, but in context of the Revolution was used derisively, as it is a homonym of \"l'autre chienne\"", "[\"the other bitch\"].", "The band chose this title for its historical relevance and double entendre meaning.", "Guitarist/vocalist Valentine had been intrigued with this period of history, and Marie Antoinette's poor treatment by peers and historians, since receiving a historical paper doll book including Antoinette at the age of six.", "During the intervening 30 years, Valentine read voraciously about the time period and was inspired to write most of the double album's worth of songs (the remainder written by drummer and co-founding member Edgar Livengood).", "The album's liner notes feature a historical commentary to each song, written by Valentine and based on her lifelong research about the French Revolution.", "\"L' Autrichienne\" was given a 4.5 out of 5 in AllMusic and an 8.0 of 10 in Pitchfork Media.", "Both praised the musical variety which can be appreciated in the album.", "Gazelle Amber Valentine's work as a singer in this album has been compared to young PJ Harvey's as well as Courtney Love's.", "Her ability to shift from one vocal technique to another has been praised specially by Greg Prato from Allmusic, who asserts only very talented vocalists are able to do what she does.", "Music by Jucifer.", "Lyrics written by Amber Valentine." ]

[ 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 ]

[ "L'Autrichienne is the fourth album by the American metal band Jucifer." ]

[ "Conceived as a single-seat fighter, the Fa 269 project resulted from a design study order issued by the Reich Air Ministry to Focke-Achgelis in 1941.", "The order called for a local defence fighter which would combine the VTOL capabilities of a helicopter with the speed and economy of a conventional fixed-wing aircraft.", "A large amount of wind tunnel testing was undertaken, along with work on gearboxes, drives and power-pivoting mechanisms, and a full-scale mock-up of the aircraft was built to demonstrate the VTOL concept, but much of this was destroyed by Allied bombing raids and all work was shelved in 1944, when Focke-Achgelis estimated that there was little likelihood of a practical prototype being available before 1947.", "A mid-wing monoplane, the Fa 269 was to have been powered by a single BMW 801 air-cooled radial engine buried in the fuselage behind the cockpit, which was to have driven transverse drive shafts in the leading edges of the fixed wing, the shafts turning three-bladed rotors via synchronised gearboxes.", "The plane of rotation of the rotors would have been capable of being swivelled through 80° using angled extension shafts.", "It was proposed that the Fa 269 would adopt a high angle of attack when at rest using extremely long undercarriage units.", "For vertical take-off, the rotors would be lowered till their plane of rotation was parallel with the ground.", "For translation to conventional flight following take-off, the extension shafts were to pivot to the rear, the rotors then behaving as pusher propellers." ]

[ 0, 1, 2 ]

[ "The Focke-Achgelis Fa 269 was a tiltrotor VTOL aircraft project designed by Henrich Focke." ]

[ "In 1929, MG were attempting to develop their M-type Midget for racing.", "The rear axle leaf springs were mounted in sliding trunnions at the rear end, rather than the more usual shackles.", "The improved axle location encouraged good handling, which compensated when racing for the 750cc engine's low power output.", "Captain George Eyston and Ernest Eldridge saw this chassis under development and decided that it could form the basis for a speed record breaker.", "Fitted with larger brakes from a Mark II, a four speed gearbox and streamlined bodywork, it became the EX120.", "On 30 December 1930 at Montlhéry, EX120 set its first records, beating the Austin Sevens.", "In search of even faster speeds, it was decided to supercharge the car, using Eyston's own Powerplus design of supercharger.", "In February 1931, again at Montlhéry, this became the first 750cc car to exceed 100 mph, at 103.13 mph.", "After this success, MG were prompted to produce a racing replica of it: the C-type or Montlhéry Midget, which was available with or without supercharger.", "Eyston was never satisfied with merely reaching a speed when he could use the same car to break several records by maintaining it for longer periods.", "He set out to hold 100 mph for an hour, using EX120.", "The car reached this speed, but then the engine caught fire.", "Still at a speed of around 60 mph, the Eyston's tall figure managed to jump from the tiny enclosed cockpit, counting on his past fox-hunting experience to roll through the landing without serious injury.", "The car was destroyed, and Eyston then filed another of his many patents for fire-proof asbestos overalls.", "View of MG with driver (from above).", "Round-topped aeroscreen.", "Eyston in Magic Midget (EX120).", "Front R quarter view (newsprint photograph reproduction).", "No screen.", "Eyston in Magic Midget (EX120?), detail of cockpit rear LH wheel and tail.", "Small square flush-mounted screen.", "EX127 was built for Eyston, but initially driven by Eldridge.", "With this car, MG claimed a number of class records at Montlhéry in late 1931 and reached a speed of 120 mph on Pendine Sands in February 1932.", "This was built for Eyston in 1933, based on the supercharged K3 Magnette.", "It had two alternative bodyshells: one with the usual exposed wheels for racing, the other a full-width streamlined body for record-breaking.", "In 1935 Eyston sold it to Goldie Gardner, who then had Reid Railton re-design another bodyshell for it." ]

[ 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 ]

[ "The Magic Midgets were a number of record-breaking 750cc \"midget\" MG cars of the 1930s.", "They were most notably, but not always, driven by George Eyston." ]

