title: Melusine

text: A similar story became attached to Eleanor of Aquitaine, as seen in the 14th-century romance "Richard Coer de Lyon." In this fantastical account, Henry II's wife is not named Eleanor but Cassodorien, and she always leaves Mass before the elevation of the Host. They have three children: Richard, John, and a daughter named Topyas. When Henry forces Cassodorien to stay in Mass, she flies through the roof of the church carrying her daughter, never to be seen again.


title: Melusine

text: "The Travels of Sir John Mandeville" recounts a legend about Hippocrates' daughter. She was transformed into a hundred-foot long dragon by the goddess Diane, and is the "lady of the manor" of an old castle. She emerges three times a year, and will be turned back into a woman if a knight kisses her, making the knight into her consort and ruler of the islands. Various knights try, but flee when they see the hideous dragon; they die soon thereafter. This appears to be an early version of the legend of Melusine.


title: The Hertz Corporation

text: The Hertz Corporation is an American car rental company based in Estero, Florida. The company operates its namesake Hertz brand, along with the brands Dollar Rent A Car, Firefly Car Rental and Thrifty Car Rental.


title: The Hertz Corporation

text: It is one of the three big rental car holding companies in the United States, holding a 36% market share, placing it ahead of both Enterprise Holdings and the Avis Budget Group. As one of the largest worldwide vehicle rental companies by sales, locations, and fleet size, Hertz operates in 160 countries in North America, Europe, Latin America, Africa, Asia, Australia, the Caribbean, the Middle East and New Zealand.


title: The Hertz Corporation

text: Hertz was ranked 326th in the 2020 "Fortune" 500 list. The company filed for bankruptcy on May 22, 2020, citing a sharp decline in revenue and future bookings caused by the COVID-19 pandemic. As of December 31, 2021, the company had revenues of $7.3 billion, assets of $19.7 billion, and 23,000 employees. As of July 1, 2021, the company is no longer in Chapter 11 bankruptcy.


title: The Hertz Corporation

text: The Hertz Corporation, originally known as Rent-a-Car Inc., was founded by Chicago, Illinois native Walter L. Jacobs in 1918. This small car rental operation began with a dozen Model T Ford cars. Within five years, Jacobs' fleet expanded to 600 vehicles—generating annual revenues of approximately US$1 million. John D. Hertz, owner of Yellow Truck and Coach Manufacturing Company, developed an interest in the brand, leading to him purchasing the company in 1923. It was then renamed to Hertz Drive-Ur-Self System. Jacobs continued to serve as president and chief operating officer of Hertz Drive-Ur-Self System until 1961.


title: The Hertz Corporation

text: After three years of ownership, John Hertz sold the rental car brand to General Motors Corporation in 1926. GM purchased the rest of Yellow Truck and Coach Manufacturing Company in 1943. Under the ownership of General Motors, the company released the first rental car charge card in 1926, opened its first rental car location at Chicago's Midway Airport in 1932, and introduced the first one-way rental plan in 1933. Hertz Drive-Ur-Self System expanded services to Canada in 1938 and Europe (France) in 1950.


title: The Hertz Corporation

text: John Hertz repurchased the brand from General Motors in 1953 through his other company, The Omnibus Corporation, which he renamed to The Hertz Corporation. In 1954, its stock began trading on the New York Stock Exchange, and it purchased a New York-based truck leasing company, Metropolitan Distributors, including a fleet of 4,000 trucks. This acquisition increased The Hertz Corporation's fleet to 15,500 trucks and 12,900 passenger cars. During the General Motors ownership, the company had sold many local Hertz franchises to independent business entities. With the financial backing of investment bankers Lehman Brothers, led by Lehman partner and Hertz director, Frank J. Manheim, Hertz began a buyback program for the franchises in the US, then expanded globally. Manheim predicted the global growth and devised the strategy which made “Hertz” a household name and led to dynamic growth in the company's market capitalization from $7 million in 1953 to $100 million in 1965.


title: The Hertz Corporation

text: The company expanded to South America in 1961. In 1967, The Hertz Corporation became a subsidiary of Radio Corporation of America. In 1985, the car rental company was sold to UAL Corporation, later known as Allegis Corporation, for a cash deal of US$587.5 million. This acquisition expanded Hertz's vehicle renting and leasing, with nearly 400,000 cars and trucks in 120 countries across the globe.


title: The Hertz Corporation

text: In the summer of 1987, Allegis Corporation chairman and president Frank A. Olson announced the company would be selling Hertz due to internal changes. Park Ridge Corporation, which was owned and operated under Ford Motor Company, purchased Hertz in October 1987 for US$1.3 billion, and Hertz relocated its headquarters from Midtown Manhattan to Park Ridge, New Jersey in 1988.


title: The Hertz Corporation

text: In 2002, Hertz became the first international car rental company to open in China. In 2013, Hertz began partnering with China's largest car rental company, China Auto Rental. In 2016, it reduced its ownership stake but announced a continuing commercial relationship through 2023.


title: The Hertz Corporation

text: By the second quarter of 2005, Hertz produced about ten percent of Ford's overall pre-tax profit. However, after 18 years of ownership, the Ford Motor Company announced it would be selling the Hertz brand with the intent to focus more on building Ford cars and trucks. Private equity firms Clayton, Dubilier & Rice, The Carlyle Group, and Merrill Lynch Global Private Equity agreed to purchase all shares of common stock in Hertz for an estimated US$15 billion, including debt, and the business itself for US$5.6 billion in 2005.


title: The Hertz Corporation

text: The Clayton, Dubilier & Rice consortium took Hertz Global Holdings public again on the New York Stock Exchange in November 2006, and Hertz began to expand through Europe.


title: The Hertz Corporation

text: Hertz launched subbrand "Simply Wheelz" in September 2007 for economy-minded and leisure-market audiences. By 2008, the service expanded to airports in California, Florida, and the McCarran International Airport in Las Vegas, Nevada. Once an online reservation was made, customers were able to choose one of six types of vehicles at self-service rental kiosks. Simply Wheelz was rebranded as Advantage Rent-a-Car in the fall of 2009.


title: The Hertz Corporation

text: In late December 2009, Hertz announced the acquisition of used cars dealer British Car Auctions (BCA) from London-based equity firm Montagu Private Equity for an estimated £390 million.


