title: Seagram Building

text: In 1963, the New York City government gave the Seagram Company an award for the building's "notable contribution" to the city and raised the company's property taxes. The recalculated tax assessment of $21 million was based on the potential value if the building were to be demolished, whereas Seagram fought to keep the assessment at $17 million, based on the rental income it earned. The higher tax assessment was upheld by the New York Court of Appeals, a decision the Regional Plan Association criticized as potentially destroying "the hope of great commercial architecture in New York State". Architectural writer Ada Louise Huxtable called the tax a beginning of the city's "architectural annihilation", saying the higher tax assessment was a "special method of taxing architectural excellence".


title: Seagram Building

text: There was still high demand for office space in Midtown Manhattan, despite a myriad of new development in the area. For example, when real estate investment firm Realty Equities moved its headquarters to the Seagram Building in 1968, another company immediately offered to sublet Realty's space at a much higher price. Even the Seagram Company found its own headquarters' rent to be too high, giving up half of its in the building and moving approximately 600 of its 983 employees elsewhere in 1972. In a letter to mayor John Lindsay, Seagram officials attributed the relocation in part because of the high tax assessment on the Seagram Building. In 1971, building management conducted what city officials believed was the first voluntary fire drill at a New York City office building.


title: Seagram Building

text: During the 1970s, Seagram received several offers for the building from potential buyers, and the company contemplated selling it and leasing back its own space. However, Seagram had decided to retain ownership of the building by 1976, as it brought publicity to the company. The same year, Bronfman's son and Seagram's president Edgar Bronfman Sr. asked the New York City Landmarks Preservation Commission (LPC) to grant city-landmark status to the building. The move surprised mayor Abraham Beame, since the city's landlords typically attempted to prevent their buildings from being listed as landmarks. The LPC ultimately did not hold a hearing for the Seagram Building. LPC rules specified that individual New York City landmarks be at least 30 years old at the time of their designation; the building had been completed only 18 years earlier. Bronfman proposed that the LPC allow designations of buildings less than 30 years old if their owners supported landmark status, but no action was taken on the proposal.


title: Seagram Building

text: In February 1979, Seagram offered the tower for sale at $75 million. In the absence of official landmark status, the company mandated that the new owner preserve the exterior and public spaces in their original condition. The new owner was obligated to keep the building for at least fifteen years, and would have to take over the high land-assessment taxes. Seagram sold the building to the Teachers Insurance and Annuity Association (TIAA) for $85.5 million in June 1979, leasing some space back from them. This fee included $70.5 million for the structure and $15 million for the underlying land. As part of the sale, the building retained the "Seagram" name, although it was only identified on signage by its address. For decades after the sale, Lambert continued to be involved with the Seagram Building's operation.


title: Seagram Building

text: The TIAA, like the Seagram Company, supported landmark status for the building. In early 1988, just over thirty years after the Seagram Building had been completed, the TIAA filed documentation with the LPC requesting that the Seagram Building's exterior, lobby, and plaza be considered for landmark status. The Four Seasons' operators also separately endorsed landmark designation for their restaurant's interior in the Seagram Building. On October 3, 1989, the LPC designated the Seagram Building's exterior, the lobby, and the Four Seasons Restaurant as landmarks. The Four Seasons was only the second restaurant interior in the city to be designated a landmark, after Gage and Tollner in Brooklyn. The New York City Board of Estimate ratified all three designations in January 1990. While the TIAA had strongly supported the exterior and lobby landmark designations, it sued the LPC in 1990 to have the designation for the Four Seasons removed. The TIAA argued that the restaurant was personal property and that the designation would force the restaurant to continue operating even if the owners wished to close it. The state's Court of Appeals upheld the designation in 1993. The Brasserie, not covered in any of the landmark designations, was renovated in 1999 after being damaged by a fire in 1995.


title: Seagram Building

text: Real estate investor Aby Rosen entered a contract in October 2000 to purchase a majority ownership stake in the building for $375 million, completing his purchase that December. At the time, 99.5 percent of the building's space was occupied, but only six original tenants remained. The following year, the Seagram Company moved its headquarters out of the building. Rosen's RFR Holding retained ownership of the Seagram Building. Meanwhile, French media conglomerate Vivendi, which acquired the Seagram Company in 2000, started selling off the building's art in 2003 to raise money. RFR received the LPC's permission in 2005 to transfer unused development rights at the Seagram Building site to a neighboring building. In exchange, the Seagram Building's owners would be required to keep the facade in near-original condition. The Seagram Building was nominated for inclusion on the National Register of Historic Places (NRHP) on January 12, 2006, and was added to the NRHP on February 24, 2006. RFR did not have full ownership of the Seagram Building until 2013, when it purchased a 14 percent stake from Harry Lis.


title: Seagram Building

text: In 2015, RFR decided to terminate Four Seasons' and the Brasserie's leases ahead of schedule, and the restaurants were closed. RFR proposed changes to the Four Seasons' interior, including removing the glass wall between the Grill Room and Pool Room, as well as converting the wine cellar to restrooms. The LPC rejected RFR's proposal to change the interior of The Four Seasons Restaurant, except for a carpet replacement, which the commission allowed. Annabelle Selldorf restored the physical structure while William Georgis oversaw the interior design. The Grill and the Pool were opened within the former Four Seasons space in mid-2017. That year, architect Peter Marino designed the Lobster Club within the former Brasserie space in the basement. In addition, the facade was restored in 2016, and RFR spent $400,000 to install waterproofing on the fountains and $250,000 to renovate the plaza benches. RFR was also planning to change the underground garage, which did not have landmark status. Initially, RFR did not seek the LPC's permission to change the landmark-designated Four Seasons interior, only requesting permission in late 2017 after the renovations were completed. The LPC retroactively approved the renovations nearly two years later, with some modifications. To conform to the plans that the LPC had approved, the Pool's lounge room was closed in December 2019 for a one-month renovation. The next month, the Grill took over the Pool because of higher demand for cuisine in the Grill.


title: Seagram Building

text: Rosen announced in mid-2020 that he would renovate much of the garage into the Seagram Playground, a communal workers' space and gym, over the following one and a half years. The communal space was announced as a way to attract tenants in light of the COVID-19 pandemic in New York City, as well as the departure of Wells Fargo, a major tenant. The Seagram Playground was completed in August 2022 for $25 million; at the time, 80 percent of the space in the building was occupied. "Curbed" wrote that the Seagram Playground was one of several large investments that Rosen had made in "prime midtown real estate at a time when it hasn't exactly bounced back" from the pandemic. The building was almost fully occupied by the end of 2022, after firms such as Blue Owl Capital and Clayton, Dubilier & Rice signed or renewed their leases.


title: Seagram Building

text: When the Seagram Building was completed, Lewis Mumford described the structure as a "Rolls-Royce" of buildings and wrote that "it has the aesthetic impact that only a unified work of art carried through without paltry compromises can have". In 1957, Thomas W. Ennis of "The New York Times" wrote the building was "one of the most notable of Manhattan's post-war buildings" and characterized its design as the high point of Mies's career. Similarly, "Progressive Architecture" described the Seagram Building as "probably the most heralded new building in the U.S." in 1958. According to "Architectural Forum" in 1958, "Seagram challenges accepted skyscraper practice all the way down the line." At a meeting of the Italian Cultural Institute the following year, architect Gino Pollini said the Seagram Building was "a masterpiece of functional and esthetic architecture".


title: Seagram Building

text: Critical acclaim for the Seagram Building continued. Eight years after the building opened, Ada Louise Huxtable wrote that it was "dignified, sumptuous, severe, sophisticated, cool, consummately elegant architecture". "The New York Times Magazine" described the lobby in 1975 as one of "The Ten Best Lobbies in New York". In 1981, architectural writer G. E. Kidder Smith found the building and its features to be "in toto incomparable". According to Jerold Kayden, who wrote about the building in 2000, the Seagram Building "remains the city's quintessential International Style masterpiece of 'tower in the park' architecture". Ricardo Scofidio of Diller Scofidio + Renfro said the construction of the Seagram Building "was the first time you really realized that architecture brought something to the city that didn't exist". In 2001, architecture critic Herbert Muschamp referred to it as "the Building of Two Millenniums," writing that it encompassed "everything essential in Western architecture".


title: Seagram Building

text: While the public and architectural critics generally appreciated the Seagram Building, there were also comments about the design's drawbacks. Stern stated that there were negative remarks about the plaza's "austerity" and the exterior's lack of purity. Stern cited architect Louis Kahn, who believed the rear "spine" took away from the purity of the slab, though Kahn also said the hidden wind bracing made the building appear like "a beautiful bronze lady in hidden corsets". While Mumford largely praised the design, he found the plaza's pools and fountains to be a "gross defect" in what was otherwise a "masterpiece". Italian architecture writers Manfredo Tafuri and Francesco Dal Co, in their 1976 book "Modern Architecture", wrote that the Seagram Building stood "aloof from the city" and saw the juxtaposition as a symbol of absence. Architect Frank Lloyd Wright dismissed the building as "a whisky bottle on a playing card."


title: Seagram Building

text: The Fifth Avenue Association called the Seagram Building the best edifice constructed on Park Avenue between 1956 and 1957. The city government gave the Seagram Company an award in 1963 for the building's positive impact on the city's beauty. The Board of Trade awarded its 1965 architecture prize to the building, citing its plaza, form, and material. The following year, the Municipal Art Society (MAS) gave a bronze plaque to the building, recognizing it as a "modern landmark". Philip Johnson received the city's Bronze Medallion for the Seagram Building's design in 1979. Simultaneously, the AIA's New York division gave the Seagram Company a special citation recognizing the company's "most elegant contribution to the art of architecture and the care with which it is maintained". The AIA further recognized the Seagram Building in 1984 with a Twenty-five Year Award for its "ability to stand to the test of time".


title: Seagram Building

text: The Seagram Building's plaza was popular immediately when the building opened, being frequented by both office workers and tourists. In 1971, the plaza was the setting of a planning study by sociologist William H. Whyte, whose film "Social Life of Small Urban Spaces", produced with the Municipal Art Society of New York (MAS), records the daily patterns of people socializing around the plaza. Whyte praised the plaza as allowing a sense of choice, in that patrons could lie down or sit on the ledges or steps, despite their relatively plain design.


title: Seagram Building

text: The plaza's presence helped influence the 1961 Zoning Resolution, a zoning ordinance that allowed New York City developers to increase their edifices' maximum floor areas in exchange for adding open space in front of their buildings. This was in sharp contrast to the "wedding cake" model of the 1916 Zoning Resolution, which had required setbacks at intervals of several stories, similar to a wedding cake. Even before the 1961 zoning codes had been implemented, some New York City buildings followed the Seagram's model of a slab behind a plaza, such as the Time–Life Building at 1271 Avenue of the Americas, the former Union Carbide Building at 270 Park Avenue, and the One Chase Manhattan Plaza building at 28 Liberty Street. of plazas were built in New York City in the decade after the zoning-code revision.