[ "In 1929, MG were attempting to develop their M-type Midget for racing.", "The rear axle leaf springs were mounted in sliding trunnions at the rear end, rather than the more usual shackles.", "The improved axle location encouraged good handling, which compensated when racing for the 750cc engine's low power output.", "Captain George Eyston and Ernest Eldridge saw this chassis under development and decided that it could form the basis for a speed record breaker.", "Fitted with larger brakes from a Mark II, a four speed gearbox and streamlined bodywork, it became the EX120.", "On 30 December 1930 at Montlhéry, EX120 set its first records, beating the Austin Sevens.", "In search of even faster speeds, it was decided to supercharge the car, using Eyston's own Powerplus design of supercharger.", "In February 1931, again at Montlhéry, this became the first 750cc car to exceed 100 mph, at 103.13 mph.", "After this success, MG were prompted to produce a racing replica of it: the C-type or Montlhéry Midget, which was available with or without supercharger.", "Eyston was never satisfied with merely reaching a speed when he could use the same car to break several records by maintaining it for longer periods.", "He set out to hold 100 mph for an hour, using EX120.", "The car reached this speed, but then the engine caught fire.", "Still at a speed of around 60 mph, the Eyston's tall figure managed to jump from the tiny enclosed cockpit, counting on his past fox-hunting experience to roll through the landing without serious injury.", "The car was destroyed, and Eyston then filed another of his many patents for fire-proof asbestos overalls.", "View of MG with driver (from above).", "Round-topped aeroscreen.", "Eyston in Magic Midget (EX120).", "Front R quarter view (newsprint photograph reproduction).", "No screen.", "Eyston in Magic Midget (EX120?), detail of cockpit rear LH wheel and tail.", "Small square flush-mounted screen.", "EX127 was built for Eyston, but initially driven by Eldridge.", "With this car, MG claimed a number of class records at Montlhéry in late 1931 and reached a speed of 120 mph on Pendine Sands in February 1932.", "This was built for Eyston in 1933, based on the supercharged K3 Magnette.", "It had two alternative bodyshells: one with the usual exposed wheels for racing, the other a full-width streamlined body for record-breaking.", "In 1935 Eyston sold it to Goldie Gardner, who then had Reid Railton re-design another bodyshell for it." ]

[ 21, 22 ]

[ "They were most notably, but not always, driven by George Eyston." ]

[ "Harley was the eldest surviving son of Thomas Harley, of Kinsham Court, Herefordshire and his wife Abigail Saltonstall, daughter of Sir Richard Saltonstall of Huntwick and Woodsome, Yorkshire and granddaughter of Sir Richard Saltonstall .", "He succeeded his father in 1685.", "He was admitted at Middle Temple in 1682 and called to the bar in 1690.", "Harley was made a deputy lieutenant of Herefordshire in 1694, and was a commissioner for subscriptions to the land bank in 1696.", "He went abroad to Spain and Portugal in 1697, and observed the negotiations for the Treaty of Ryswick on the way home.", "With the support of his cousin Robert, he was returned in a contest as Member of Parliament for Radnorshire at the 1698 English general election.", "Like the rest of his family, he was politically a Tory, and a loyal supporter of his cousin.", "He was returned for Radnorshire unopposed at the first general election of 1701.", "He was blacklisted for opposing preparations being made for war in 1701, and signed a Tory rejoinder.", "He was returned unopposed again at the second general election of 1701 and voted on 26 February 1702 for the motion which vindicated the proceedings of the Commons in impeaching the four Whig Lords.", "Harley was returned unopposed again at the 1702 English general election.", "He was returned again at the 1705 English general election and although a Tory, supported the Court over the Court candidate for Speaker on 25 October 1705, and over the ‘place clause’ in the proceedings on the regency bill on 18 February 1706.", "At the 1708 British general election, he was returned as Tory MP for Radnorshire, and voted against the impeachment of Dr Sacheverell.", "He was returned again at the 1710 British general election and was listed as a ‘worthy patriot’ who exposed the mismanagements of the previous ministry, and a ‘Tory patriot’ favouring peace in April 1711.", "He was a commissioner for taking subscriptions to the South Sea Company in 1711.", "Under his cousin's Administration, he was appointed Junior Secretary to the Treasury in June 1711.", "Harley was an entertaining wit, and a member of Jonathan Swift's circle, and was invited to join the 'Society of Brothers', a dining/drinking-club founded by Henry St John.", "However he was turned out in January 1712 for non-attendance.", "However his tactfulness and subtle dialogue marked him out as a natural diplomat, and he was chosen envoy to Hanover in 1712 to soothe the Elector over Great Britain's willingness to negotiate a peace with France, ending the War of the Spanish Succession.", "While he was well received in Holland and in Hanover, his mission was ultimately unsuccessful.", "In Parliament, he voted in favour of the French commerce bill on 18 June 1713.", "He was returned again for Radnorshire at the 1713 British general election.", "He was sent on another embassy to Hanover in 1714, and was again well-received but unsuccessful.", "The Elector was suspicious of him, and upon King George's ascent to the British throne he lost his place at the Treasury.", "At the 1715 British general election he was defeated in Radnorshire and lost his place on the Commission of the Peace.", "He was also arrested at the request of the committee of secrecy investigating the peace negotiations, and imprisoned for two months.", "Harley died unmarried in January 1738, leaving most of his estate to Edward Harley, 3rd Earl of Oxford and Earl Mortimer." ]

[ 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 ]

[ "He was an ally of his cousin Robert Harley." ]