title: The Hertz Corporation

text: In November 2012, Hertz Global Holdings Chairman and CEO Mark P. Frissora announced the company's purchase of Dollar Thrifty Automotive Group, a U.S.-based car rental brand with headquarters in Tulsa, Oklahoma, for US$2.3 billion. The business transaction included Hertz paying $87.50 per share of the Dollar Thrifty stock. The deal was finalized on November 19, 2012, and resulted in a combined 10,400 locations in approximately 150 countries. Before the merge, Dollar Thrifty was the fourth-largest car rental company.


title: The Hertz Corporation

text: In December 2012, Hertz announced it would sell its Advantage Rent a Car unit to Franchise Services of North America and Macquarie Capital after the acquisition of Dollar Thrifty Automotive Group was finalized.


title: The Hertz Corporation

text: In May 2013, Frissora and Florida Governor Rick Scott announced Hertz Global Holdings would relocate their worldwide headquarters from Park Ridge, New Jersey to Estero, Florida. Relocation to Southwest Florida was influenced by the state's travel and tourism industry, proximity to Orlando and Miami, to condense corporate offices, and to increase efficiency of Hertz Global brands. A temporary office building in Naples, Florida housed 640 employees until construction of a new facility was completed in 2015.


title: The Hertz Corporation

text: John P. Tague replaced Frissora as chief executive officer and president of The Hertz Corporation in November 2014.


title: The Hertz Corporation

text: Kathryn V. Marinello, former CEO of Stream Global Services, was appointed president and chief executive officer of The Hertz Corporation on January 2, 2017, following John Tague's retirement.


title: The Hertz Corporation

text: Marinello resigned as CEO on May 18, 2020, and Hertz announced that Paul Stone as new president and chief executive. Stone previously served as Hertz's executive vice president and chief retail operations officer for North America.


title: The Hertz Corporation

text: On Oct. 5, Hertz announced it has named Mark Fields interim CEO and Paul Stone president and chief operations officer.


title: The Hertz Corporation

text: As a result of the COVID-19 pandemic, on April 30, 2020, Hertz announced that it had missed lease payments on its fleet and was seeking support from its lenders, including activist investor Carl Icahn, in an attempt to avoid bankruptcy. Marinello resigned as CEO on May 18, 2020, and Hertz announced that Paul Stone would be the new president and chief executive. Stone previously served as Hertz's executive vice president and chief retail operations officer for North America. On May 22, 2020, the "Wall Street Journal" reported that Hertz was preparing to file for bankruptcy because it did not reach an agreement with top lenders. That same day, the company filed for Chapter 11 bankruptcy. Carl Icahn held 39% of Hertz's shares when it filed for bankruptcy on May 22, 2020, and he controlled three board seats. He invested a total of $2.3 billion into Hertz shares from 2014 to 2020.


title: The Hertz Corporation

text: Hertz financed itself mostly by taking out loans secured by its fleet of cars, and if the cars fell in value, Hertz's lenders had the right to demand an immediate payment, reducing the amount of the loan, so they were still comfortably covered by the cars’ now-lower value. Because of the crisis, used-car values and sales volumes fell right as Hertz lost most of its customers. The bankruptcy filing started a 60-day clock, during which Hertz's secured lenders must wait before they can foreclose on the 400,000 U.S. cars that were financed through such arrangements.


title: The Hertz Corporation

text: Despite the bankruptcy filing, Hertz announced on June 11 that it was seeking to raise up to $1 billion in new equity (with disclaimers that there is a "risk that the common stock could ultimately be worthless"). The Wall Street Journal characterized the potential stock sale as a "seemingly unprecedented move for a large bankrupt company eager to capitalize on market anomalies," as its stock price rose nearly 1000% from a low of 59 cents after its bankruptcy filing to $5.50 a share. Hertz's stock has been heavily traded by retail investors, becoming one of the most-traded stocks. Hertz sold $29 million in stock before the Securities Exchange Commission halted further sales. The stock was delisted from the New York Stock Exchange in October 2020.


title: The Hertz Corporation

text: On July 1, 2021, Hertz emerged from Chapter 11 bankruptcy and changed its ticker symbol from HTZGQ to HTZZ.


title: The Hertz Corporation

text: In October 2021, Mark Fields was named interim CEO of Hertz with a focus on forward looking investments. On October 25, 2021, Fields announced that Hertz will buy 100,000 Tesla vehicles citing his goal of fleet electrification and that Tesla is the "only manufacturer that can produce EVs at scale".


title: The Hertz Corporation

text: Since 2019, Hertz has been embroiled in a mounting controversy where numerous reports have emerged of Hertz falsely accusing its customers of having stolen automobiles which were under an active rental agreement. Many of the victims report having been arrested in full view of their families and at gun point. Victims report loss of licensure, professional credentials and employment while their falsely filed felonies languish through the system, depriving them of income and their rights. Victims report being jailed for months before being released. Victim reports that Hertz claims that outdated computer systems are to blame, local and corporate systems "not communicating correctly", but victim profiles indicate that these false arrests are more likely to happen to minority groups. In February 2022, a judge forced Hertz to reveal that it reports about 3,365 of its customers to the police every year for theft. Hertz claims that such instances are only a "rare situation" as this is only 0.014% of their 25 million annual transactions in the United States. According to reports, 47 customers have filed lawsuits against Hertz for misreporting cars as stolen resulting in many false arrests and imprisonment.


title: The Hertz Corporation

text: In December 2022, Hertz announced the settlement of 364 pending claims relating to vehicle theft reporting, bringing resolution to more than 95% of its pending theft reporting claims. In this settlement, Hertz agreed to pay approximately $168 million by year-end to resolve these disputes.


title: The Hertz Corporation

text: Hertz has approximately 12,000 corporate and franchisee locations in 160 countries throughout North America, Europe, Latin America, Africa, Asia, Australia, the Caribbean, the Middle East and New Zealand.


title: The Hertz Corporation

text: Wilford Gwilliam of Overland West purchased a portion of Hertz franchise in 1941. Overland West is the largest Hertz franchise licensee in North America, operating 27 car rental and four car sales locations in eight states. Gwilliam sold it to Devere J. Sparrow, who led the organization until selling it to his son-in-law, Jerry H. Petersen, in 1976. As the current owner, president and CEO, Petersen oversees franchises and employees.


title: The Hertz Corporation

text: The Hertz rental car fleet has consisted of a variety of vehicle manufacturers, ranging from BYD, Mercedes, Infiniti, Cadillac, Land Rover, BMW, Porsche, Jaguar, Mazda, Volvo, Toyota, Jeep, and Lincoln, along with various others. By December 2012, the company had over 490,000 cars in the United States. As of 2014, 78 percent of Hertz's fleet includes vehicles that reach 28 miles per gallon or more on the highway.