title: Seagram Building

text: Paul Goldberger wrote in "The New York Times" in 1976 that the Seagram Building was one of "New York's most copied buildings", its design having been copied in several structures internationally. According to William H. Jordy, these structures included 270 Park Avenue and the Inland Steel Building. Mies reused the building's design for towers in Pittsburgh, Chicago, and Toronto, and a replica of the Seagram Building was constructed at the New York-New York Hotel and Casino in Paradise, Nevada. According to writer E. C. Relph, the design was "widely and shapes by other architects", though Relph considered some of the other towers to be "devoid of interesting copies".


title: Seagram Building

text: In mid-2005, the Skyscraper Museum in Lower Manhattan asked 100 architects, builders, critics, engineers, historians, and scholars, among others, to choose their 10 favorites among 25 of the city's towers. The Seagram Building came in second place behind the Chrysler Building, with 76 respondents placing it on their ballots.


title: Andi Oliver

text: Andrea "Andi" Oliver (born 1964) is a British chef, television and radio broadcaster, and former singer. She is best known for her appearances on the BBC cooking show the "Great British Menu".


title: Andi Oliver

text: Oliver is a former member of the band Rip Rig + Panic who appeared on an episode of Series 1 of "The Young Ones". She used to co-host the Channel 4 television show "Baadasss TV" alongside Ice-T and frequently appears on the BBC World Service and the BBC's annual coverage of the Glastonbury Festival.


title: Andi Oliver

text: After 1983, Oliver became involved in Kalimba, an African inspired band. In 1990 she joined forces with her brother, forming the Mighty Hog.


title: Andi Oliver

text: In April 2007, she started presenting a six-part cookery show "Neneh and Andi Dish it Up" with her friend Neneh Cherry for BBC2.


title: Andi Oliver

text: Oliver was born in London. Her mother's family is of Antiguan descent. Oliver’s daughter is television presenter Miquita Oliver. Her brother Sean died in 1990 of sickle cell anaemia aged 27.


title: True Jackson, VP

text: True Jackson, VP is an American teen sitcom created by Andy Gordon for Nickelodeon. It aired from November 8, 2008, to August 20, 2011. The series stars Keke Palmer, Ashley Argota, Matt Shively, Danielle Bisutti, Greg Proops, Robbie Amell, and Ron Butler. The theme song was written by Toby Gad and Keke Palmer and is performed by Palmer. The series was shot before a live audience, although a laugh track was used for sweetening. The pilot episode garnered 4.8 million viewers on its first airing and set network records among kids 6–11, tweens 9–14 and several other demographics. On May 5, 2009, Nickelodeon renewed the show for a second season. The season consisted of 34 episodes, which premiered on November 14, 2009. This season was later split, making a third season.


title: True Jackson, VP

text: In August 2011, Palmer posted a video on her YouTube account and posted on her blog, confirming that "Mystery in Peru" is the series' finale. After the show ended, Palmer renewed her contract with the network; she did voiceover work for Nickelodeon's "Winx Club" and starred in the Nick TV movie "Rags".


title: True Jackson, VP

text: Fifteen-year-old True Jackson is selling sandwiches and lemonade with her friend Ryan in the fashion district of New York City, when she is complimented by fashion designer Max Madigan, founder and CEO of Mad Style. Max realizes the clothes True is wearing are his designs, but True had altered them to suit her own purposes. Max likes the altered design and hires True to be the Vice President of his fashion company's youth apparel division. True hires her best friend Lulu to be her assistant after firing Cricket, her former assistant, who was upset and bitter about being surpassed in the business world by a child. True must juggle teenage antics with her new role as VP, aided by her friends and coworkers.


title: True Jackson, VP

text: The series was shot on stage 25 at Paramount Studios in Hollywood, California. This is the same stage where series "The Lucy Show", "Here's Lucy", "Cheers", and "Frasier" were shot.


title: True Jackson, VP

text: The series has aired on-and-off on TeenNick in the United States since 2008, with the most recent airing in 2020. BET also briefly aired episodes of the series in 2009.


title: True Jackson, VP

text: The show also premiered on the Canadian network YTV on March 5, 2009 and every Thursday since, but was changed to Friday to accommodate with "iCarly" & Big Fun Fridays. Then, the show moved again to Mondays at 6:30pm. As of 2010, the series no longer airs on YTV.


title: True Jackson, VP

text: The series continues to air regularly on Nickelodeon networks around the world. The show ended in Australia and New Zealand on 17 December 2011. The last two remaining episodes premiered in the UK on Wednesday 4 January 2012 and Thursday 5 January 2012 and with "Mystery in Peru" premiering on Friday 6 January 2012.


title: True Jackson, VP

text: The series is currently shown in Jamaica on one of the national stations TVJ (Television Jamaica) at 4:30pm on Tuesdays and Wednesdays.


title: True Jackson, VP

text: "True Jackson, VP: Season 1, Vol. 1" was released in a 2 disc set on September 8, 2009. Running time is 321 minutes, presented in full screen video, and English stereo audio. The set also includes behind-the-scenes, cast member's screen tests, bloopers and the first 13 episodes of season 1. Even though there is Season 1 Volume 1, for unknown reasons, a Volume 2 was never released.


title: True Jackson, VP

text: In August 2009, a line of clothing inspired by the show called ""Mad Style by True Jackson"" was released. The line was available exclusively at Walmart and is aimed at children and teens. This was the first line of clothing for the show and was a first for Nickelodeon releasing a line of clothing from one of their television shows. Commercials advertising the clothing line can be seen on Nickelodeon and TeenNick. Featured in the show and commercials is an instrumental version of the show's theme song.


title: Aubrey Beardsley

text: Aubrey Vincent Beardsley (21 August 187216 March 1898) was an English illustrator and author. His black ink drawings were influenced by Japanese woodcuts, and depicted the grotesque, the decadent, and the erotic. He was a leading figure in the aesthetic movement which also included Oscar Wilde and James McNeill Whistler. Beardsley's contribution to the development of the Art Nouveau and poster styles was significant despite his early death from tuberculosis. He is one of the important Modern Style figures.


title: Aubrey Beardsley

text: Beardsley was born in Brighton, Sussex, England, on 21 August 1872 and christened on 24 October 1872. His father, Vincent Paul Beardsley (1839–1909), was the son of a Clerkenwell jeweler; Vincent had no trade himself (partly owing to inherited tuberculosis, from which his own father had died aged only 40), and relied on a private income from an inheritance that he received from his maternal grandfather, a property developer, when he was 21. Vincent's wife, Ellen Agnus Pitt (1846–1932), was the daughter of Surgeon-Major William Pitt of the Indian Army. The Pitts were a well-established and respected family in Brighton, and Beardsley's mother married a man of lesser social status than might have been expected. Soon after their wedding, Vincent was obliged to sell some of his property in order to settle a claim for his breach of promise of marriage from another woman, the widow of a clergyman, who claimed that he had promised to marry her. At the time of his birth, Beardsley's family, which included his sister Mabel who was one year older, were living in Ellen's familial home at 12 Buckingham Road. The number of the house in Buckingham Road was 12, but the numbers were changed, and it is now 31. At the age of seven, Beardsley contracted tuberculosis.


title: Aubrey Beardsley

text: With the loss of Vincent Beardsley's fortune soon after his son's birth, the family settled in London in 1883, where Vincent would work first for the West India & Panama Telegraph Company, then irregularly as a clerk at breweries; they would spend the next 20 years in rented accommodation, battling poverty. Ellen took to presenting herself as the "victim of a "mésalliance"". In 1884, Aubrey appeared in public as an "infant musical phenomenon", playing at several concerts with his sister. In January 1885, he began to attend Brighton, Hove and Sussex Grammar School, where he spent the next four years. His first poems, drawings, and cartoons appeared in print in "Past and Present", the school's magazine. In 1888, he obtained a post in an architect's office and afterward one in the Guardian Life and Fire Insurance Company. In 1891, under the advice of Sir Edward Burne-Jones and Pierre Puvis de Chavannes, he took up art as a profession. In 1892, he attended the classes at the Westminster School of Art, then under Professor Fred Brown.


title: Aubrey Beardsley

text: Beardsley traveled to Paris in 1892, where he discovered the poster art of Henri de Toulouse-Lautrec and the Parisian fashion for Japanese prints. His first commission was "Le Morte d'Arthur" by Thomas Malory (1893), illustrated for the publishing house J.M. Dent and Company. In 1894, a new translation of Lucian’s "True History", with illustrations by Beardsley, William Strang, and J. B. Clark, was privately printed in an edition of 251 copies.


title: Aubrey Beardsley

text: Beardsley had six years of creative output, which can be divided into several periods, identified by the form of his signature. In the early period, his work is mostly unsigned. During 1891 and 1892, he progressed to using his initials A.V.B. In mid-1892, the period of "Le Morte d'Arthur" and "The Bon Mots", he used a Japanese-influenced mark that became progressively more graceful, sometimes accompanied by A.B. in block capitals.


title: Aubrey Beardsley

text: He co-founded "The Yellow Book" with American writer Henry Harland, and for the first four editions, he served as art editor and produced the cover designs and many illustrations for the magazine. He was aligned with Aestheticism, the British counterpart of Decadence and Symbolism. Most of his images are done in ink and feature large dark areas contrasted with large blank ones as well as areas of fine detail contrasted with areas with none at all.


title: Aubrey Beardsley

text: Beardsley was the most controversial artist of the Art Nouveau era, renowned for his dark and perverse images and grotesque erotica, which were the main themes of his later work. His illustrations were in black and white against a white background. Some of his drawings, inspired by Japanese shunga artwork, featured enormous genitalia. His most famous erotic illustrations concerned themes of history and mythology; these include his illustrations for a privately printed edition of Aristophanes' "Lysistrata" and his drawings for Oscar Wilde's play "Salome", which eventually premiered in Paris in 1896. Other major illustration projects included an 1896 edition of "The Rape of the Lock" by Alexander Pope.


title: Aubrey Beardsley

text: He also produced extensive illustrations for books and magazines (e.g., for a deluxe edition of Sir Thomas Malory's "Le Morte d'Arthur") and worked for magazines such as "The Studio" and "The Savoy", of which he was a co-founder. As a co-founder of "The Savoy", Beardsley was able to pursue his writing as well as illustration, and a number of his writings, including "Under the Hill" (a story based on the Tannhäuser legend) and "The Ballad of a Barber" appeared in the magazine.