[ "Campbell was educated at Long Eaton Grammar School and Bedford College of Physical Education, followed by the University of Leicester where she obtained a Master of Education degree.", "She worked as a physical education teacher at Whalley Range High School in Manchester for two years in the early 1970s, before becoming deputy director of Physical Education at Leicester University in 1972.", "She was a lecturer in the Department of Physical Education and Sports Science at Loughborough University from 1976.", "Campbell has received the following Honorary academic degrees:\nHon Doctorate of Education from the Council for National Academic Awards 1992,\nHon Doctorate of Science from the University of Brighton 1993,\nHon Doctorate of Education from De Montfort University 1996,\nHon Doctorate of Technology from the University of Loughborough 1997,\nHon Doctorate of Education from the University of Leicester 2000,\nHon Doctorate of Sport Science from the Leeds Metropolitan University 2006,\nHon Doctorate of Law from the University of Exeter 2010,\nHon Doctor of Humane Letters Endicott College Boston USA 2011,\nHon Doctorate of Art from the Bedfordfordshire University 2011,\nHon Doctorate for Exceptional Service to Sport from the Queen's University 2013,\nHon Degree of Science from the Nottingham Trent University 2016.", "In 1980, Campbell was appointed regional officer for the East Midlands by the Sports Council of Great Britain.", "She was deputy chief executive of the National Coaching Foundation for one year in 1984, before becoming its chief executive for a decade, 1985 to 1995.", "She was appointed MBE in 1991.", "Campbell became chief executive of the Youth Sport Trust in 1995, having played a key role in setting it up.", "She was an adviser to the Department of Culture, Media and Sport and the Department for Education and Skills from 2000 to 2003.", "In 2003 Campbell was appointed as chairman of UK Sport, the new name for the Sports Council of Great Britain, and appointed Commander of the Order of the British Empire (CBE) in the same year.", "She held this position for two terms until April 2013, presiding over Team GB and Paralympic GB's performance at the London 2012 games.", "Campbell retained her executive position with the Youth Sport Trust until 2005 when she became its chairman.", "Campbell stepped down as Chair of the Youth Sport Trust in December 2017.", "On 10 November 2008 she was, on recommendation by the House of Lords Appointments Commission, created Baroness Campbell of Loughborough, of Loughborough in the County of Leicestershire.", "Lady Campbell of Loughborough sits on the crossbenches of the House of Lords.", "She chose to make her maiden speech on the subject of the London 2012 Olympic and Paralympic Games.", "Campbell was appointed Head of Women's Football with The Football Association in March 2016, and became Director of Women's Football in January 2018.", "She was appointed Dame Commander of the Order of the British Empire (DBE) in the 2020 New Year Honours for services to sport.", "In February 2013 she was assessed as one of the 100 most powerful women in the United Kingdom by \"Woman's Hour\" on BBC Radio 4." ]

[ 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 ]

[ "Susan Catherine Campbell, Baroness Campbell of Loughborough, (born 10 October 1948) is a British sports administrator who was chairman of UK Sport between 2003 and 2013." ]

[ "Loftin graduated in 1990 from The Barstow School, an independent private school in Kansas City, Missouri, before attending the U.S. Military Academy at West Point for two years where he was a 1992 All Patriot League soccer player.", "He transferred to the University of Evansville in 1993.", "After completing his collegiate eligibility in the fall of 1994, Loftin attended an open tryout with the Kansas City Attack of the National Professional Soccer League.", "He impressed the coaches and was signed to a contract, becoming a regular on the Attack front line for four seasons.", "In 1997, he played for the Carolina Dynamo in the USISL.", "In March 1998, the Tampa Bay Mutiny selected Loftin in the first round (second overall) in the 1998 MLS Supplemental Draft.", "He played eight games for the Mutiny that season.", "He also played five games for the Charleston Battery of USISL.", "In April 1999, he signed with the Milwaukee Rampage of the USL A-League.", "He would play outdoor summer soccer with the Rampage through the 2000 season.", "In 2000, he was First Team All League with the Rampage.", "Loftin also signed with the Milwaukee Wave of the NPSL and remained with them for four seasons before retiring in 2003.", "One of his most notable goals came in the Game 5 of the 2000 NPSL finals, in which Loftin executed a spectacular bicycle kick to score.", "In his last two seasons, the Wave played in the Major Indoor Soccer League.", "Loftin also earned twelve caps, scoring five goals, with the U.S. national futsal team between 1996 and 2000.", "In between his playing career with the Wave and becoming commissioner of the XSL, Loftin was the GM/CEO of the Chicago Storm." ]

[ 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 ]

[ "He played one season in Major League Soccer with the Tampa Bay Mutiny, as well as several seasons in the USISL.", "However, his greatest fame as a player came in eight seasons of indoor soccer where he was a consistent scoring threat with the Kansas City Attack and Milwaukee Wave.", "He also earned twelve caps, scoring five goals, with the United States national futsal team." ]

[ "Shinty was traditionally played throughout the Highlands of Scotland until the early 20th century when it died off in many areas and there was a tradition of play in North West Sutherland.", "In 2007, as part of Highland 2007, the pupils of Kinlochbervie High School took a vote and decided to spend more time playing shinty.external_link_1 This led to Kinlochbervie being a founder member of the Far North Shinty League in 2007.", "The club also supplied some players to Naver Athletic, the first team from Sutherland to compete in national shinty.", "In their first season in 2007-08, Kinlochbervie came second in the Far North League to Farr.", "They finished just behind Farr again in the same position for the 2008-09 season.", "This season they finished in 1st place ahead of their rivals Farr Camanachd.", "In 2011, the club entered the Development League run by the Camanachd Association and also took a trip to Ireland to play Shinty/Hurling.", "The club defeated Strathspey in their final match 6-5.external_link_2" ]

[ 0, 1, 2, 3, 4, 5, 6, 7 ]

[ "Kinlochbervie Camanachd Club is a shinty club from Kinlochbervie, Sutherland, Scotland." ]