title: The Hertz Corporation

text: In 1966, Hertz engaged racing and automotive designer Carroll Shelby to develop an exclusive version of his modified Ford Mustang. The objective was to attract more customers to Hertz and the Hertz fleet would tempt car renters to buy a Mustang or a Shelby-Mustang. One thousand GT350H Mustangs were built as rental cars, although urban legend also maintains that many were missing original engines when returned. The "Rent-a-Racer" program was available in selected locations during the late 1960s for a limited time. The fleet has included Corvettes, Jaguar XK-Es, and AMC AMXs.


title: The Hertz Corporation

text: In 2006, Hertz partnered with Shelby to rent specially-modified Ford Mustang GT-H Coupes as a tribute to the original 1966 Ford Mustang Shelby GT350-H. These 500 cars in 2006 were followed by convertibles in 2007. In 2008, Hertz began to rent modified Chevrolet Corvette (C6) "ZH-Z" Coupes, followed by convertibles in 2009.


title: The Hertz Corporation

text: Hertz reintroduced the program in 2016, and includes vehicles such as Hendrick Motorsports-modified Chevrolet Corvette (C7) Stingray Z/06 and Chevrolet Camaro SS and ZL-1, and a Shelby-modified Ford Mustang GT.


title: The Hertz Corporation

text: In 2007, the company began testing hourly car rentals at three locations in New York City. It launched a global carsharing service under the name Connect by Hertz in December 2008, serving customers who paid a fee to rent cars by the hour in Park Ridge, New York, Orlando, London, Paris, and Sydney. Later branded as Hertz on Demand and Hertz 24/7, operation in the United States ceased in September 2015.


title: The Hertz Corporation

text: It introduced ExpressRent kiosks at various rental locations in November 2011. This was the first introduction of large-scale car rental kiosks in the United States that used a live agent through video chat.


title: The Hertz Corporation

text: Hertz launched its Green Collection of rental cars in September 2006. This fleet of environmentally friendly vehicles has included the Toyota Prius, Ford Fusion, Buick LaCrosse, Toyota Camry, and Hyundai Sonata. In the US vehicles within this group feature Environmental Protection Agency (EPA) highway fuel efficiency ratings of 28 miles per gallon-highway. Different models and different standards apply in other markets. The Green Collection was introduced in Singapore in 2014.


title: The Hertz Corporation

text: In October 2021, Hertz announced it was investing in electric vehicles with the purchase of 100,000 Teslas, primarily Tesla Model 3 sedans. In March 2022, Tesla Model Y crossovers were added to the order. The Hertz Tesla fleet will have access to Tesla’s supercharger network as Hertz develops their own vehicle charging infrastructure.


title: The Hertz Corporation

text: Hertz and Uber announced a partnership in October 2022 where Hertz will offer up to 50,000 Tesla vehicles for rent to Uber drivers.


title: The Hertz Corporation

text: In April 2022, Hertz announced its intent to purchase up to 65,000 Polestar 2 vehicles over 5 years from electric carmaker Polestar.


title: The Hertz Corporation

text: In September 2022, Hertz unveiled a deal with General Motors to purchase up to 175,000 electric vehicles from Chevrolet, Buick, GMC, Cadillac and BrightDrop over a period of 5 years.


title: The Hertz Corporation

text: As part of its investment in electrification , Hertz announced in September 2022 a memorandum of understanding (MOU) for the development of a national network of EV charging stations powered by bp pulse, bp’s global electrification and charging solution brand.


title: The Hertz Corporation

text: Hertz opened a heavy equipment rental division in 1965, the Hertz Equipment Rental Corporation, with its first location in Houston, Texas and headquarters in Park Ridge, New Jersey. HERC became an independently publicly traded company called Herc Rentals Inc. on July 1, 2016. Herc Rentals wasn't affected by its former parent's bankruptcy on May 22, 2020.


title: The Hertz Corporation

text: In 1959, the advertising firm of Norman, Craig & Kummel (NCK) was selected as the new advertising agency for Hertz. NCK developed the slogan "Hertz puts you in the driver's seat", which was first used commercially in September 1959. NCK changed the wording to "Let Hertz put you in the driver's seat" by October 1959. Popular a cappella quartet The Hi-Lo's sang the Hertz song for the commercials. Hertz used the line in the early 1960s in print, signs, and television. The series is listed as number 65 in the top 100 advertising campaigns of the 20th century by "Advertising Age" magazine.


title: The Hertz Corporation

text: Former football player O. J. Simpson appeared as a spokesperson in Hertz ads. Simpson's place in advertising is said to have sparked African-American athletes being featured in film and television. One spot from the mid-1970s showed Simpson, at that point an American football player, running through an airport terminal, dressed in business attire, leaping over rows of seats to get to his Hertz rental car. A woman yelled, "Go, O. J., Go!" The tagline of the ad, as spoken by Simpson, was "Hertz, the superstar in rent-a-car". Through the 1980s and 1990s, Simpson appeared with golfer Arnold Palmer and actress Jamie Lee Curtis. After O.J. Simpson's Ford Bronco chase and his murder trial, Hertz cut all ties to him.


title: Dutch Caribbean

text: The Dutch Caribbean (historically known as the Dutch West Indies) are the territories, colonies, and countries, former and current, of the Dutch Empire and the Kingdom of the Netherlands in the Caribbean Sea. They are in the north and south-west of the Lesser Antilles archipelago.


title: Dutch Caribbean

text: Currently, it comprises the constituent countries of Aruba, Curaçao and Sint Maarten (CAS islands), and the special municipalities of Bonaire, Sint Eustatius and Saba (BES islands). The term "Dutch Caribbean" is sometimes also used for the Caribbean Netherlands, an entity consisting of the three special municipalities forming part of the constituent country of the Netherlands since 2010. The Dutch Caribbean has a population of 337,617 as of January 2019.


title: Dutch Caribbean

text: The islands in the Dutch Caribbean were, from 1815, part of the colonies Curaçao and Dependencies (1815–1828) or Sint Eustatius and Dependencies (1815–1828), which were merged with the colony of Suriname (not considered part of the Dutch Caribbean, although it was on the Caribbean coast of Northeastern South America) and governed from Paramaribo until 1845, when all islands again became part of Curaçao and Dependencies.