title: Aubrey Beardsley

text: Beardsley was a caricaturist and did some political cartoons, mirroring Wilde's irreverent wit in art. Beardsley's work reflected the decadence of his era and his influence was enormous, clearly visible in the work of the French Symbolists, the Poster Art Movement of the 1890s and the work of many later-period Art Nouveau artists such as Papé and Clarke. Some alleged works of Beardsley's were published in a book titled "Fifty Drawings by Aubrey Beardsley, Selected from the Collection of Mr. H.S. Nicols". These later were discovered to be forgeries, distinguishable by their almost pornographic erotic elements rather than Beardsley's subtler use of sexuality.


title: Aubrey Beardsley

text: Beardsley's work continued to cause controversy in Britain long after his death. During an exhibition of Beardsley's prints held at the Victoria and Albert Museum in London in 1966, a private gallery in London was raided by the police for exhibiting copies of the same prints on display at the museum, and the owner charged under obscenity laws.


title: Aubrey Beardsley

text: Beardsley was a public as well as private eccentric. He said "I have one aim—the grotesque. If I am not grotesque, I am nothing." Wilde said Beardsley had "a face like a silver hatchet, and grass green hair." Beardsley was meticulous about his attire: dove-grey suits, hats, ties, yellow gloves. He appeared at his publisher's in a morning coat and court shoes.


title: Aubrey Beardsley

text: Although Beardsley was associated with the homosexual clique that included Oscar Wilde and other aesthetes, the details of his sexuality remain in question. Speculation about his sexuality includes rumours of an incestuous relationship with his elder sister, Mabel, who may have become pregnant by her brother and miscarried.


title: Aubrey Beardsley

text: During his entire career, Beardsley had recurrent attacks of tuberculosis. He suffered frequent lung haemorrhage and often was unable to work or leave his home.


title: Aubrey Beardsley

text: Beardsley converted to Catholicism in March 1897. The next year, the last letter before his death was to his publisher Leonard Smithers and close friend Herbert Charles Pollitt: Postmark: March 7, 1898 | Jesus is our Lord and Judge | Dear Friend, I implore you to destroy "all" copies of "Lysistrata" and bad drawings … By all that is holy, "all" obscene drawings. | Aubrey Beardsley | In my death agony.Both men ignored Beardsley's wishes, and Smithers actually continued to sell reproductions as well as forgeries of Beardsley's work.


title: Aubrey Beardsley

text: In December 1896, Beardsley suffered a violent haemorrhage, leaving him in precarious health. By April 1897, a month after his conversion to Catholicism, his deteriorating health prompted a move to the French Riviera. There he died a year later, on 16 March 1898, of tuberculosis at the Cosmopolitan Hotel in Menton, Alpes-Maritimes, France, attended by his mother and sister. He was 25 years old. Following a requiem mass in Menton Cathedral the following day, his remains were interred in the Cimetière du Trabuquet.


title: Aubrey Beardsley

text: In the 1982 "Playhouse" drama "Aubrey", written by John Selwyn Gilbert, Beardsley was portrayed by actor John Dicks. The drama concerned Beardsley's life from the time of Oscar Wilde's arrest in April 1895, which caused Beardsley to lose his position at "The Yellow Book", to his death from tuberculosis in 1898. The BBC documentary "Beardsley and His Work" was made in 1982. Beardsley is featured on the cover of The Beatles' "Sgt. Pepper's Lonely Hearts Club Band". The 1977 horror film is narrated by the entombed spirit of an unnamed artist whose work and manner of death identify him as Beardsley.


title: Aubrey Beardsley

text: In March 2020, BBC Four broadcast the hour-long documentary, "Scandal & Beauty: Mark Gatiss on Aubrey Beardsley", presented by Mark Gatiss. The programme coincided with the Beardsley exhibition at Tate Britain.


title: Aubrey Beardsley

text: Beardsley’s art is also mentioned briefly in the 2011 version of the Car Seat Headrest song, "Beach Life-in-Death."


title: Aubrey Beardsley

text: In 2019 the National Leather Association International established an award named after Beardsley for creators of abstract erotic art.


title: Yellow badge

text: Yellow badges (or yellow patches), also referred to as Jewish badges (), are badges that Jews were ordered to wear at various times during the Middle Ages by some caliphates, at various times during the Medieval and early modern period by some European powers, and from 1939 to 1945 by the Axis powers, including Nazi Germany. The badges served to mark the wearer as a religious or ethnic outsider, and often served as a badge of shame.


title: Yellow badge

text: The practice of wearing special clothing or markings to distinguish Jews and other non-Muslims (dhimmis) in Muslim-dominated countries seems to have been introduced in the Umayyad Caliphate by Caliph Umar II in the early 8th century. The practice was revived and reinforced by the Abbasid caliph al-Mutawakkil (847–861), subsequently remaining in force for centuries. A genizah document from 1121 gives the following description of decrees issued in Baghdad:


title: Yellow badge

text: In largely Catholic Medieval Europe, Jews and Muslims were required to wear distinguishable clothing in some periods. These measures were not seen as being inconsistent with '. Although not the first ecclesiastic requirement for non-Christians to wear distinguishable clothing, the Fourth Council of the Lateran headed by Pope Innocent III ruled in 1215 that Jews and Muslims must wear distinguishable dress (Latin '). Canon 68 reads, in part:


title: Yellow badge

text: Innocent III had in 1199 confirmed "", which was also confirmed by Pope Honorius III in 1216. In 1219, Honorius III issued a dispensation to the Jews of Castile, the largest Jewish population in Europe. Spanish Jews normally wore turbans, which presumably met the requirement to be distinctive. Elsewhere, local laws were introduced to bring the canon into effect. The identifying mark varied from one country to another, and from period to period.


title: Yellow badge

text: However, these ecclesiastic pronouncements required legal sanctions of a temporal authority. In 1228, James I of Aragon ordered Jews of Aragon to wear the badge; and in 1265, the ', a legal code enacted in Castile by Alfonso X but not implemented until many years later, included a requirement for Jews to wear distinguishing marks. On 19 June 1269, Louis IX of France imposed a fine of ten livres (one livre was equivalent to a pound of silver) on Jews found in public without a badge (, "wheel", or '). The enforcement of wearing the badge is repeated by local councils, with varying degrees of fines, at Arles 1234 and 1260, Béziers 1246, Albi 1254, Nîmes 1284 and 1365, Avignon 1326 and 1337, Rodez 1336, and Vanves 1368. The "rota" looked like a ring of white or yellow. The shape and colour of the patch also varied, although the colour was usually white or yellow. Married women were often required to wear two bands of blue on their veil or head-scarf.


title: Yellow badge

text: In German-speaking Europe, a requirement for a badge was less common than the ' or ' (a cone-shaped head dress, common in medieval illustrations of Jews). In 1267, in a special session, the Vienna city council required Jews to wear a ""; the badge does not seem to have been worn in Austria. There is a reference to a dispensation from the badge in Erfurt on 16 October 1294, the earliest reference to the badge in Germany.


title: Yellow badge

text: There were also attempts to enforce the wearing of full-length robes, which in late 14th century Rome were supposed to be red. In Portugal a red star of David was used.


title: Yellow badge

text: Enforcement of the rules was variable; in Marseilles the magistrates ignored accusations of breaches, and in some places individuals or communities could buy exemption. Cathars who were considered "first time offenders" by the Catholic Church and the Inquisition were also forced to wear yellow badges, albeit in the form of crosses, about their person.


title: Yellow badge

text: The yellow badge is different from the Jewish hat (or '), a cone-shaped hat, which is seen in many illustrations from before this date, and remained the key distinguishing mark of Jewish dress in the Middle Ages. From the 16th century, the use of the ' declined, but the badge tended to outlast it, surviving into the 18th century in places.


title: Yellow badge

text: After the German invasion of Poland in 1939 there were initially different local decrees requiring Jews to wear a distinctive sign under the General Government. The sign was a white armband with a blue Star of David on it; in the Warthegau a yellow badge in the form of a Star of David on the left side of the breast and on the back. The requirement to wear the Star of David with the word ' (German for Jew) – inscribed in letters meant to resemble Hebrew writing – was then extended to all Jews over the age of six in the Reich and the Protectorate of Bohemia and Moravia (by a decree issued on September 1, 1941, signed by Reinhard Heydrich) and was gradually introduced in other German-occupied areas, where local words were used (e.g., ' in French, "" in Dutch).


title: Yellow badge

text: One observer reported that the star increased German non-Nazi sympathy for Jews as the impoverished citizens who wore them were, contrary to Nazi propaganda, obviously not the cause of German failure in the east. In the Protectorate of Bohemia and Moravia, government had to ban hat tipping toward Jews and other courtesies that became popular as protests against the German occupation. A whispering campaign that claimed that the action was in response to the United States government requiring German Americans to wear swastikas was unsuccessful.


title: Yellow badge

text: In May 2021, in response to the anti-vaccine movement in the United States, hatWRKS, a hat store in Nashville, Tennessee, sold badges that resembled the yellow stars with the words "Not vaccinated" on them. In response, the Stetson company announced they would no longer sell any hats to the store. This also sparked protests outside the store.


title: Yellow badge

text: The practice of wearing yellow stars in anti-vaccine movements spread to other parts of the world, such as protests in Montreal, London, Amsterdam and Paris. The practice sparked condemnation by various Jewish advocacy groups and Holocaust survivors.


title: Cortana (virtual assistant)

text: Cortana is a virtual assistant developed by Microsoft that uses the Bing search engine to perform tasks such as setting reminders and answering questions for the user.


title: Cortana (virtual assistant)

text: Cortana is currently available in English, Portuguese, French, German, Italian, Spanish, Chinese, and Japanese language editions, depending on the software platform and region in which it is used.


title: Cortana (virtual assistant)

text: Microsoft began reducing the prevalence of Cortana and converting it from an assistant into different software integrations in 2019. It was split from the Windows 10 search bar in April 2019. In January 2020, the Cortana mobile app was removed from certain markets, and on March 31, 2021, the Cortana mobile app was shut down globally.


title: Cortana (virtual assistant)

text: Cortana was demonstrated for the first time at the Microsoft Build developer conference in San Francisco in April 2014. It was launched as a key ingredient of Microsoft's planned "makeover" of future operating systems for Windows Phone and Windows.


title: Cortana (virtual assistant)

text: It is named after Cortana, a synthetic intelligence character in Microsoft's "Halo" video game franchise originating in Bungie folklore, with Jen Taylor, the character's voice actress, returning to voice the personal assistant's US-specific version.