[ "The Gallatin Bank structure, which opened in 1887, was built for the Gallatin National Bank on land purchased after the resignation of bank president James Gallatin, in 1868, and the beginning of the term of his successor, Frederick D. Tappen.", "The edifice endured for forty-two years and was the home of important financial firms.", "The Gallatin Bank Building was one of the most distinguished establishments on Wall Street from the late 19th century through the second decade of the 20th century.", "It was destroyed to make room for 40 Wall Street, a new structure completed by the Bank of Manhattan Company in late 1929, the tallest office building in the world when finished." ]

[ 0, 1, 2, 3 ]

[ "The Gallatin Bank Building was constructed in 1887 on a plot at 34 Wall Street in the Financial District of Manhattan, New York City for the Gallatin National Bank." ]

[ "Oteng began his career 1998 with VAV Beerschot.", "After merger named: Germinal Beerschot.", "He served Germinal Beerschot in the Jupiler League for one year and joined Verbroedering Geel in July 2007.", "He was released by his club on January 2009 and joined to Greek side AE Larissa.", "After he plays with V.C. Herentals the season 2009-2010.", "At the end he quit there and go plays for fun in an Antwerp pubteam.", "He joined than in summer 2010 to Dutch side VV Axel., before in Juni 2011 returned to Belgium and signed for K. Merksem SC.", "Oteng is of Ghanaian descent and his parents are Belgian immigrants from Accra." ]

[ 7 ]

[ "He is of Ghanaian descent." ]

[ "The title of the book refers to the contradistiction between \"first\" and second death in the Apocalypse of St. John the Divine, the \"first death\" referring to the natural end of life (death of the body) as opposed to the second death (annihilation, death of the soul).", "Insofar as the \"first death\" is not of a spiritual kind it is not considered as \"real death\", that is to say, annihilation.", "In such spiritual sense, the protagonist of the book subsists in a \"hellish\" kind of existence, presumably awaiting the occurrence of future redemption or definitive extinction.", "The title also refers to the occurrence of \"the\" first death in the context of the biblical history of the human race, namely the murder of Abel by his brother Cain.", "\"The First Death\" recounts the ordeal of a 40 year old male named adam stranded on a desert-like island.", "The book starts with a description of his mutilated body which grinds against the rocks.", "The poem expands on the theme of his continuing degradation, physical and mental, as even the mechanisms of memory are dislocated.", "Yet, the bond between person and body ensures life still persists, and, \"at that point without substance/ where the world collides and takes off\", the mechanical instincts of the cosmos rumble into action and sling this irreducible substance again into space - prompting, perhaps, a future regeneration.", "\"The First Death\", recounts the result of its protagonist's voyaging towards annihilation.", "His body and mind are on the verge of dissolution while fighting for continuance and survival.", "Portrayed as a victim of nature and presumably expelled by society, he is represented both as a castaway and an abortion, dying before he has ever achieved birth.", "The work describes his purgatorial-like torture, mapping a desert and rocky island as the locus of his suffering.", "His exclusion and solitude allude to Greek Tragedy, most importantly Philoctetes, while images of mutilation and dismemberment relate to ancient Greek sacrifices and rituals.", "The myth of the dismemberment of Dionysus by the Titans is also hinted at as the text resorts to the concept of sparagmos (, from σπαράσσω \"sparasso\", \"tear, rend, pull to pieces\"), an act of rending, tearing apart, or mangling, Other oblique classical references are equally embedded in the text, such as the presence of Orpheus, also suggested by images of dismemberment.", "In its role of epilogue of the Poena Damni trilogy the poem also witnesses the aftermath of the impending violence of the first volume, Z213: Exit.", "The original Greek employs an unconventional modern idiom, accommodating a variety of ancient Greek words and integrating them into the flow of the text.", "Contrary to the previous book of the trilogy, With the People from the Bridge, which makes use of predominantly bare, simple sentences in a theatrical context, \"The First Death\" is written in a dense, highly tropical style.", "Each poem-section unravels a multi-layered concatenation of images in order to illustrate the unremitting torment of the book's protagonist.", "Often, the weightiness of surreal abstraction lends a metaphysical atmosphere to the work, thus investing the ordeal undergone by the protagonist with a sublime-like quality as, he, in spite of the world, continues his struggle to the limits of his powers.", "Images of spoiled, rotten, maimed nature, artifacts, architecture and especially bodies are described in such rich detail they take on an eerie, atrocious, paradoxical glory.", "The book brings to bear aspects of the Homeric clarity of description which are in their turn coupled with fierce and expressionistic depictions of a nightmarish setting.", "In its aligning disparate literary traditions in order to intensely depict the clash of the human subject in the midst of a hostile world, \"The First Death\", is considered as one of the most violent works of Greek literature in modern times.", "Being the first to have been published among the three installments of the Poena Damni trilogy The First Death has received a number of reviews that span over two decades.", "Some critics underline the work's close connection with Ancient Greek Literature due to its hybrid linguistic character and its allusions to Tragedy\" while others see a strong connection with current events.", "Critic Toti O' Brien notes: \"As I read The First Death, I imagine the carpet of corpses lining the Mediterranean.", "Strata and strata of limbs—now bones—piled up during recent decades, all belonging to shiploads of migrants seeking escape through Europe.", "I can’t help connecting the poetry under my eyes with this precise scenery.", "The most powerful, the most disturbing imagery Lyacos paints makes sense in this context where it naturally embeds itself.", "\"\nThe book was originally published in Greek in 1996 and has been translated in English, German, Spanish and Italian.", "The first English edition appeared in 2000 and went out of print in 2005.", "A second revised English edition was launched as an e-book in spring 2017 and subsequently appeared in print in the autumn of the same year ().", "The new edition contains extended Translator's Notes explaining the Ancient Greek references of the original Greek text." ]