title: Dutch Caribbean

text: In 1954, the islands became the country () Netherlands Antilles (1954−2010). The autonomy of the Netherlands Antilles' island territories was stipulated in the Islands Regulation of the Netherlands Antilles. Initially the Netherlands Antilles consisted of four island territories: Aruba, Bonaire, Curaçao and the Windward Islands. The latter split into the Island Territories Saba, Sint Eustatius and Sint Maarten in 1983.


title: Dutch Caribbean

text: The island of Aruba seceded from the Netherlands Antilles in 1986 to become a separate constituent country of the Kingdom of the Netherlands, leaving five island territories within the Netherlands Antilles. This situation remained until the complete dissolution of the Netherlands Antilles as a unified political entity in 2010. In that year Curaçao and Sint Maarten became autonomous constituent countries within the Kingdom (like Aruba); while Bonaire, Sint Eustatius, and Saba became special municipalities of the Netherlands proper. The Netherlands proper is located in the European Union.


title: Dutch Caribbean

text: Geographically, the six entities of the Dutch Caribbean are clustered in two widely separated areas of the Caribbean.


title: Dutch Caribbean

text: Politically, each of the six entities of the Dutch Caribbean currently has one of two relationships with the Netherlands:


title: Dutch Caribbean

text: Three Caribbean polities are countries () within the Kingdom of the Netherlands: Aruba, Curaçao, and Sint Maarten. The Netherlands is the fourth and largest constituent country in the Kingdom.


title: Dutch Caribbean

text: Sint Maarten comprises the southern half of the island of Saint Martin. The northern half of the island – the Collectivity of Saint Martin – is an overseas territory of France. Aruba and Curacao are located in the far south of the Caribbean being 30 kilometres and 65 kilometres from the coast of Venezuela.


title: Dutch Caribbean

text: The three Caribbean islands that are special municipalities of the Netherlands alone are Bonaire, Sint Eustatius, and Saba. Collectively, these special municipalities of the Netherlands are also known as the "BES islands" or the Caribbean Netherlands. Bonaire is located in the far south of the Caribbean, being about 80 kilometres from the coast of Venezuela, whilst Saba is located about 50 kilometres south of Sint Maarten (where you can find the highest mountain in the whole of the Netherlands Mount Scenery, being 880 metres above sea level) and Sint Eustatius is located directly north of the Saint Kitts.


title: Tonsillectomy

text: Tonsillectomy is a surgical procedure in which both palatine tonsils are fully removed from the back of the throat. The procedure is mainly performed for recurrent tonsillitis, throat infections and obstructive sleep apnea (OSA). For those with frequent throat infections, surgery results in 0.6 (95% confidence interval: 1.0 to 0.1) fewer sore throats in the following year, but there is no evidence of long term benefits. In children with OSA it results in improved quality of life.


title: Tonsillectomy

text: While generally safe, complications may include bleeding, vomiting, dehydration, trouble eating, and trouble talking. Throat pain typically lasts about one to two weeks after surgery. Bleeding occurs in about 1% within the first day and another 2% after that. Death occurs as a result in between 1 out of 2,360 and 1 in 56,000 procedures. Tonsillectomy does not appear to affect long term immune function.


title: Tonsillectomy

text: Following the surgery ibuprofen and paracetamol (acetaminophen) may be used to treat postoperative pain. The surgery is often done using metal instruments or electrocautery. The adenoid may also be removed in which case it is known as an "adenotonsillectomy". The partial removal of the tonsils is called a "tonsillotomy", which may be preferred in cases of OSA.


title: Tonsillectomy

text: The surgery has been described since at least as early as 50 AD by Celsus. In the United States, as of 2010, tonsillectomy is performed less frequently than in the 1970s although it remains the second most common outpatient surgical procedure in children. The typical cost when done as an inpatient in the United States is US$4,400 as of 2013. There is some controversy as of 2019 as to when the surgery should be used. There are variations in the rates of tonsillectomy between and within countries.


title: Tonsillectomy

text: Tonsillectomy is mainly undertaken for sleep apnea and recurrent or chronic tonsillitis. It is also carried out for peritonsillar abscess, periodic fever, aphthous stomatitis, pharyngitis and adenitis (PFAPA), guttate psoriasis, nasal airway obstruction, tonsil cancer and diphtheria carrier state. For children, tonsillectomy is usually combined with the removal of the adenoid. However, it is unclear whether the removal of the adenoid has any additional positive or negative effects for the treatment of recurrent sore throat.


title: Tonsillectomy

text: Surgery is not recommended for those with fewer than seven documented throat infections in the last year, fewer than five each year for the last two years, or fewer than three each year for three years. Severely affected children who undergo surgery on average have one fewer sore throat per year in the subsequent one or two years, compared to those who do not. Specifically one review of five randomized controlled trials, found a decrease from 3.6 to 3.0 episodes in the year following surgery. In less severely affected children, surgery results in an increase, rather than a decrease of sore throats when the sore throat directly following surgery is included. Surgery results in a reduction in school absence in the year after surgery, but the strength of evidence is low. Surgery does not result in an improvement in the quality of life. Benefits of surgery do not persist over time. Those with frequent throat infections often spontaneously improve over a year without surgery. Therefore, a certain number of people who undergo surgery will do so unnecessarily as they would not have had further episodes of tonsillitis had they not had surgery. Evidence in adults is unclear.


title: Tonsillectomy

text: In 2019, the American Academy of Otolaryngology & Head and Neck Surgery (AAO-HNS) recommended:Many cases of the sore throat have other causes than tonsillitis and tonsillectomy is therefore not indicated for those cases. The diagnosis of tonsillitis is often made without testing for bacteria. The UK National Health Service states, that it's very rare that someone needs to have their tonsils taken out, and it is usually only necessary in case of severe tonsillitis that keeps coming back.


title: Tonsillectomy

text: Tonsillectomy improves obstructive sleep apnea (OSA) in most children. A 2015 Cochrane review found moderate quality evidence for benefits in terms of quality of life and symptoms but no benefit in attention or academic performance. It recommended that physicians and parents should weigh the benefits and risks of surgery as OSA symptoms may spontaneously resolve over time. An AHRQ review however did find improvements at school. The procedure is recommended for those who have OSA that has been verified by a sleep study. Studies have shown that treatment success of uvulopalatopharyngoplasty with tonsillectomy increases with tonsil size.


title: Tonsillectomy

text: There is no good evidence for other uses such as tonsil stones, bad breath, trouble swallowing, and an abnormal voice in children.