title: Cortana (virtual assistant)

text: The development of Cortana started in 2009 in the Microsoft Speech products team with general manager Zig Serafin and Chief Scientist Larry Heck. Heck and Serafin established the vision, mission, and long-range plan for Microsoft's digital personal assistant and they built a team with the expertise to create the initial prototypes for Cortana. Some of the key researchers in these early efforts included Microsoft Research researchers Dilek Hakkani-Tür, Gokhan Tur, Andreas Stolcke, and Malcolm Slaney, research software developer Madhu Chinthakunta, and user experience designer Lisa Stifelman. To develop the Cortana digital assistant, the team interviewed human personal assistants. The interviews inspired a number of unique features in Cortana, including the assistant's "notebook" feature. Originally, "Cortana" was meant to be only a codename, but a petition on Windows Phone's UserVoice site proved to be popular and made the codename official.


title: Cortana (virtual assistant)

text: In January 2015, Microsoft announced the availability of Cortana for Windows 10 desktops and mobile devices as part of merging Windows Phone into the operating system at large.


title: Cortana (virtual assistant)

text: On May 26, 2015, Microsoft announced that Cortana would also be available on other mobile platforms. An Android release was set for July 2015, but the Android APK file containing Cortana was leaked ahead of its release. It was officially released, along with an iOS version, in December 2015.


title: Cortana (virtual assistant)

text: During E3 2015, Microsoft announced that Cortana would come to the Xbox One as part of a universally designed Windows 10 update for the console.


title: Cortana (virtual assistant)

text: In 2017, Microsoft partnered with Amazon to integrate Echo and Cortana with each other, allowing users of each smart assistant to summon the other via a command. This feature preview was released in August 2018. Windows 10 users can just say "Hey Cortana, open Alexa" and Echo users can say "Alexa, open Cortana" to summon the other assistant.


title: Cortana (virtual assistant)

text: In January 2019, Microsoft CEO Satya Nadella stated that he no longer sees Cortana as a direct competitor against Alexa and Siri.


title: Cortana (virtual assistant)

text: On July 24, 2020, Cortana was removed from the Xbox dashboard as part of a redesign, then on January 31, 2020, Microsoft removed the Cortana mobile application in certain markets (including UK, Australia, Germany, Mexico, China, Spain, Canada, and India).


title: Cortana (virtual assistant)

text: On March 31, 2021, Microsoft shut down the Cortana apps entirely for iOS and Android and removed them from corresponding app stores. To access previously recorded content, users have to use Cortana on Windows 10 or another specialized Microsoft application.


title: Cortana (virtual assistant)

text: Microsoft has also reduced emphasis on Cortana in Windows 11. Cortana is not used during the new device setup process and isn't pinned to the taskbar by default.


title: Cortana (virtual assistant)

text: Microsoft has integrated Cortana into numerous products such as Microsoft Edge, the browser bundled with Windows 10. Microsoft's Cortana assistant is deeply integrated into its Edge browser. Cortana can find opening hours when on restaurant sites, show retail coupons for websites, or show weather information in the address bar. At the Worldwide Partners Conference 2015 Microsoft demonstrated Cortana integration with products such as GigJam. Conversely, Microsoft announced in late April 2016 that it would block anything other than Bing and Edge from being used to complete Cortana searches, again raising questions of anti-competitive practices by the company.


title: Cortana (virtual assistant)

text: Microsoft's "Windows in the car" concept includes Cortana. The concept makes it possible for drivers to make restaurant reservations and see places before they go there.


title: Cortana (virtual assistant)

text: At Microsoft Build 2016, Microsoft announced plans to integrate Cortana into Skype (Microsoft's video-conferencing and instant messaging service) as a bot to allow users to order food, book trips, transcribe video messages and make calendar appointments through Cortana in addition to other bots. , Cortana can underline certain words and phrases in Skype conversations that relate to contacts and corporations. A writer from Engadget has criticised the Cortana integration in Skype for responding only to very specific keywords, feeling as if she was "chatting with a search engine" due to the impersonal way the bots replied to certain words such as "Hello" causing the Bing Music bot to bring up Adele's song of that name.


title: Cortana (virtual assistant)

text: Microsoft also announced at Microsoft Build 2016 that Cortana would be able to cloud-synchronise notifications between Windows 10 Mobile's and Windows 10's Action Center, as well as notifications from Android devices.


title: Cortana (virtual assistant)

text: In December 2016, Microsoft announced the preview of Calendar.help, a service that enabled people to delegate the scheduling of meetings to Cortana. Users interact with Cortana by including her in email conversations. Cortana would then check people's availability in Outlook Calendar or Google Calendar, and work with others Cc'd on the email to schedule the meeting. The service relied on automation and human-based computation.


title: Cortana (virtual assistant)

text: In May 2017, Microsoft in collaboration with Harman Kardon announced INVOKE, a voice-activated speaker featuring Cortana. The premium speaker has a cylindrical design and offers 360 degree sound, the ability to make and receive calls with Skype, and all of the other features currently available with Cortana.


title: Cortana (virtual assistant)

text: Cortana can set reminders, recognize natural voice without the requirement for keyboard input, and answer questions using information from the Bing search engine (For example, current weather and traffic conditions, sports scores, biographies). Searches using Windows 10 are made only with the Microsoft Bing search engine, and all links will open with Microsoft Edge, except when a screen reader such as Narrator is being used, where the links will open in Internet Explorer. Windows Phone 8.1's universal Bing SmartSearch features are incorporated into Cortana, which replaces the previous Bing Search app, which was activated when a user presses the "Search" button on their device. Cortana includes a music recognition service. Cortana can simulate rolling dice and flipping a coin. Cortana's "Concert Watch" monitors Bing searches to determine the bands or musicians that interest the user. It integrates with the Microsoft Band watch band for Windows Phone devices if connected via Bluetooth, it can make reminders and phone notifications.


title: Cortana (virtual assistant)

text: Since the Lumia Denim mobile phone series, launched in October 2014, active listening was added to Cortana enabling it to be invoked with the phrase: "Hey Cortana". It can then be controlled as usual. Some devices from the United Kingdom by O2 received the Lumia Denim update without the feature, but this was later clarified as a bug and Microsoft has since fixed it.


title: Cortana (virtual assistant)

text: Cortana integrates with services such as Foursquare to provide restaurant and local attraction recommendations and LIFX to control smart light bulbs.


title: Cortana (virtual assistant)

text: Cortana stores personal information such as interests, location data, reminders, and contacts in the "Notebook". It can draw upon and add to this data to learn a user's specific patterns and behaviors. Users can view and specify what information is collected to allow some control over privacy, said to be "a level of control that goes beyond comparable assistants". Users can delete information from the "Notebook".


title: Cortana (virtual assistant)

text: Cortana has a built-in system of reminders, which can, for example, be associated with a specific contact; it will then remind the user when in communication with that contact, possibly at a specific time or when the phone is in a specific location. Originally, these reminders were specific to the device Cortana was installed on but starting on February 12, 2015, Cortana synchronizes reminders across devices.


title: Cortana (virtual assistant)

text: Most versions of Cortana take the form of two nested circles, which are animated to indicate activities such as searching or talking. The main color scheme includes a black or white background and shades of blue for the respective circles.


title: Cortana (virtual assistant)

text: Cortana on Windows mobile and Android is capable of capturing device notifications and sending them to a Windows 10 device. This allows a computer user to view notifications from their phone in the Windows 10 Action Center. The feature was announced in early 2016 and released later in the year.


title: Cortana (virtual assistant)

text: Cortana has a "do-not-disturb" mode in which users can specify "quiet hours", as was available for Windows Phone 8.1 users. Users can change the settings so that Cortana calls users by their names or nicknames. It also has a library of "Easter Eggs", pre-determined remarks.


title: Cortana (virtual assistant)

text: When asked for a prediction, Cortana correctly predicted the winners of the first 14 matches of the football 2014 FIFA World Cup knockout stage, including the semi-finals, before it incorrectly picked Brazil over the Netherlands in the third place play-off match; this streak topped Paul the Octopus who correctly predicted all 7 of Germany's 2010 FIFA World Cup matches as well as the Final. Cortana can forecast results in various other sports such as the NBA, the NFL, the Super Bowl, the ICC Cricket World Cup and various European football leagues. Cortana can solve mathematical equations, convert units of measurement, and determine the exchange rates between currencies including Bitcoin.


title: Cortana (virtual assistant)

text: Cortana can integrate with third-party apps on Windows 10 or directly through the service. Starting in late 2016, Cortana integrated with Microsoft's Wunderlist service, allowing Cortana to add and act on reminders.


title: Cortana (virtual assistant)

text: At Microsoft's Build 2017 conference, Microsoft announced that Cortana would get a consumer third-party skills capability, similar to that in Amazon Alexa.


title: Cortana (virtual assistant)

text: On February 16, 2018, Microsoft announced connected home skills were added for ecobee, Honeywell Lyric, Honeywell Total Connect Comfort, LIFX, TP-Link Kasa, and Geeni, as well as support for IFTTT. At Microsoft's Ignite 2018 conference, Microsoft announced an Technology Adopters Program that Enterprises could build skills that could be developed and deployed into Azure tenants, accessible by organizational units or security groups.


title: Cortana (virtual assistant)

text: Cortana indexes and stores user information. Cortana can be disabled; this will cause Windows search to search Bing as well as the local computer, but that can also be disabled. Turning Cortana off does not in itself delete user data stored on Microsoft's servers, but it can be deleted by user action. Microsoft has further been criticized for requests to Bing's website for a file called "threshold.appcache", which contains Cortana's information through searches made through the Start Menu even when Cortana is disabled on Windows 10.


title: Cortana (virtual assistant)

text: The British version of Cortana speaks with a British accent and uses British idioms, while the Chinese version, known as Xiao Na, speaks Mandarin Chinese and has an icon featuring a face and two eyes, which is not used in other regions.


title: Cortana (virtual assistant)

text: The English United Kingdom localised version of Cortana is voiced by voice actress Ginnie Watson, while the United States localised version is voiced by Jen Taylor. Taylor is the voice actress who voices Cortana, the namesake of the virtual assistant, in the Halo video game series.


title: Cortana (virtual assistant)

text: The following table identifies the localized version of Cortana currently available. Except where indicated, this applies to both Windows Mobile and Windows 10 versions of the assistant.


title: Cortana (virtual assistant)

text: The natural language processing capabilities of Cortana are derived from Tellme Networks (bought by Microsoft in 2007) and are coupled with a Semantic search database called Satori.


title: Cortana (virtual assistant)

text: While many of Cortana's U.S. English responses are voiced by Jen Taylor, organic responses require the use of a text-to-speech engine. Microsoft Eva is the name of the text-to-speech voice for organic response in Cortana's U.S. English.