[ 0, 1, 2, 3 ]

[ "The First Death is a book by Dimitris Lyacos." ]

[ "The title of the book refers to the contradistiction between \"first\" and second death in the Apocalypse of St. John the Divine, the \"first death\" referring to the natural end of life (death of the body) as opposed to the second death (annihilation, death of the soul).", "Insofar as the \"first death\" is not of a spiritual kind it is not considered as \"real death\", that is to say, annihilation.", "In such spiritual sense, the protagonist of the book subsists in a \"hellish\" kind of existence, presumably awaiting the occurrence of future redemption or definitive extinction.", "The title also refers to the occurrence of \"the\" first death in the context of the biblical history of the human race, namely the murder of Abel by his brother Cain.", "\"The First Death\" recounts the ordeal of a 40 year old male named adam stranded on a desert-like island.", "The book starts with a description of his mutilated body which grinds against the rocks.", "The poem expands on the theme of his continuing degradation, physical and mental, as even the mechanisms of memory are dislocated.", "Yet, the bond between person and body ensures life still persists, and, \"at that point without substance/ where the world collides and takes off\", the mechanical instincts of the cosmos rumble into action and sling this irreducible substance again into space - prompting, perhaps, a future regeneration.", "\"The First Death\", recounts the result of its protagonist's voyaging towards annihilation.", "His body and mind are on the verge of dissolution while fighting for continuance and survival.", "Portrayed as a victim of nature and presumably expelled by society, he is represented both as a castaway and an abortion, dying before he has ever achieved birth.", "The work describes his purgatorial-like torture, mapping a desert and rocky island as the locus of his suffering.", "His exclusion and solitude allude to Greek Tragedy, most importantly Philoctetes, while images of mutilation and dismemberment relate to ancient Greek sacrifices and rituals.", "The myth of the dismemberment of Dionysus by the Titans is also hinted at as the text resorts to the concept of sparagmos (, from σπαράσσω \"sparasso\", \"tear, rend, pull to pieces\"), an act of rending, tearing apart, or mangling, Other oblique classical references are equally embedded in the text, such as the presence of Orpheus, also suggested by images of dismemberment.", "In its role of epilogue of the Poena Damni trilogy the poem also witnesses the aftermath of the impending violence of the first volume, Z213: Exit.", "The original Greek employs an unconventional modern idiom, accommodating a variety of ancient Greek words and integrating them into the flow of the text.", "Contrary to the previous book of the trilogy, With the People from the Bridge, which makes use of predominantly bare, simple sentences in a theatrical context, \"The First Death\" is written in a dense, highly tropical style.", "Each poem-section unravels a multi-layered concatenation of images in order to illustrate the unremitting torment of the book's protagonist.", "Often, the weightiness of surreal abstraction lends a metaphysical atmosphere to the work, thus investing the ordeal undergone by the protagonist with a sublime-like quality as, he, in spite of the world, continues his struggle to the limits of his powers.", "Images of spoiled, rotten, maimed nature, artifacts, architecture and especially bodies are described in such rich detail they take on an eerie, atrocious, paradoxical glory.", "The book brings to bear aspects of the Homeric clarity of description which are in their turn coupled with fierce and expressionistic depictions of a nightmarish setting.", "In its aligning disparate literary traditions in order to intensely depict the clash of the human subject in the midst of a hostile world, \"The First Death\", is considered as one of the most violent works of Greek literature in modern times.", "Being the first to have been published among the three installments of the Poena Damni trilogy The First Death has received a number of reviews that span over two decades.", "Some critics underline the work's close connection with Ancient Greek Literature due to its hybrid linguistic character and its allusions to Tragedy\" while others see a strong connection with current events.", "Critic Toti O' Brien notes: \"As I read The First Death, I imagine the carpet of corpses lining the Mediterranean.", "Strata and strata of limbs—now bones—piled up during recent decades, all belonging to shiploads of migrants seeking escape through Europe.", "I can’t help connecting the poetry under my eyes with this precise scenery.", "The most powerful, the most disturbing imagery Lyacos paints makes sense in this context where it naturally embeds itself.", "\"\nThe book was originally published in Greek in 1996 and has been translated in English, German, Spanish and Italian.", "The first English edition appeared in 2000 and went out of print in 2005.", "A second revised English edition was launched as an e-book in spring 2017 and subsequently appeared in print in the autumn of the same year ().", "The new edition contains extended Translator's Notes explaining the Ancient Greek references of the original Greek text." ]

[ 8, 9, 10, 11, 12, 13, 14 ]

[ "It is part of the \"Poena Damni\" trilogy." ]