title: Tonsillectomy

text: While generally safe, tonsillectomy may result in several complications, some of which are serious. Complications are divided into primary (first 24 hours after surgery), and secondary (after 24 hours), with bleeding being the most common complication. Other common complications are postoperative nausea and vomiting, dehydration, trouble eating, ear pain, taste dysfunction and trouble talking. In rare cases, tonsillectomy may also cause damage to the teeth (because of the clamp that is placed in the mouth during surgery), larynx and pharyngeal wall, aspiration, respiratory compromise, laryngospasm, laryngeal edema and cardiac arrest. Throat pain typically lasts about one to two weeks after surgery.


title: Tonsillectomy

text: Significant post-operative primary bleeding occurs in 0.2–2.2% of people, and secondary bleeding in 0.1–3.3%.


title: Tonsillectomy

text: Also in veterinary surgery, bleeding was a common complication. A meta-analysis reported that frequency of bleeding after tonsillectomy across different techniques did not differ.


title: Tonsillectomy

text: It is estimated 1.3% of people will have a delayed discharge (of 4 to 24 hours) due to a complication, and up to 3.9% will require repeat admission to hospital. The main reasons for either keeping a person in hospital, or readmitting them after tonsillectomy are uncontrolled pain, vomiting, fever, or bleeding. Death occurs as a result in between 1 in 2,360 and 56,000 procedures. Bleeding accounts for one-third of deaths. As the procedure is done under general anesthesia, there are anesthesia risks.


title: Tonsillectomy

text: There is no evidence tonsillectomy affects long term immune function. It does not appear to affect the long term risk of infections in other areas of the body. Some studies have found small changes in immunoglobulin concentrations after tonsillectomy but these are of unclear significance. The association between tonsillectomy and risk for inflammatory bowel disease (e.g., Crohn's disease or ulcerative colitis) is unclear. There is an association suggesting an increase in the risk of developing multiple sclerosis if done before the age of 20. A meta-analysis published in 2020 indicated a statistically significant association between a history of tonsillectomy and the development of Hodgkin's disease. A meta-analysis from 2022 concluded that a history of tonsillectomy is associated with an increased risk of breast cancer. The relationship between childhood tonsillectomy and the development of other cancer types in adulthood remains unclear.


title: Tonsillectomy

text: For the past 50 years at least, tonsillectomy has been performed by dissecting the tonsil from its surrounding fascia, a so-called total, or extra-capsular tonsillectomy. Problems including pain and bleeding led to a recent resurgence in interest in sub-total tonsillectomy or "tonsillotomy", which was popular 60 to 100 years ago, in an effort to reduce these complications. The generally accepted procedure for 'total' tonsillectomy uses a scalpel and blunt dissection, electrocautery, or diathermy. Harmonic scalpels or lasers have also been used. Bleeding is stopped with electrocautery, ligation by sutures, and the topical use of thrombin, a protein that induces blood clotting. The most effective surgical approach has not been well studied.


title: Tonsillectomy

text: It is not known whether the benefits of subtotal tonsillectomy in obstructive sleep apnea are enduring. But this is also the case for tonsillectomy for sleep apnea. There have been no randomised controlled trials of long term effectiveness of tonsillectomy for sleep apnea.


title: Tonsillectomy

text: The scalpel is the preferred surgical instrument of many ear, nose, and throat specialists. However, there are other techniques and a brief review of each follows:


title: Tonsillectomy

text: A single dose of the corticosteroid drug dexamethasone may be given during surgery to prevent post-operative vomiting. A dose of dexamethasone during surgery prevents vomiting in one out of every five children. A dose of dexamethasone may help children return to a normal diet more quickly and have less post-operative pain. Many people are prescribed antibiotics following a tonsillectomy, however, the benefits and potential harms have not been well studied. Antibiotics are not suggested to be used routinely following tonsillectomy.


title: Tonsillectomy

text: A sore throat will persist approximately two weeks following surgery while pain following the procedure is significant and may necessitate a hospital stay. Recovery can take from 7 to 10 days and proper hydration is very important during this time, since dehydration can increase throat pain, leading to a circle of poor fluid intake. Tonsillectomy appears to be more painful in adults than children. Controlling the pain following tonsillectomy is important to ensure that people can start eating again normally following the procedure.


title: Tonsillectomy

text: At some point, most commonly 7 to 11 days after the surgery (but occasionally as long as two weeks after), bleeding can occur when scabs begin sloughing off from the surgical sites. The overall risk of bleeding is approximately 1–2%. It is higher in adults, especially males over age 70 and three-quarters of bleeding incidents occur on the same day as the surgery. Approximately 3% of adults develop bleeding at this time which may sometimes require surgical intervention.


title: Tonsillectomy

text: Recommendations for pain management include ibuprofen and paracetamol (acetaminophen). The opioid codeine is not recommended for those less than 12 years old. There is a theoretical concern that NonSteroidal Anti-Inflammatory Drugs (NSAIDs) may increase the risk of bleeding but evidence does not support such a risk. Further research is required to determine if mouth rinses, mouthwashes and sprays help improve recovery following surgery.


title: Tonsillectomy

text: There are variations in tonsillectomy rates, both between and within countries. In 2015, tonsillectomy rates in the Netherlands, Belgium, Finland and Norway were at least twice those in the UK but rates in Spain, Italy and Poland were at least a quarter lower. Tonsillectomy rates even vary considerably between neighbouring countries. For example, rates in Croatia are three times those in Slovenia. Variations between countries may be explained by a lack of or differences between guidelines. However differences in guidelines cannot explain the seven-fold variation between local authority areas within England.


title: Tonsillectomy

text: In Germany tonsillectomy rates between regions differ by up to a factor of 8. A 2010 study in England found the annual tonsillectomy rate per 100,000 between 2000 and 2005 was 754 in the highest region, the national average was 304 and the lowest region was 102. This means there is a seven-fold difference between the region with the highest tonsillectomy rate and the region with the lowest one. In 2006, English Chief Medical Officer Liam Donaldson revealed that unnecessary tonsillectomies and unnecessary hysterectomies combined cost the British National Health Service 21 million pounds a year.


title: Tonsillectomy

text: The rise in adenotonsillectomies for sleep apnea in the USA has been greater than the decline in tonsillectomies for sore throat.