title: Cortana (virtual assistant)

text: Cortana updates were delivered independently of those to the main Windows Phone OS, allowing Microsoft to provide new features at a faster pace. Not all Cortana-related features could be updated in this manner, as some features such as "Hey Cortana" required the Windows Phone update service and the Qualcomm Snapdragon SensorCore Technology.


title: Don't Go Breaking My Heart

text: "Don't Go Breaking My Heart" is a 1976 duet by English musician Elton John and English singer Kiki Dee. It was written by John with Bernie Taupin under the pseudonyms "Ann Orson" and "Carte Blanche", respectively, and intended as an affectionate pastiche of the Motown style, notably the various duets recorded by Marvin Gaye and singers such as Tammi Terrell and Kim Weston.


title: Don't Go Breaking My Heart

text: John and Taupin originally intended to record the song with Dusty Springfield, but ultimately withdrew the offer; Springfield's partner Sue Cameron later said this was because she was too ill at the time.


title: Don't Go Breaking My Heart

text: "Cash Box" said that "there are some great harmonies in the chorus" and that John and Dee "seem perfectly wedded in this tune."


title: Don't Go Breaking My Heart

text: Unlike many of John's singles from the 1970s, it was never included on an original album (although it was recorded during the "Blue Moves" sessions), but was subsequently released as the third single on the album "Duets", in early 1994. This version of the song was recorded with RuPaul and reached number seven on the UK Singles Chart and number one in Iceland.


title: Don't Go Breaking My Heart

text: "Don't Go Breaking My Heart" was the first No. 1 single in the UK for both John and Kiki Dee, topping the chart for six weeks in mid 1976. John would not enjoy a solo British chart-topper until "Sacrifice" in 1990. It also became his sixth No. 1 single in the US, topping the "Billboard" Hot 100 for four weeks and spent one week on the Easy Listening chart. "Billboard" ranked it as the No. 2 song for 1976, giving him his second consecutive appearance in the "Billboard" Year-end Top 3. In the U.S., it has been certified platinum by the Recording Industry Association of America. After this duet with Dee, John failed to have another US solo number one single until "Candle in the Wind 1997". This 21-year period included two intervening number one hits in America with musical partners: "That's What Friends Are For" by Dionne & Friends in 1986, and a 1992 re-make of John's "Don't Let the Sun Go Down on Me" with George Michael credited as a duet.


title: Don't Go Breaking My Heart

text: The B-side, "Snow Queen", was supposedly inspired by Cher, with John quoting past Sonny & Cher hits "I Got You Babe" and "The Beat Goes On", as well as the solo Cher song "Bang Bang (My Baby Shot Me Down)" during the fadeout of the song.


title: Don't Go Breaking My Heart

text: In 1977, John guest-starred on "The Muppet Show" and performed the track with Miss Piggy. In 1985, John and Dee performed the track to the crowd at Wembley Stadium during John's set at Live Aid (where Dee sang backup). In 1987, John appeared with Minnie Mouse on the NBC series "Totally Minnie" miming to the track. He performed the track with Alan Partridge (Steve Coogan) at the 2001 British Comedy awards. He also performed it with the Spice Girls on his ITV tribute programme "An Audience with ... Elton John".


title: Don't Go Breaking My Heart

text: The B-side, "Snow Queen", remained unavailable on CD outside Australia until April 2019 when it was included as a bonus track on the reissue of Kiki Dee's "Cage the Songbird" album, included in the 5-CD box set "The Rocket Years". In May 2019 it was also included on the 3-CD box set "Gold", a retrospective of Dee's career spanning various labels. In 2020, it was also included on Elton John's 8-CD box set "".


title: Don't Go Breaking My Heart

text: In 1994, Elton John and American drag queen, actor, model, singer, songwriter, and television personality RuPaul released the song as a duet. It was released as the third single from the album, "Duets" and reached number three on the "Billboard" Dance Club Songs in the US. In Europe, the song peaked at number-one in Iceland and within the top 10 in Portugal and the UK, the top 20 in Denmark, Ireland and Italy, and the top 30 in Austria, France and Switzerland. On the Eurochart Hot 100, "Don't Go Breaking My Heart" peaked at number 18 in March 1994. Outside Europe, the song reached number 39 in New Zealand, number 45 in Australia, and number 92 on the Billboard Hot 100 in the US.


title: Don't Go Breaking My Heart

text: AllMusic editor Stephen Thomas Erlewine described the song as a "kitschy number". Larry Flick from "Billboard" wrote that John "recreates his classic Kiki Dee duet with the world's favorite drag queen. Revamped quasi-rave/hi-NRG version of the track is way stronger than the less-than-pleasing mix on John's current collection, rendering it a formidable contender for action on both dancefloors and radio. Oodles of good fun." Dave Sholin from the "Gavin Report" commented, "Thanks to producer Giorgio Moroder, there's a few more beats per minute, as well as a hilarious video, and a super performance of a great tune." Alan Jones from "Music Week" rated it four out of five, calling it "somewhat soulessly produced" and a "smash-bound but tacky remake". John Kilgo from "The Network Forty" stated that this remake of the previous number-one smash "is for real..." Tom Doyle from "Smash Hits" gave it one out of five, saying that "the music sounds like it was done with the help of a Gameboy running low on batteries".


title: Don't Go Breaking My Heart

text: A music video was made to accompany the song, featuring Elton John and RuPaul. It was directed by Randy Barbota. The video was uploaded to YouTube in December 2016. , it has amassed more than 2 million views.


title: Don't Go Breaking My Heart

text: The musical comedy troupe the Capitol Steps recorded a parody of the song, in which then President George W. Bush is told by his wife Laura Bush, "Don't go faking you're smart".


title: Primary sclerosing cholangitis

text: Primary sclerosing cholangitis (PSC) is a long-term progressive disease of the liver and gallbladder characterized by inflammation and scarring of the bile ducts, which normally allow bile to drain from the gallbladder. Affected individuals may have no symptoms or may experience signs and symptoms of liver disease, such as yellow discoloration of the skin and eyes, itching, and abdominal pain.


title: Primary sclerosing cholangitis

text: The bile duct scarring that occurs in PSC narrows the ducts of the biliary tree and impedes the flow of bile to the intestines. Eventually, it can lead to cirrhosis of the liver and liver failure. PSC increases the risk of various cancers, including liver cancer, gallbladder carcinoma, colorectal cancer, and cholangiocarcinoma. The underlying cause of PSC is unknown. Genetic susceptibility, immune system dysfunction, and abnormal composition of the gut flora may play a role. This is further suggested by the observation that around 75% of individuals with PSC also have inflammatory bowel disease (IBD), most often ulcerative colitis.


title: Primary sclerosing cholangitis

text: No effective medical treatment for primary sclerosing cholangitis is known. Its most definitive treatment is a liver transplant, but it can recur after transplantation. Many people affected by PSC require a liver transplant.


title: Primary sclerosing cholangitis

text: PSC is a rare disease and most commonly affects people with IBD. About 3.0 to 7.5% of people with ulcerative colitis have PSC, and 80% of people with PSC have some form of IBD. Diagnosis usually occurs in people in their 30s or 40s. Individuals of Northern European ancestry are affected more often than people of Southern European or Asian descent. Men are affected more often than women. The disease was initially described in the mid-1800s, but was not fully characterized until the 1970s with the advent of improved medical-imaging techniques such as endoscopic retrograde cholangiopancreatography.


title: Primary sclerosing cholangitis

text: Nearly half of people with PSC do not have symptoms, and are often incidentally discovered to have PSC due to abnormal liver function tests; however, a substantial proportion have debilitating signs and symptoms of the disease. Signs and symptoms of PSC may include severe itching and nonspecific fatigue. Yellowing of the skin and white portion of the eyes may also be seen. Enlargement of the liver and spleen are seen in roughly 40% of affected individuals. Abdominal pain affects about 20% of people with PSC.


title: Primary sclerosing cholangitis

text: Multiple episodes of life-threatening acute cholangitis (infection within the bile ducts) can be seen due to impaired drainage of the bile ducts, which increases the risk of infection.


title: Primary sclerosing cholangitis

text: The exact cause of primary sclerosing cholangitis is unknown, and its pathogenesis is improperly understood. Although PSC is thought to be caused by autoimmune disease, it does not demonstrate a clear response to immunosuppressants. Thus, many experts believe it to be a complex, multifactorial (including immune-mediated) disorder and perhaps one that encompasses several different hepatobiliary diseases.


title: Primary sclerosing cholangitis

text: In addition, longstanding, well-recognized associations are seen between PSC and human leukocyte antigen alleles (A1, B8, and DR3).


title: Primary sclerosing cholangitis

text: PSC is characterized by inflammation of the bile ducts (cholangitis) with consequent stricturing (i.e., narrowing) and hardening (sclerosis) of these ducts due to scar formation, be it inside and/or outside the liver. The resulting scarring of the bile ducts obstructs the flow of bile, which further perpetuates bile duct and liver injury. Chronic impairment of bile flow due to blockage and dysfunctional bile transport (cholestasis) causes progressive biliary fibrosis and ultimately biliary cirrhosis and liver failure.


title: Primary sclerosing cholangitis

text: The primary physiological function of bile is to assist in the breakdown and absorption of fat in the intestinal tract; a relative deficiency of bile can lead to fat malabsorption and deficiencies of fat-soluble vitamins (A, D, E, K).


title: Primary sclerosing cholangitis

text: Liver enlargement is seen due to portal hypertension caused by compression of portal veins by the proximate sclerosed intrahepatic bile ducts, and leads to right upper quadrant abdominal pain.


title: Primary sclerosing cholangitis

text: PSC is generally diagnosed on the basis of having at least two of three clinical criteria after secondary causes of sclerosing cholangitis have been ruled out:


title: Primary sclerosing cholangitis

text: Historically, a cholangiogram would be obtained via endoscopic retrograde cholangiopancreatography (ERCP), which typically reveals "beading" (alternating strictures and dilation) of the bile ducts inside and/or outside the liver. Currently, the preferred option for diagnostic cholangiography, given its noninvasive yet highly accurate nature, is magnetic resonance cholangiopancreatography (MRCP), a magnetic resonance imaging technique. MRCP has unique strengths, including high spatial resolution, and can even be used to visualize the biliary tract of small animal models of PSC.