[ "Debbie Purdy and her counsel David Pannick QC argued that the Director of Public Prosecutions (Ken Macdonald QC) was infringing on her human rights by failing to clarify how the Suicide Act 1961 is enforced.", "The DPP counsel took the position that the law does not require the DPP to make any further clarification of the Act: they argue that the Act and further information contained in the Code for Crown Prosecutors provide sufficient information.", "Purdy's particular concern was to discover if any actions her husband, Omar Puente, took in assisting her suicide would lead to his prosecution.", "The penalty for those who \"aid, abet, counsel or procure the suicide of another\" is a maximum of 14 years.", "No family member of the 92 Britons who have gone abroad for an assisted suicide has been prosecuted but some have been charged and have had to wait for months before hearing the charges have been dropped.", "Purdy said that if her husband would be exposed to prosecution for helping her travel to Switzerland to a Dignitas clinic to die, she would make the journey sooner whilst she was able to travel unassisted.", "This would save her husband from exposure to the law but would have forced Purdy to make her decision on dying before she felt it was absolutely necessary.", "The hearing began on 2 October 2008 and was complete soon after.", "The venue was the High Court of Justice.", "It proceeded before Lord Justice Scott Baker and Mr Justice Aikens.", "In court the DPP said that Purdy could not be given any reassurance that her husband would not be prosecuted as the law was clear that assisting suicide is an offence.", "On 10 December 2008 Sky TV broadcast a programme on which a man with motor neurone disease was shown committing suicide with assistance.", "There had also been the UK case of a Mr James who went to Switzerland with the aid of his parents after being paralysed whilst playing rugby and the Department of Public Prosecutions determined that to prosecute the parents would be against the public interest.", "These two events led to the issue of assisted suicide making the first story on the BBC's \"Newsnight\".", "Purdy appeared to debate the issue and denied that it is society that makes disabled people wish to kill themselves and reasserted her belief that it is right to be able to seek assistance when one is physically incapable of committing suicide oneself.", "Purdy met her husband Omar Puente in Singapore when he was playing with a band, and they married in 1998.", "She was diagnosed with multiple sclerosis after she found her feet felt heavy when out dancing.", "She later used a wheelchair for mobility and both her sight and hearing began to deteriorate.", "Purdy entered the Marie Curie Hospice in Bradford in June 2013 and in December 2013 she began to intermittently refuse food.", "She described the length of time it was taking to die as \"agonising\".", "Purdy died on 23 December 2014, aged 51.", "Purdy published her story as It's Not Because I Want to Die (2010, HarperTrue: ).", "On 26 February 2019 BBC Radio 4 broadcast Joy Wilkinson's dramatisation of Purdy's book, as \"Test case: Debbie Purdy\".", "It was followed by a discussion, \"Test Case: The Legacy of Debbie Purdy\", between professor Deborah Bowman, Purdy's husband Omar Puente, her lawyer Saimo Chahal QC, and barrister and peer Charlie Falconer." ]

[ 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 ]

[ "The guidelines for England and Wales \"come after a legal battle won by Debbie Purdy\", as \"Law Lords accepted earlier this year that [Purdy] had a right to know whether her husband would be prosecuted if he helped her to travel abroad to commit suicide." ]

[ "His nickname is .", "Bosti and his clan are aligned with the long established Licciardi and Contini Camorra clans.", "The power, influence and wealth his clan held allowed Bosti to become one of the top Camorra leaders within the Secondigliano Alliance (\"Alleanza di Secondigliano\") of leading Naples area clans.", "Bosti was included on the list of most wanted fugitives in Italy and had been a fugitive from 2005, but was eventually arrested on 10 August 2008, in Girona, Spain.", "He was spotted when he took a flight from Naples to Barcelona a week before and traced to nearby Girona, where he was spending some time in a luxurious villa.", "Bosti was convicted in absentia of heading a clan of the Naples-based Camorra crime syndicate and sentenced to 23 years in prison for the murder of two rival mobsters during a feud in 1984.", "He was later extradited to Italy to face the murder charges.", "Patrizio Bosti is married to Rita Aieta, sister in law of Edoardo Contini and Francesco Mallardo.", "According to some reports, in the 1980s and 1990s, he was the lover of Erminia Giuliano, sister of Luigi Giuliano, then boss of one of the most powerful Camorra clans of the time.", "Bosti is the father of Ettore Bosti, called \"o'russ\", who is also in jail.", "O'russ was known for his expensive lifestyle, often partying in exclusive nightclubs, spending large amounts of money and always being in the company of football players and influential people.", "Ettore is also known to have laundered money several times in the island of Ibiza, Spain.", "In December 2019, Patrizio's wife, Rita Aieta, was moved to the 41-bis prison regime, giving another hard blow to the Secondigliano Alliance.", "In May 2020 Patrizio Bosti was released from prison.", "Bosti also claimed inhumane treatment while in prison, and will be compensated by the Italian State.", "The Camorra boss, that was serving a prison sentence since his arrest in Spain in 2008, should have been released from prison in 2023, however he was charged for three years and the halfway between early release and the time calculated as credit for the \"inhuman treatment\".", "According to the investigations, Bosti would have returned to live in Naples, in the Rione Amicizia area, his historical stronghold.", "On 16 May 2020 Bosti was arrested again.", "The new prison order concerned a recalculation of the sentence by the Emilia-Romagna judiciary, as he was serving his sentence in the region, on the basis of documents provided by the Naples Public Prosecutor.", "According to the authorities, Bosti had to serve another six years in jail." ]

[ 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 ]

[ "Patrizio Bosti (; born 5 September 1959, in Naples) is a powerful Italian Camorra boss and current head of the Secondigliano Alliance, a Camorra crime syndicate based in the city of Naples." ]