title: Tonsillectomy

text: In 2018, a study of the medical records of 1.6 million UK children found 15,760 had sufficient sore throats to justify tonsillectomy and 13.6% (2,144) underwent surgery. The same study found 18,281 children who had undergone tonsillectomy, and of these only 11.7% (2,144) had evidence-based indications (i.e. frequent enough sore throats to justify surgery). The majority of tonsillectomies were undertaken for indications which did not have an evidence-base: five to six sore throats in one year (12.4%), two to four sore throats in one year (44.6%), sleep disordered breathing (12.3%), or obstructive sleep apnoea (3.9%). In the UK therefore, most children who undergo tonsillectomy probably do not benefit and most children who might benefit do not undergo tonsillectomy. The study concluded that 32,500 (close to 90%) out of the 37,000 children who have their tonsils removed annually "are unlikely to benefit" and that surgery therefore may do more harm than good to those children. Tonsillectomy rates are lower in the UK than in most other western European countries.


title: Tonsillectomy

text: Table: Numbers of children (from 1.6 million children between 2005 and 2016 in the UK) identified with possible indications for tonsillectomy and the numbers who subsequently undergo tonsillectomy.


title: Tonsillectomy

text: According to a study from 2009, surgery rates on average increase by 78% when surgeons are paid fee-for-service reimbursements instead of a fixed salary. Regarding tonsillectomy, a 1968 Canadian study pointed out that ENT specialists working on a fee-for-service programme were twice as likely to perform a tonsillectomy than those who were not. In 2009 then US President Obama remarked:


title: Tonsillectomy

text: Tonsillectomies have been practiced for over 2,000 years, with varying popularity over the centuries. The earliest mention of the procedure is in "Hindu medicine" from about 1000 BCE. Roughly a millennium later, the Roman aristocrat Aulus Cornelius Celsus (25 BCE–50 CE) described a procedure whereby using the finger (or a blunt hook if necessary), the tonsil was separated from the neighboring tissue before being cut out. Galen (121–200 CE) was the first to advocate the use of the surgical instrument known as the snare, a practice that was to become common until Aetius (490 CE) recommended partial removal of the tonsil, writing "Those who extirpate the entire tonsil remove, at the same time, structures that are perfectly healthy, and, in this way, give rise to serious Hæmorrhage". In the 7th century Paulus Aegineta (625–690) described a detailed procedure for tonsillectomy, including dealing with the inevitable post-operative bleeding. 1,200 years pass before the procedure is described again with such precision and detail.


title: Tonsillectomy

text: The Middle Ages saw tonsillectomy fall into disfavor; Ambroise Pare (1509) wrote it to be "a bad operation" and suggested a procedure that involved gradual strangulation with a ligature. This method was not popular with the patients due to the immense pain it caused and the infection that usually followed. Scottish physician Peter Lowe in 1600 summarized the three methods in use at the time, including the "snare", the "ligature", and the "excision". At the time, the function of the tonsils was thought to be absorption of secretions from the nose; it was assumed that removal of large amounts of tonsillar tissue would interfere with the ability to remove these secretions, causing them to accumulate in the larynx, resulting in hoarseness. For this reason, physicians like Dionis (1672) and Lorenz Heister censured the procedure.


title: Tonsillectomy

text: In 1828, physician Philip Syng Physick modified an existing instrument originally designed by Benjamin Bell for removing the uvula; the instrument, known as the tonsil guillotine (and later as a tonsillotome), became the standard instrument for tonsil removal for over 80 years. By 1897, it became more common to perform complete rather than partial removal of the tonsil after American physician Ballenger noted that partial removal failed to completely alleviate symptoms in a majority of cases. His results using a technique involving removal of the tonsil with a scalpel and forceps were much better than partial removal; tonsillectomy using the guillotine eventually fell out of favor in America.


title: Tonsillectomy

text: In the beginning of the 20th century, tonsillectomy became more common in the United Kingdom and the United States and by the 1930s was very common in both countries. For example, a study conducted in 1934 found that 61% of 1,000 New York schoolchildren had been tonsillectomized; doctors recommended surgery for all but 65 of the remaining children. Complications were often simply accepted. The medical community considered enlarged tonsils a disease, attributing their enlargement to infection rather than a physiologic response. Because of the theory of focal infection, many surgeons believed that not only enlarged tonsils, but all tonsils should be removed. In the 1940s tonsillectomy became controversial as several studies linked it to bulbar poliomyelitis. From the 1940s to 1970s, further studies found an association between tonsillectomy and bulbar poliomyelitis with recommendations not to do the operation during outbreaks. Controversy surrounding tonsillectomy increased further in the United Kingdom in the 1960s because of the financial costs associated with the number of surgeries being performed and because of unexplainable variations in tonsillectomy rates between geographic regions and between social classes. In the media, tonsillectomy was criticised for being "fashionable" or a "status symbol". There was also an increasing concern regarding the psychological and physical suffering of young children as a result of surgery. Furthermore, opponents of surgery argued that the tonsils should be retained whenever possible because of their role in the immune system and that the benefits of surgery were marginal. In the 1970s, tonsillectomy rates in the United Kingdom started to decline after several studies concluded that tonsillectomy was not as effective for sore throats and many other indications as previously thought.


title: Tonsillectomy

text: Tonsillectomy rates in the United States have declined since 1978, when experts of the National Institutes of Health concluded that there was insufficient evidence that the benefits of tonsillectomy outweighed the risks and therefore recommended more research, which subsequently led to stricter guidelines.


title: Tonsillectomy

text: As doctors took a more conservative approach towards tonsillectomy, parental pressure became one of the most important reasons for surgery.


title: Deccan Traps

text: The Deccan Traps is a large igneous province of west-central India (17–24°N, 73–74°E). It is one of the largest volcanic features on Earth, taking the form of a large shield volcano. It consists of numerous layers of solidified flood basalt that together are more than about thick, cover an area of about , and have a volume of about . Originally, the Deccan Traps may have covered about , with a correspondingly larger original volume. This volume overlies the Archean age Indian Shield, which is likely the lithology the province passed through during eruption. The province is commonly divided into four subprovinces: the main Deccan, the Malwa Plateau, the Mandla Lobe, and the Saurashtran Plateau.


title: Deccan Traps

text: The term "trap" has been used in geology since 1785–1795 for such rock formations. It is derived from the Swedish word for stairs () and refers to the step-like hills forming the landscape of the region. The name Deccan has Sanskrit origins meaning "southern".