title: Primary sclerosing cholangitis

text: Most people with PSC have evidence of autoantibodies and abnormal immunoglobulin levels. For example, approximately 80% of people with PSC have perinuclear antineutrophil cytoplasmic antibodies (P-ANCA); however, this and other immunoglobulin findings are not specific to those with PSC and are of unclear clinical significance/consequence. Antinuclear antibodies and anti-smooth muscle antibody are found in 20-50% of PSC patients, and likewise are not specific for the disease,but may identify a subgroup of PSC patients who also have autoimmune hepatitis (i.e. PSC-AIH overlap syndrome).


title: Primary sclerosing cholangitis

text: The differential diagnosis can include primary biliary cholangitis (formerly referred to as primary biliary cirrhosis), drug-induced cholestasis, cholangiocarcinoma, IgG4-related disease, post-liver transplantation nonanastomotic biliary strictures, and HIV-associated cholangiopathy. Primary sclerosing cholangitis and primary biliary cholangitis are distinct entities and exhibit important differences, including the site of tissue damage within the liver, associations with IBD, which includes ulcerative colitis and Crohn's disease, response to treatment, and risks of disease progression.


title: Primary sclerosing cholangitis

text: Primary sclerosing cholangitis is typically classified into three subgroups based on whether the small and/or large bile ducts are affected. The subgroups of PSC include:


title: Primary sclerosing cholangitis

text: No pharmacologic treatment has been approved by the U.S. Food and Drug Administration for PSC. Some experts recommend a trial of ursodeoxycholic acid (UDCA), a bile acid occurring naturally in small quantities in humans, as it has been shown to lower elevated liver enzyme numbers in patients with PSC and has proven effective in other cholestatic liver diseases. However, UDCA has yet to be shown to clearly lead to improved liver histology and survival. Guidelines from the American Association for the Study of Liver Diseases and the American College of Gastroenterology do not support the use of UDCA but guidelines from the European Association for the Study of the Liver do endorse the use of moderate doses (13-15 milligrams per kilogram) of UDCA for PSC.


title: Primary sclerosing cholangitis

text: Supportive treatment for PSC symptoms is the cornerstone of management. These therapies are aimed at relieving symptoms such as itching with antipruritics (e.g. bile acid sequestrants such as cholestyramine); antibiotics to treat episodes of ascending cholangitis; and vitamin supplements, as people with PSC are often deficient in fat-soluble vitamins (A, D, E, and K).


title: Primary sclerosing cholangitis

text: ERCP and specialized techniques may also be needed to help distinguish between a benign PSC stricture and a bile-duct cancer (cholangiocarcinoma).


title: Primary sclerosing cholangitis

text: Liver transplantation is the only proven long-term treatment of PSC. Indications for transplantation include recurrent bacterial ascending cholangitis, decompensated cirrhosis, hepatocellular carcinoma, hilar cholangiocarcinoma, and complications of portal hypertension. Not all patients are candidates for liver transplantation, and some experience disease recurrence afterward. The reasons why some patients develop recurrent PSC remains largely obscure, but surprisingly, those without recurrence of disease (hence protected from recurrence) are characterized by an increased presence of the potentially pathogenic " Shigella" species.


title: Primary sclerosing cholangitis

text: Estimated median survival from diagnosis until liver transplant or PSC-related death is 21.3 years. Various models have been developed to help predict survival, but their use is generally best suited for research and not clinical purposes. A serum alkaline phosphatase less than 1.5 times the upper limit of normal has been associated with better outcomes, but its use in predicting long-term outcomes is unclear. An IgA isotype autoantibody to the pancreatic GP2 protein (anti-GP2 IgA antibody) is the first verified prognostic biomarker in PSC. The role of anti-GP2 IgA in PSC was simultaneously investigated and reported by two research groups, and later confirmed by others. Association was demonstrated between anti-GP2 IgA and progressive liver fibrosis, cholangiocarcinoma development and shorter transplantation free survival in PSC patients.


title: Primary sclerosing cholangitis

text: Other markers which may be measured and monitored are a complete blood count, serum liver enzymes, bilirubin levels (usually grossly elevated), kidney function, and electrolytes. Fecal fat measurement is occasionally ordered when symptoms of malabsorption (e.g., gross steatorrhea) are prominent.


title: Primary sclerosing cholangitis

text: The development of any of the cancers associated with PSC predicts a poor prognosis. Complications from PSC-associated cancers account for 40% of deaths from PSC. Primary sclerosing cholangitis is one of the major known risk factors for cholangiocarcinoma, a cancer of the biliary tree, for which the lifetime risk among patients with PSC is 10-15%. This represents a 400-fold greater risk of developing cholangiocarcinoma compared to the general population. Surveillance for cholangiocarcinoma in patients with PSC is encouraged, with some experts recommending annual surveillance with a specialized imaging study and serum markers, although consensus regarding the modality and interval has yet to be established. Similarly, a screening colonoscopy is recommended in people who receive a new diagnosis of primary sclerosing cholangitis since their risk of colorectal cancer is 10 times higher than that of the general population.


title: Primary sclerosing cholangitis

text: PSC is strongly associated with IBD, in particular ulcerative colitis (UC) and to a lesser extent Crohn's disease. As many as 5% of patients with IBD are co-diagnosed with PSC, and approximately 70% of people with PSC have IBD. Of note, the presence of colitis appears to be associated with a greater risk of liver disease progression and bile duct cancer (cholangiocarcinoma) development, although this relationship remains poorly understood. Close monitoring of PSC patients is vital.


title: Primary sclerosing cholangitis

text: Various forms of gallbladder disease such as gallstones and gallbladder polyps are also common in those with PSC. Approximately 25% of people with PSC have gallstones. Ultrasound surveillance of the gallbladder every year is recommended for people with PSC. Any person with PSC who is found to have a mass in the gallbladder should undergo surgical removal of the gallbladder due to the high risk of cholangiocarcinoma. Osteoporosis (hepatic osteodystrophy) and hypothyroidism are also associated with PSC.


title: Primary sclerosing cholangitis

text: A 2–3:1 male-to-female predilection occurs in primary sclerosing cholangitis. PSC can affect men and women at any age, although it is commonly diagnosed in the fourth decade of life, most often in the presence of IBD. PSC progresses slowly and is often asymptomatic, so it can be present for years before it is diagnosed and before it causes clinically significant consequences. Relatively few data are available on the prevalence and incidence of PSC, with studies in different countries showing annual incidence of 0.068–1.3 per 100,000 people and prevalence 0.22–8.5 per 100,000; given that PSC is closely linked with ulcerative colitis, the risk is likely higher in populations where UC is more common. In the United States, an estimated 29,000 individuals have PSC.


title: Primary sclerosing cholangitis

text: Although no curative treatment is known, several clinical trials are underway that aim to slow progression of this liver disease. Obeticholic acid is being investigated as a possible treatment for PSC due to its antifibrotic effects. Simtuzumab is a monoclonal antibody against the profibrotic enzyme LOXL2 that is being developed as a possible therapy for PSC.


title: 2021 NBA All-Star Game

text: The 2021 NBA All-Star Game was an exhibition basketball game played on March 7, 2021, during the National Basketball Association's (NBA) 2020–21 season. It was the 70th edition of the NBA All-Star Game, and was hosted at State Farm Arena in Atlanta, home of the Atlanta Hawks. With teams captained by LeBron James and Kevin Durant, Team LeBron won the game 170–150. Giannis Antetokounmpo of Team LeBron was named the All-Star Game Most Valuable Player. The game was originally scheduled to be held in Indianapolis, but it was relocated to Atlanta due to the COVID-19 pandemic and resulting scheduling conflicts with the 2021 NCAA Division I men's basketball tournament. The game was televised nationally on TNT for the 19th consecutive year, and simulcast on TBS for the 7th consecutive year.


title: 2021 NBA All-Star Game

text: This was the third time that Atlanta hosted the All-Star Game; the previous times were 1978 and 2003. This was the last All-Star game Marv Albert would call in his career.


title: 2021 NBA All-Star Game

text: On December 13, 2017, at a press conference held by the Indiana Pacers, it was announced that the 2021 NBA All-Star Game would be hosted at the Bankers Life Fieldhouse in Indianapolis, Indiana. In attendance at the announcement was NBA Commissioner Adam Silver, Pacers owner Herb Simon, Governor Eric Holcomb, and Mayor Joe Hogsett. The team had submitted its bid for the game in grand fashion with then-team president and NBA legend Larry Bird delivering the bid in an Dallara IR-05.


title: 2021 NBA All-Star Game

text: On November 25, 2020, the NBA announced that the All-Star Game would be postponed due to NBA schedule changes as a result of the COVID-19 pandemic and potential schedule conflicts with the 2021 NCAA Division I men's basketball tournament (which, for logistical considerations, was relocated in and around the Indianapolis area). Silver confirmed that Indianapolis will instead host the 2024 NBA All-Star Game. On February 4, 2021, the NBA and the NBA Players Association announced the 2021 All-Star Game had been relocated to State Farm Arena in Atlanta, home of the Atlanta Hawks.


title: 2021 NBA All-Star Game

text: The NBA placed a focus on supporting African-American communities through the All-Star Game; on February 15, it was announced that the NBA and the NBA Players Association would donate $2.5 million to support equitable COVID-19 care and relief, and historically black colleges and universities (HBCUs). The two teams played in support of the Thurgood Marshall College Fund and United Negro College Fund respectively, recorded performances of bands from Florida A&M University and Grambling State University were used for player introductions, and the court was decorated with artwork from students of HBCUs.


title: 2021 NBA All-Star Game

text: All participants in the game were required to test negative on a COVID-19 PCR test before they were transported to Atlanta, and they could only bring limited family and friends. They were required to use private transport provided by the league. All NBA players were subject to daily testing during the All-Star break, even if they were not participating in the game, and they were prohibited from travelling internationally or using public accommodations if they did travel out of their home market. For the first week after the break, all players were subject to gameday testing protocols (one rapid test and two PCR tests) daily, even if they were not scheduled to play that day.


title: 2021 NBA All-Star Game

text: The NBA faced criticism for going on with the All-Star Game, raising the possibility of a superspreading event due to participation by players from multiple teams. The possibility that exposure could also occur at events tied to the game was also raised. Multiple players expressed resentment to the decision, including Carmelo Anthony, LeBron James (who described it as a "slap in the face"), and Kawhi Leonard among others. Critics acknowledged that the All-Star Game has been a major source of revenue for the NBA and its media partners which likely factored into the decision to still go on with the event. On March 8, the NBA reported that there were no positive tests among players and staff present on gameday.