[ "Six months after Douglass was born in Sherman, Texas, his extended family relocated to Los Angeles in an effort to escape Jim Crow laws.", "A member of a musical family, Douglass took an early interest in music.", "He cited as a pivotal moment in his life when he first heard Benny Goodman's drummer Gene Krupa performing \"Sing, Sing, Sing\" on the radio, when he realized, \"That's what I had to do.", "That's all there was to it.\"", "Douglass met and befriended Dexter Gordon while attending McKinley Junior High School in Los Angeles, at which point he first began playing drums.", "At Jefferson High School, both Douglass and Gordon began taking band under teacher Lloyd Reese, who encouraged the rudiments and private instruction.", "Though a drummer, Douglass took private keyboard instructions, which he credited with helping him to understand how the various instruments in an ensemble relate.", "Douglass never took private drum lessons, but eventually made the acquaintance of Cab Calloway drummer Cozy Cole, who used to allow Douglass to watch him practice.", "Douglass learned a lot watching Cole and other drummers, who gradually helped him evolve a style of his own.", "Along with Gordon and Lammar Wright, Jr., Douglass began playing night clubs while still in school and frequently haunted Central Avenue, an important nexus of African-American jazz music at the time.", "Douglass eventually began playing drums for pianist Gerald Wiggins, along with double bass and tuba player Red Callender, until he and Callender left to form a trio with blind pianist Art Tatum.", "In 1941, Douglass graduated high school.", "He enlisted in the United States Army and was assigned to the African-American 10th Cavalry Regiment at Camp Lockett in Campo, California, where he served along with his high-school band teacher as a member of the band.", "Fifteen months after enlisting, he was shipped overseas, serving in such diverse locations as Casablanca, Oran, Algiers, Naples and Rome.", "During these travels, Douglass became drum major of his 28-piece ensemble, a position he attributed to his \"great height\".", "After leaving the service, in about 1949, Douglass began a three-year stint with Benny Goodman, where he was at the time the only black member of the band.", "During that period, Goodman often complained of the need to deal with a separate local chapter of the American Federation of Musicians for Douglass, as the chapters of the union were segregated.", "Lloyd Reese encouraged Douglass, along with fellow musicians Buddy Collette, Charlie Mingus and Chico Hamilton, to work against the discrimination in the unions, which they did along with Marl Young and Benny Carter.", "Not allowed to voice opinions at their local union from the floor, the group ran for office, succeeding well enough to take the majority position on the board of directors, though only Douglass took a high position, the vice presidency.", "At the same time, white members of the American Federation of Musicians were applying pressure within their local.", "In spite of significant opposition, a majority vote of both of the unions eventually led to their joining into one in 1953.", "The amalgamation of the unions was not without some difficulty.", "Horace Tapscott, who was a 15-year-old member of the union at the time and remembered Douglass as among the \"vanguard of the movement,\" indicated in his 2001 autobiography that after the amalgamation, the union was separated by cliques, where a \"particular, small, black group of guys would work all the time, because they were in that particular clique with these particular guys who ran the studios.\"", "Though he said that the work seemed to get better \"for certain people\", he also said that many of the older musicians \"didn't have anyplace to go\" after the closing of the black union.", "Even as a working musician, Douglass expanded into teaching drums at Drum City.", "Among his students, Douglass taught Ray Brown, Jr. (the adopted son of bassist Ray Brown), Karen Carpenter, and Ella Fitzgerald." ]

[ 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 ]

[ "William Douglass (February 28, 1923 – December 19, 1994) was an American jazz drummer born in Sherman, Texas." ]

[ "Six months after Douglass was born in Sherman, Texas, his extended family relocated to Los Angeles in an effort to escape Jim Crow laws.", "A member of a musical family, Douglass took an early interest in music.", "He cited as a pivotal moment in his life when he first heard Benny Goodman's drummer Gene Krupa performing \"Sing, Sing, Sing\" on the radio, when he realized, \"That's what I had to do.", "That's all there was to it.\"", "Douglass met and befriended Dexter Gordon while attending McKinley Junior High School in Los Angeles, at which point he first began playing drums.", "At Jefferson High School, both Douglass and Gordon began taking band under teacher Lloyd Reese, who encouraged the rudiments and private instruction.", "Though a drummer, Douglass took private keyboard instructions, which he credited with helping him to understand how the various instruments in an ensemble relate.", "Douglass never took private drum lessons, but eventually made the acquaintance of Cab Calloway drummer Cozy Cole, who used to allow Douglass to watch him practice.", "Douglass learned a lot watching Cole and other drummers, who gradually helped him evolve a style of his own.", "Along with Gordon and Lammar Wright, Jr., Douglass began playing night clubs while still in school and frequently haunted Central Avenue, an important nexus of African-American jazz music at the time.", "Douglass eventually began playing drums for pianist Gerald Wiggins, along with double bass and tuba player Red Callender, until he and Callender left to form a trio with blind pianist Art Tatum.", "In 1941, Douglass graduated high school.", "He enlisted in the United States Army and was assigned to the African-American 10th Cavalry Regiment at Camp Lockett in Campo, California, where he served along with his high-school band teacher as a member of the band.", "Fifteen months after enlisting, he was shipped overseas, serving in such diverse locations as Casablanca, Oran, Algiers, Naples and Rome.", "During these travels, Douglass became drum major of his 28-piece ensemble, a position he attributed to his \"great height\".", "After leaving the service, in about 1949, Douglass began a three-year stint with Benny Goodman, where he was at the time the only black member of the band.", "During that period, Goodman often complained of the need to deal with a separate local chapter of the American Federation of Musicians for Douglass, as the chapters of the union were segregated.", "Lloyd Reese encouraged Douglass, along with fellow musicians Buddy Collette, Charlie Mingus and Chico Hamilton, to work against the discrimination in the unions, which they did along with Marl Young and Benny Carter.", "Not allowed to voice opinions at their local union from the floor, the group ran for office, succeeding well enough to take the majority position on the board of directors, though only Douglass took a high position, the vice presidency.", "At the same time, white members of the American Federation of Musicians were applying pressure within their local.", "In spite of significant opposition, a majority vote of both of the unions eventually led to their joining into one in 1953.", "The amalgamation of the unions was not without some difficulty.", "Horace Tapscott, who was a 15-year-old member of the union at the time and remembered Douglass as among the \"vanguard of the movement,\" indicated in his 2001 autobiography that after the amalgamation, the union was separated by cliques, where a \"particular, small, black group of guys would work all the time, because they were in that particular clique with these particular guys who ran the studios.\"", "Though he said that the work seemed to get better \"for certain people\", he also said that many of the older musicians \"didn't have anyplace to go\" after the closing of the black union.", "Even as a working musician, Douglass expanded into teaching drums at Drum City.", "Among his students, Douglass taught Ray Brown, Jr. (the adopted son of bassist Ray Brown), Karen Carpenter, and Ella Fitzgerald." ]