title: Deccan Traps

text: The Deccan Traps began forming 66.25 million years ago, at the end of the Cretaceous period, although it is possible that some of the oldest material may underlie younger material. The bulk of the volcanic eruption occurred at the Western Ghats between 66 and 65 million years ago when lava began to extrude through fissures in the crust known as fissure eruptions. Determining the exact age for Deccan rock is difficult due to a number of limitations, one being that the transition between eruption events may be separated by only a few thousand years and the resolution of dating methods used is not able to pinpoint these events. In this way, determining the rate of magma emplacement is also difficult to constrain. This series of eruptions may have lasted for less than 30,000 years.


title: Deccan Traps

text: The original area covered by the lava flows is estimated to have been as large as , approximately half the size of modern India. The Deccan Traps region was reduced to its current size by erosion and plate tectonics; the present area of directly observable lava flows is around .


title: Deccan Traps

text: The Deccan Traps are segmented into three stratigraphic units: the Upper, Middle, and Lower traps. While it was previously interpreted that these groups represented their own key points in the sequence of events in Deccan extrusion, it is now more widely accepted that these horizons relate more closely to paleo topography and distance from the eruption site.


title: Deccan Traps

text: The release of volcanic gases, particularly sulfur dioxide, during the formation of the traps may have contributed to climate change. An average drop in temperature of about was recorded during this period.


title: Deccan Traps

text: Because of its magnitude, scientists have speculated that the gases released during the formation of the Deccan Traps played a major role in the Cretaceous–Paleogene (K–Pg) extinction event (also known as the Cretaceous–Tertiary or K–T extinction). It has been theorized that sudden cooling due to sulfurous volcanic gases released by the formation of the traps and toxic gas emissions may have contributed significantly to the K–Pg mass extinction. However, the current consensus among the scientific community is that the extinction was primarily triggered by the Chicxulub impact event in North America, which would have produced a sunlight-blocking dust cloud that killed much of the plant life and reduced global temperature (this cooling is called an impact winter).


title: Deccan Traps

text: Work published in 2014 by geologist Gerta Keller and others on the timing of the Deccan volcanism suggests the extinction may have been caused by both the volcanism and the impact event. This was followed by a similar study in 2015, both of which consider the hypothesis that the impact exacerbated or induced the Deccan volcanism, since the events occurred approximately at antipodes.


title: Deccan Traps

text: However, the impact theory is still the best supported and has been determined by various reviews to be the consensus view.


title: Deccan Traps

text: Within the Deccan Traps at least 95% of the lavas are tholeiitic basalts. Major mineral constituents are olivine, pyroxenes, and plagioclase, as well as certain Fe-Ti-rich oxides. These magmas are <7% MgO. Many of these minerals are observed however, as highly altered forms. Other rock types present include: alkali basalt, nephelinite, lamprophyre, and carbonatite.


title: Deccan Traps

text: Mantle xenoliths have been described from Kachchh (northwestern India) and elsewhere in the western Deccan and contain spinel lherzolite and pyroxenite constituents.


title: Deccan Traps

text: While the Deccan traps have been categorized in many different ways including the three different stratigraphic groups, geochemically the province can be split into as many as eleven different formations. Many of the petrologic differences in these units are a product of varying degrees of crustal contamination.


title: Deccan Traps

text: The Deccan Traps are famous for the beds of fossils that have been found between layers of lava. Particularly well known species include the frog "Oxyglossus pusillus" (Owen) of the Eocene of India and the toothed frog "Indobatrachus", an early lineage of modern frogs, which is now placed in the Australian family Myobatrachidae. The Infratrappean Beds (Lameta Formation) and Intertrappean Beds also contain fossil freshwater molluscs.


title: Deccan Traps

text: It is postulated that the Deccan Traps eruption was associated with a deep mantle plume. High He/He ratios of the main pulse of the eruption are often seen in magmas with mantle plume origin. The area of long-term eruption (the hotspot), known as the Réunion hotspot, is suspected of both causing the Deccan Traps eruption and opening the rift that separated the Mascarene Plateau from India. Regional crustal thinning supports the theory of this rifting event and likely encouraged the rise of the plume in this area. Seafloor spreading at the boundary between the Indian and African Plates subsequently pushed India north over the plume, which now lies under Réunion island in the Indian Ocean, southwest of India. The mantle plume model has, however, been challenged.


title: Deccan Traps

text: Data continues to emerge that supports the plume model. The motion of the Indian tectonic plate and the eruptive history of the Deccan traps show strong correlations. Based on data from marine magnetic profiles, a pulse of unusually rapid plate motion began at the same time as the first pulse of Deccan flood basalts, which is dated at 67 million years ago. The spreading rate rapidly increased and reached a maximum at the same time as the peak basaltic eruptions. The spreading rate then dropped off, with the decrease occurring around 63 million years ago, by which time the main phase of Deccan volcanism ended. This correlation is seen as driven by plume dynamics.


title: Deccan Traps

text: The motions of the Indian and African plates have also been shown to be coupled, the common element being the position of these plates relative to the location of the Réunion plume head. The onset of accelerated motion of India coincides with a large slowing of the rate of counterclockwise rotation of Africa. The close correlations between the plate motions suggest that they were both driven by the force of the Réunion plume.


title: Deccan Traps

text: When comparing the Na, Fe, and Si contents of the Deccan to other major igneous provinces, the Deccan appears to have undergone the greatest degree of melting suggesting a deep plume origin. Olivine appears to have fractionated at near-Moho depths with additional fractionation of gabbro ~6 km below the surface. Features such as widespread faulting, frequent diking events, high heat flux, and positive gravity anomalies suggest that the extrusive phase of the Deccan Traps is associated with the existence of a triple junction which may have existed during the Late Cretaceous, having been caused by a deep mantle plume. Not all of these diking events are attributed to large-scale contributions to the overall flow volume. It can be difficult, however, to locate the largest dikes as they are often located towards the west coast and are therefore believed to currently reside under water.


title: Deccan Traps

text: There is some evidence to link the Deccan Traps eruption to the contemporaneous asteroid impact that created the nearly antipodal Chicxulub crater in the Mexican state of Yucatán. Although the Deccan Traps began erupting well before the impact, argon–argon dating suggests that the impact may have caused an increase in permeability that allowed magma to reach the surface and produced the most voluminous flows, accounting for around 70% of the volume. The combination of the asteroid impact and the resulting increase in eruptive volume may have been responsible for the mass extinctions that occurred at the time that separates the Cretaceous and Paleogene periods, known as the K–Pg boundary.