title: 2021 NBA All-Star Game

text: The All-Star Game was closed to the public, and there were no other official festivities tied to the game. Spectators were limited to 1,200–1,500 invited guests and were expected to include vaccinated health care workers and the students and faculty of HBCUs. Mayor of Atlanta Keisha Lance Bottoms publicly stated that "we are in agreement that this is a made-for-TV event only"; she asked fans to refrain from travelling to Atlanta for the game and strongly discouraged the hospitality industry from hosting events relating to the game. This request was enforced by the NBA which sent cease-and-desist notices to various local businesses for using its trademarks to promote events tied to the All-Star Game. Artificial crowd noise and virtual fans on screens along the court, similarly to the NBA Bubble, were also utilized.


title: 2021 NBA All-Star Game

text: Quin Snyder, coach of the Utah Jazz, qualified as the head coach of Team LeBron on February 15. Doc Rivers, coach of the Philadelphia 76ers, also qualified as the head coach of Team Durant on February 19, after their win over the Bulls.


title: 2021 NBA All-Star Game

text: As had been the case in previous years, the rosters for the All-Star Game were selected through a voting process. The fans could vote through the NBA website as well as through their Google account. The starters were chosen by the fans, media, and current NBA players. Fans made up 50% of the vote, and NBA players and media each comprised 25% of the vote. The two guards and three frontcourt players who received the highest cumulative vote totals in each conferences were named the All-Star starters and two players in each conferences with the highest votes were named team captains. NBA head coaches voted for the reserves for their respective conferences, none of which could be players from their own team. Each coach selected two guards, three frontcourt players, and two wild cards, with each selected player ranked in order of preference within each category. If a multi-position player was to be selected, coaches were encouraged to vote for the player at the position that was "most advantageous for the All-Star team", regardless of where the player was listed on the All-Star ballot or the position he was listed in box scores.


title: 2021 NBA All-Star Game

text: The All-Star Game starters were announced on February 18, 2021. Bradley Beal of the Washington Wizards and Kyrie Irving of the Brooklyn Nets were named the backcourt starters in the East, earning their third and seventh all-star appearances, respectively. Kevin Durant of the Brooklyn Nets and Giannis Antetokounmpo of the Milwaukee Bucks were named the frontcourt starters in the East, earning their 11th and fifth all-star appearances, respectively. Joining in the East frontcourt was Joel Embiid of the Philadelphia 76ers, his fourth selection.


title: 2021 NBA All-Star Game

text: Luka Dončić of the Dallas Mavericks and Stephen Curry of the Golden State Warriors were named to the starting backcourt in the West, earning their second and seventh all-star appearances, respectively. In the frontcourt, Kawhi Leonard of the Los Angeles Clippers and LeBron James of the Los Angeles Lakers was named to their fifth and 17th all-star selections, respectively. Joining them was Nikola Jokić of the Denver Nuggets, in his third all-star selection.


title: 2021 NBA All-Star Game

text: The All-Star Game reserves were announced on February 23, 2021. The West reserves included Anthony Davis of the Los Angeles Lakers, his eighth selection; Paul George of the Los Angeles Clippers, his seventh selection; Rudy Gobert of the Utah Jazz, his second selection; Damian Lillard of the Portland Trail Blazers, his sixth selection; Donovan Mitchell of the Utah Jazz, his second selection; Chris Paul of the Phoenix Suns, his 11th selection; and Zion Williamson of the New Orleans Pelicans, his first selection.


title: 2021 NBA All-Star Game

text: The East reserves included Jaylen Brown of the Boston Celtics, his first selection; James Harden of the Brooklyn Nets, his ninth selection; Zach LaVine of the Chicago Bulls, his first selection; Julius Randle of the New York Knicks, his first selection; Ben Simmons of the Philadelphia 76ers, his third selection; Jayson Tatum of the Boston Celtics, his second selection; and Nikola Vučević of the Orlando Magic, his second selection.


title: 2021 NBA All-Star Game

text: The NBA All-Star Draft took place on March 4, 2021. LeBron James and Kevin Durant were named captains, as they both received the most votes from the West and East, respectively. This was the fourth straight year that James was named an All-Star team captain, while this was Durant's first selection as team captain. The first eight players that were drafted were starters. The next fourteen players (seven from each conference) were chosen by NBA head coaches. NBA Commissioner Adam Silver selected replacements for any player unable to participate in the All-Star Game, choosing a player from the same conference as the player who was being replaced. Silver's selection joined the team that drafted the replaced player. If a replaced player was a starter, the head coach of that team would choose a new starter from their cast of players instead.


title: 2021 NBA All-Star Game

text: James picked Giannis Antetokounmpo with his first pick, and Durant picked Kyrie Irving second. Team Durant was the home team due to the Eastern Conference having home team status for the game.


title: 2021 NBA All-Star Game

text: Hours before the opening tip, the 76ers' Embiid and Simmons were scratched from the game due to NBA COVID-19 protocols as they had visited a local barber in Philadelphia who later tested positive before they traveled to Atlanta. No replacements were named, and each squad went with 11 players. Coach Rivers chose Williamson to start for Team Durant in place of Embiid.


title: 2021 NBA All-Star Game

text: Giannis Antetokounmpo scored 35 points on a perfect 16-of-16 shooting from the field to lead Team LeBron to a 170–150 win and capture All-Star MVP honors. He set an All-Star record for most attempts without a miss, surpassing Hal Greer's 8-for-8 in 1968. Damian Lillard and Stephen Curry added 32 and 28 points, respectively, and both made eight three-point field goals for Team LeBron, including several from more than 30 feet from the basket. Team Durant was led by Bradley Beal's 26 points.


title: 2021 NBA All-Star Game

text: The game used the same format as the 2020 edition: the team that scored the most points during each of the first three 12-minute quarters would receive a cash prize to be donated to a designated charity. The fourth quarter was untimed, with the first team to meet or exceed a "target score"—the score of the leading team in total scoring after three quarters plus 24—declared the winner. Team LeBron controlled the contest after winning the second quarter by 19 points, while also taking the first and third quarters by one point each. Lillard made a walk-off three-pointer to win it. LeBron James finished with just four points in 13 minutes, played the first half and rested thereafter. His prior low in his 16 previous All-Star games was 13 points. Team LeBron donated over $1 million to the Thurgood Marshall College Fund, while Team Durant gave $500,000 to the United Negro College Fund.


title: 2021 NBA All-Star Game

text: Most NBA All-Star Weekend festivities were canceled, while some of the traditional Saturday-night competitions were moved to Sunday with the All-Star Game itself. The Skills Challenge and Three-Point Contest were held before the game, and the Slam Dunk Contest at halftime.


title: 2021 NBA All-Star Game

text: A Rising Stars roster was named to honor the league's top first- and second-year players, but the game was not played.


title: 2021 NBA All-Star Game

text: Curry won his second Three-Point Contest after making his last shot in the final round to edge Mike Conley Jr. 28–27.


title: 2021 NBA All-Star Game

text: The All-Star Game was broadcast by TNT for the 19th consecutive year. The game was seen by 5.94 million viewers, an 18% decrease over 2020 and the least-watched All-Star Game overall, but it beat CBS's "Oprah with Meghan and Harry" special in key demographic audience share"."


title: 2021 NBA All-Star Game

text: Additionally, this was the final NBA All-Star Game to ever be called by Marv Albert, as he announced his retirement from broadcasting following the 2021 Playoffs.


title: Vivek Ranadivé

text: Vivek Yeshwant Ranadivé (; born 7 October 1957) is an Indian-American business executive, engineer, author, speaker and philanthropist. Ranadivé is the founder and former chief executive officer (CEO) of TIBCO Software, a business intelligence software company, and of Teknekron Software Systems. Ranadivé is also a co-owner and chairman of the National Basketball Association's Sacramento Kings.


title: Vivek Ranadivé

text: Ranadivé grew up in the Juhu area of Mumbai, India, and was the youngest of three children. He studied at the Bombay International School, located at Babulnath, Mumbai. He is the nephew of the Indian Communist leaders Balkrishna Trimbak Ranadive and Ahilya Rangnekar. At 16, Ranadivé was accepted to MIT, but in the 1970s the Indian government did not release foreign currency for citizens to study abroad. Ranadivé talked his way into the office of the Reserve Bank of India and got the required foreign exchange for one quarter of the tuition.


title: Vivek Ranadivé

text: After earning bachelor's and master's degrees in electrical engineering from MIT, he obtained an MBA from Harvard Business School in 1983. While at MIT, Ranadivé started his first company, a UNIX consulting company. He also held management and engineering positions with Ford Motor Company, M/A-Com Linkabit and Fortune Systems.


title: Vivek Ranadivé

text: Teknekron Corp., a technology incubator, provided $250,000 in seed capital to Ranadivé in 1985 to found Teknekron Software Systems.


title: Vivek Ranadivé

text: In 2016, Ranadivé founded Bow Capital, an early-stage startup investment firm in partnership with the University of California Regents. Among their investments are Eversight, Workramp, Jerry.ai, and Flex.


title: Vivek Ranadivé

text: In 2010, Ranadivé became the co-owner and vice chairman of the Golden State Warriors, making him the first person of Indian descent to co-own an NBA franchise.


title: Vivek Ranadivé

text: On 21 March 2013, it was announced that Ranadivé had joined Ronald Burkle and Mark Mastrov to attempt to purchase the Sacramento Kings. In order for Ranadivé to purchase the Kings, he had to sell his share of the Golden State Warriors. On 16 May 2013, it was announced that the group reached an agreement with the Maloof family to purchase 65% of the Kings for approximately $348 million. The NBA approved the sale on 28 May. Ranadivé made waves in 2014 when he proposed a style of play that included his team keeping one player on offense the entire time, creating a 4-on-5 defense on the other end.


title: Vivek Ranadivé

text: Ranadivé has been criticized during his tenure as Kings owner and blamed for their lack of success on the court.


title: Vivek Ranadivé

text: Anjali is an R&B singer-songwriter. She wrote and released her first single, "We Turn Up" in April 2014. Her second single was called "Nobody" and features Tyga. Anjali goes by the stage name "Nani", which means maternal grandmother in Hindi, as she has always respected elderly figures in her life. Anjali, who graduated from UC Berkeley with a marine science degree, founded Jaws & Paws, a marine and wildlife conservation nonprofit that spreads awareness for the conservation of sharks, polar bears, and tigers. In October 2015, she received the 2015 Paul Walker Ocean Leadership Award from the Monterey Bay Aquarium. She was also part of the 2022 NBA All-Star Celebrity Game.


title: Vivek Ranadivé

text: Ranadivé coached his daughter's 12-and-under girls' basketball team despite, according to his own contention, never having touched a basketball until he reached his 40s. The story of Ranadivé's team's unlikely success was told by author Malcolm Gladwell in the pages of "The New Yorker", and later included in Gladwell's 2013 book, "David and Goliath".