[ 15, 16, 17, 18, 19, 20, 21, 22, 23 ]

[ "He was also known for his work in the American Federation of Musicians, where he was an active proponent of desegregation.", "He held offices in local unions both before and after their racial integration." ]

[ "Although the game nearly retains everything, including the feature of Power Pro series mascot (The Pawapurokun: a Rayman like character without face parts (other than eyes) and have its legs detached from the rest of its body) using nearly the same game system as the main series, the Power Pro Kun Pocket series is completely different from its main series (Power Pro Series) in other aspects.", "It uses a more simple system in baseball than their main series.", "Many features outside the Success Mode were removed from the series, however, features related to Success Mode is increased.", "As a feature of the whole Power Pro Series, passwords produced in the Pawapoke series can be transferred to Nintendo consoles' Power Pro Series for playing, but the ability may be weakened a lot.", "Here are some of the major differences between the two series:", "Other than the first game (one success mode), and Koshien (does not feature any success mode), all other \"Power Pro Kun Pocket\" series titles features at least two different success modes, which called \"Outer-Success\" and \"Inner-Success\".", "Unlike the Power Pro series, this series did not follow storyline with realism, and many fantasy elements were mixed into the series.", "The series was greatly influenced by Tokimeki Memorial series, which was the original success mode in power pro series intends to, even Konami itself admit the series becomes \"a Gal-game with baseball contents\", making them changed its genre to \"Baseball Variety\".", "Like the Power Pro's setting, fictional pro teams exists in the series as well, but it is completely different teams since the setting has been developing on its own now.", "There exist 10 rare abilities collectively called Super Ability, which can give a great increase to statistics (can exceed limit) or have more negative effects towards opponent players.", "Pitcher and fielders have a separate 5-set ability and no one can hold more than one Super Abilities.", "Some Super Abilities will cancel out other Super Abilities in play.", "Such abilities will not be kept when the player is transferred to the Power Pro series.", "The only way to obtain the Super Abilities is playing in Success Mode.", "In \"Outer-Success\", players can obtain Super Abilities by finishing the girl's endings, which each of them keep two (one each for pitcher and fielder)", "Super Abilities.", "However, in each of the series there exist a wild-card girl character, who can give any Super Abilities by players' choice, but usually it needs tougher requirements." ]

[ 0, 1, 2, 3, 4 ]

[ "Power Pro Kun Pocket (パワプロクンポケットシリーズ, abbrv.", ":パワポケ), sometimes simply called Pawapoke or Power Pocket, is a spin-off of the \"Power Pros\" series of baseball games developed by Pawapuro Production." ]

[ "Although the game nearly retains everything, including the feature of Power Pro series mascot (The Pawapurokun: a Rayman like character without face parts (other than eyes) and have its legs detached from the rest of its body) using nearly the same game system as the main series, the Power Pro Kun Pocket series is completely different from its main series (Power Pro Series) in other aspects.", "It uses a more simple system in baseball than their main series.", "Many features outside the Success Mode were removed from the series, however, features related to Success Mode is increased.", "As a feature of the whole Power Pro Series, passwords produced in the Pawapoke series can be transferred to Nintendo consoles' Power Pro Series for playing, but the ability may be weakened a lot.", "Here are some of the major differences between the two series:", "Other than the first game (one success mode), and Koshien (does not feature any success mode), all other \"Power Pro Kun Pocket\" series titles features at least two different success modes, which called \"Outer-Success\" and \"Inner-Success\".", "Unlike the Power Pro series, this series did not follow storyline with realism, and many fantasy elements were mixed into the series.", "The series was greatly influenced by Tokimeki Memorial series, which was the original success mode in power pro series intends to, even Konami itself admit the series becomes \"a Gal-game with baseball contents\", making them changed its genre to \"Baseball Variety\".", "Like the Power Pro's setting, fictional pro teams exists in the series as well, but it is completely different teams since the setting has been developing on its own now.", "There exist 10 rare abilities collectively called Super Ability, which can give a great increase to statistics (can exceed limit) or have more negative effects towards opponent players.", "Pitcher and fielders have a separate 5-set ability and no one can hold more than one Super Abilities.", "Some Super Abilities will cancel out other Super Abilities in play.", "Such abilities will not be kept when the player is transferred to the Power Pro series.", "The only way to obtain the Super Abilities is playing in Success Mode.", "In \"Outer-Success\", players can obtain Super Abilities by finishing the girl's endings, which each of them keep two (one each for pitcher and fielder)", "Super Abilities.", "However, in each of the series there exist a wild-card girl character, who can give any Super Abilities by players' choice, but usually it needs tougher requirements." ]

[ 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 ]

[ ":パワポケ), sometimes simply called Pawapoke or Power Pocket, is a spin-off of the \"Power Pros\" series of baseball games developed by Pawapuro Production.", "Originally, the game was planned to link the story with the Success Mode storyline in the main (Pawapuro) series.", "Since the 8th iteration, Konami used Baseball variety instead of Sport/Simulation as a game genre.", "Instead of baseball, the portion in Success Mode were much larger than the main series." ]