Hereditary nonpolyposis colorectal cancer (HNPCC) or Lynch syndrome is an autosomal dominant genetic condition that is associated with a high risk of colon cancer as well as other cancers including endometrial cancer (second most common), ovary, stomach, small intestine, hepatobiliary tract, upper urinary tract, brain, and skin. The increased risk for these cancers is due to inherited mutations that impair DNA mismatch repair. It is a type of cancer syndrome. Because patients with Lynch syndrome can have polyps, the term HNPCC has fallen out of favor.


title: Hereditary nonpolyposis colorectal cancer

text: In addition to the types of cancer found in the chart above, it is understood that Lynch syndrome also contributes to an increased risk of small bowel cancer, pancreatic cancer, ureter/renal pelvis cancer, biliary tract cancer, brain cancer, and sebaceous neoplasms. Increased risk of prostate cancer and breast cancer has also been associated with Lynch syndrome, although this relationship is not entirely understood.


text: Two-thirds of colon cancers occur in the proximal colon and common signs and symptoms include blood in the stool, diarrhea or constipation, and unintended weight loss. The mean age of colorectal cancer diagnosis is 44 for members of families that meet the Amsterdam criteria. The average age of diagnosis of endometrial cancer is about 46 years. Among women with HNPCC who have both colon and endometrial cancer, about half present first with endometrial cancer, making endometrial cancer the most common sentinel cancer in Lynch syndrome. The most common symptom of endometrial cancer is abnormal vaginal bleeding. In HNPCC, the mean age of diagnosis of gastric cancer is 56 years of age with intestinal-type adenocarcinoma being the most commonly reported pathology. HNPCC-associated ovarian cancers have an average age of diagnosis of 42.5 years-old; approximately 30% are diagnosed before age 40.


text: Significant variation in the rate of cancer has been found depending on the mutation involved. Up to the age of 75 years the risks of different cancers by the mutations are in the table below.


text: HNPCC is inherited in an autosomal dominant fashion. The hallmark of HNPCC is defective DNA mismatch repair, which causes an elevated rate of single nucleotide changes and microsatellite instability, also known as MSI-H (the H is "high"). MSI is identifiable in cancer specimens in the pathology laboratory. Most cases result in changes in the lengths of dinucleotide repeats of the nucleobases cytosine and adenine (sequence: CACACACACA...).


text: The impairment of either gene for the protein dimer impairs the protein function. These 4 genes are involved in error correction (mismatch repair), so dysfunction of the genes can lead to the inability to fix DNA replication errors and cause HNPCC. HNPCC is known to be associated with other mutations in genes involved in the DNA mismatch repair pathway:


text: People with MSH6 mutations are more likely to be Amsterdam criteria II-negative. The presentation with MSH6 is slightly different from with MLH1 and MSH2, and the term "MSH6 syndrome" has been used to describe this condition. In one study, the Bethesda guidelines were more sensitive than the Amsterdam Criteria in detecting it.


text: Up to 39% of families with mutations in an HNPCC gene do not meet the Amsterdam criteria. Therefore, families found to have a deleterious mutation in an HNPCC gene should be considered to have HNPCC regardless of the extent of the family history. This also means that the Amsterdam criteria fail to identify many people who are at risk for Lynch syndrome. Improving the criteria for screening is an active area of research, as detailed in the Screening Strategies section of this article.


text: Most people with HNPCC inherit the condition from a parent. However, due to incomplete penetrance, variable age of cancer diagnosis, cancer risk reduction, or early death, not all people with an HNPCC gene mutation have a parent who had cancer. Some people develop HNPCC de-novo in a new generation, without inheriting the gene. These people are often only identified after developing an early-life colon cancer. Parents with HNPCC have a 50% chance of passing the genetic mutation on to each child. It is also important to note, that deleterious mutation in one of MMR genes alone is not sufficient to cause cancer, but that rather further mutations in other tumour suppressor genes need to occur.


text: A diagnosis of Lynch syndrome is applied to people with a germline DNA mutation in one of the MMR genes (MLH1, MSH2, MSH6, and PMS2) or the EPCAM gene, identified by genetic testing. Candidates for germline genetic testing can be identified by clinical criteria such as the Amsterdam Clinical Criteria and Bethesda Guidelines, or through tumor analysis by immunohistochemistry(IHC), or microsatellite instability (MSI) testing. In the US, professional societies recommend testing every colon cancer for MSI or IHC as screening for Lynch syndrome, but this is not always performed because of cost and resource limitations. Genetic testing is commercially available and consists of a blood test.


text: Immunohistochemistry (IHC) is a method that can be used to detect abnormal mismatch repair (MMR) protein expression in tumours that are associated with Lynch syndrome. While it is not diagnostic of a Lynch syndrome, it can play a role in identifying people who should have germline testing. Two methods of implementation of IHC testing includes age-based testing and universal testing for all people. Currently, there is no widespread agreement regarding which screening method should be used. Age-based testing for IHC has been suggested in part due to cost-benefit analyses, whereas universal testing for all people with colorectal cancer ensures people with Lynch Syndrome are not missed. To address the costs, researchers are trying to predict MSI or IHC directly from the way the tumor looks under the microscope, without doing any molecular testing.


text: Mutations in DNA mismatch repair systems can lead to difficulty transmitting regions within the DNA which contain repeating patterns of two or three nucleotides (microsatellites), otherwise known as microsatellite instability (MSI). MSI is associated with alternate sized repetitive DNA sequences that are not present in the correlated germ line DNA resulting in 15-20% of colorectal cancers. MSI is identified through DNA extraction from both a tumor tissue sample and a normal tissue sample followed by PCR analysis of microsatellite regions. MSI analysis can be used to identify people who may have Lynch syndrome and direct them for further testing. One study noted that one third of MSI colorectal cancers showed a low immunoscore, suggesting that tumor-infiltrating lymphocytes might be a good option for therapy for these patients. High numbers of tumor-infiltrating lymphocytes were related with better survival rates and treatment responses.


text: Three major groups of MSI-H (microsatellite instability – MSI) cancers can be recognized by histopathological criteria:


text: The histopathological criteria are not sensitive enough to detect MSI from histology but researchers are trying to use artificial intelligence to predict MSI from histology.


text: In addition, HNPCC can be divided into "Lynch syndrome I" (familial colon cancer) and "Lynch syndrome II" (HNPCC associated with other cancers of the gastrointestinal tract or reproductive system).


text: After reporting a null finding from their randomized controlled trial of aspirin (acetylsalicylic acid – ASA) to prevent the colorectal neoplasia of Lynch syndrome, Burn and colleagues have reported new data, representing a longer follow-up period than reported in the initial "NEJM" paper. These new data demonstrate a reduced incidence in people with Lynch syndrome who were exposed to at least four years of high-dose aspirin, with a satisfactory risk profile. These results have been widely covered in the media; future studies will look at modifying (lowering) the dose (to reduce risk associated with the high dosage of ASA).


text: Genetic counseling and genetic testing are recommended for families that meet the Amsterdam criteria, preferably before the onset of colon cancer.


text: Colonoscopies are recommended as a preventative method of surveillance for individuals who have Lynch syndrome, or LS-associated genes. Specifically, it is recommended that colonoscopies begin at ages 20–25 for MLH1 and MSH2 mutation carriers and 35 years for MSH6 and PMS2 mutation carriers. Colonoscopic surveillance should then be performed at a 1-2 year interval for Lynch Syndrome patients.


text: A transvaginal ultrasound with or without endometrial biopsy is recommended annually for ovarian and endometrial cancer screening. For women with Lynch syndrome, a yearly CA-125 blood test can be used to screen for ovarian cancer, however there is limited data on the efficacy of this test in reducing mortality.


text: There are also strategies for detecting other cancers early or reducing the chances of developing them that people with Lynch syndrome can discuss with their doctor, however their effectiveness is not clear. These options include:


text: The following are the Amsterdam criteria in identifying high-risk candidates for molecular genetic testing:


text: "Amsterdam I Criteria (all bullet points must be fulfilled): The Amsterdam I criteria were published in 1990; however, were felt to be insufficiently sensitive."


text: The Amsterdam II criteria were developed in 1999 and improved the diagnostic sensitivity for Lynch syndrome by including cancers of the endometrium, small bowel, ureter and renal pelvis.


text: The Bethesda criteria were developed in 1997 and later updated in 2004 by the National Cancer Institute to identify persons requiring further testing for Lynch syndrome through MSI. In contrast to the Amsterdam Criteria, the Revised Bethesda Guidelines use pathological data in addition to clinical information to help health care providers identify persons at high risk.


text: 2. Presence of synchronous or metachronous colorectal or other Lynch syndrome associated cancers (e.g. cancers of endometrium, ovary, stomach, small bowel, pancreas, biliary tract, ureter, renal pelvis, brain, sebaceous glands, keratoacanthomas)


text: 4. Colorectal cancer diagnosed in a person with one or more first-degree relative with colorectal cancer or Lynch syndrome associated tumour diagnosed under age 50


text: 5. Person with colorectal cancer and two or more first- or second-degree relatives with colorectal cancer or Lynch syndrome associated cancer diagnosed at any age.


text: It is important to note that these clinical criteria can be difficult to use in practice and clinical criteria used alone misses between 12 and 68 percent of Lynch syndrome cases.


text: Prophylactic hysterectomy and salpingo-oophorectomy (removal of the uterus, Fallopian tubes, and ovaries to prevent cancer from developing) can be performed before ovarian or endometrial cancer develops.


text: Surgery remains the front-line therapy for HNPCC. Patients with Lynch syndrome who develop colorectal cancer may be treated with either a partial colectomy or total colectomy with ileorectal anastomosis. Due to increased risk of colorectal cancer following partial colectomy and similar quality of life after both surgeries, a total colectomy may be a preferred treatment for HNPCC, especially in younger patients.


text: There is an ongoing controversy over the benefit of 5-fluorouracil-based adjuvant therapies for HNPCC-related colorectal tumours, particularly those in stages I and II.


text: Checkpoint blockade with anti-PD-1 therapy is now preferred first line therapy for advanced Microsatellite-Instability–High colorectal cancer.


text: Though the exact prevalence of Lynch syndrome-causing mutations in the general population remain unknown, recent studies estimate the prevalence to be 1 in 279 individuals, or 0.35%. Certain populations are known to have a higher prevalence of founder mutations, including, but not limited to, French Canadians, Icelanders, African Americans, and Ashkenazi Jews. Lynch syndrome-causing mutations are found in approximately 3% of all diagnosed colorectal cancers, and 1.8% of all diagnosed endometrial cancers. The average age of diagnosis of cancer in patients with this syndrome is 44 years old, as compared to 64 years old in people without the syndrome.