title: Deccan Traps

text: A more recent discovery appears to demonstrate the scope of the destruction from the impact alone, however. In a March 2019 article in the Proceedings of the National Academy of Sciences, an international team of twelve scientists revealed the contents of the Tanis fossil site discovered near Bowman, North Dakota, that appeared to show a devastating mass destruction of an ancient lake and its inhabitants at the time of the Chicxulub impact. In the paper, the group reports that the geology of the site is strewn with fossilized trees and remains of fish and other animals. The lead researcher, Robert A. DePalma of the University of Kansas, was quoted in the New York Times as stating that "You would be blind to miss the carcasses sticking out... It is impossible to miss when you see the outcrop". Evidence correlating this find to the Chicxulub impact included tektites bearing "the unique chemical signature of other tektites associated with the Chicxulub event" found in the gills of fish fossils and embedded in amber, an iridium-rich top layer that is considered another signature of the event, and an atypical lack of evidence for scavenging perhaps suggesting that there were few survivors. The exact mechanism of the site's destruction has been debated as either an impact-caused tsunami or lake and river seiche activity triggered by post-impact earthquakes, though there has yet been no firm conclusion upon which researchers have settled.


title: Deccan Traps

text: A geological structure that exists in the sea floor off the west coast of India has been suggested as a possible impact crater, in this context called the Shiva crater. It has also been dated at approximately 66 million years ago, potentially matching the Deccan traps. The researchers claiming that this feature is an impact crater suggest that the impact may have been the triggering event for the Deccan Traps as well as contributing to the acceleration of the Indian plate in the early Paleogene. However, the current consensus in the Earth science community is that this feature is unlikely to be an actual impact crater.


title: Russian occupation of Kherson Oblast

text: The Russian occupation of Kherson Oblast is an ongoing military occupation of Ukraine's Kherson Oblast by Russian forces that began on 2March 2022 during the Russian invasion of Ukraine as part of the southern Ukraine campaign. The Russian-installed occupation regime was called the "Kherson military-civilian administration". Its name was changed to "Kherson Oblast" after the Russian annexation.


title: Russian occupation of Kherson Oblast

text: Russia captured the city of Kherson 2 March 2022, which is the capital city of the oblast and is therefore strategically important. Meanwhile, most of the rest of Kherson Oblast fell to Russian forces in the early months of the invasion. Kherson was the first and only regional capital that Russia managed to capture in the 2022 invasion, although the cities of Donetsk and Luhansk had already been controlled by Russian-backed separatists since 2014. Since 29 August 2022, Kherson Oblast, especially the area surrounding the city of Kherson, has been the center of the 2022 Ukrainian southern counteroffensive.


title: Russian occupation of Kherson Oblast

text: In May 2022, Russia declared its intention to annex Kherson Oblast. In September 2022, Russian forces in the oblast held disputed referendums to support the annexation. On 30 September 2022, Russia declared that it had annexed Kherson Oblast, including parts of the oblast that it did not control at the time. At the same time (30 September 2022), Russia declared that two small areas of Mykolaiv Oblast that it controlled at the time had been annexed into Kherson Oblast. These two areas are the city of Snihurivka and its surroundings, as well as the outer portion of the Kinburn Peninsula. On 12 October 2022, the United Nations General Assembly passed a resolution calling on countries not to recognise what it described as an "attempted illegal annexation" and demanded that Russia "immediately, completely and unconditionally withdraw".


title: Russian occupation of Kherson Oblast

text: On 19 October 2022, the Russian administration's executive bodies moved from the city of Kherson to the left bank of the Dnieper River as part of an evacuation. On 3 November 2022, nine months after the original battle of Kherson had ended, Russian forces removed their flag from the city's administrative building and advised people still living in the city to leave and cross the river to the southern bank. On 9 November 2022, Russia withdrew from the city of Kherson, which was followed by Ukrainian claims of liberation on 11 November 2022. Amidst the withdrawal from the west of Kherson Oblast, the Russians also withdrew from Snihurivka and its surroundings in Mykolaiv Oblast (on 10 November 2022).


title: Russian occupation of Kherson Oblast

text: After the loss of Kherson, the temporary administrative centre of the Russian occupation forces is now Henichesk. Russia still claims Kherson as the official capital city.


title: Russian occupation of Kherson Oblast

text: On 24 February, Russian forces began an invasion of Ukraine. Fighting began across the Kherson Oblast, resulting in multiple Russian victories. On 2 March, Russian forces captured the capital of the oblast, Kherson, beginning a military occupation of the city and the oblast.


title: Russian occupation of Kherson Oblast

text: Shortly after Kherson was captured, the Russian Ministry of Defence said talks between Russian forces and city administrators regarding the maintenance of order were underway. An agreement was reached in which the Ukrainian flag would still be hoisted in the city while Russia established the new administration. Mayor Ihor Kolykhaiev announced new conditions for the city's residents: citizens could only go outside during daytime and were forbidden to gather in groups. Additionally, cars were only allowed to enter the city to supply food and medicine; these vehicles were to drive at minimum speeds and were subject to searches. Citizens were warned not to provoke Russian soldiers and obey any commands given.


title: Russian occupation of Kherson Oblast

text: In the first days of the invasion, Russian forces established control over and unblocked the North Crimean Canal, effectively rescinding a longstanding water blockage imposed on Crimea by Ukraine after the 2014 Russian annexation of the peninsula.


title: Russian occupation of Kherson Oblast

text: Initial allegations that Russian soldiers had raped 11 women in Kherson, and that six of those women were killed, including a teenager, were denied by Hennadiy Lahuta, head of the Ukrainian Kherson Regional State Administration, who stated that such reports were disinformation.


title: Russian occupation of Kherson Oblast

text: On 5 March, Kolykhaiev said that there was no armed resistance in the city and Russian troops were "quite settled". He requested humanitarian aid, stating that the city lacked power, water, and medicine. Later that day, around 2,000 protesters marched in the city center. The protesters waved Ukrainian flags, sang the national anthem, and chanted patriotic slogans. A video showed Russian soldiers firing into the air to dissuade the protestors. There were also claims that the Russian force had a list of Ukrainian activists in the city that they wanted to capture. On 9 March, the General Staff of the Ukrainian Armed Forces stated that Russia had detained more than 400 people in Kherson due to ongoing protests.


title: Russian occupation of Kherson Oblast

text: On 12 March, Ukrainian officials claimed that Russia was planning to stage a referendum in Kherson to establish the Kherson People's Republic, similar to the Donetsk People's Republic and the Luhansk People's Republic. , deputy leader of the Kherson Oblast Council, claimed that the Russian military had called all the members of the council and asked them to cooperate. Lyudmyla Denisova, Ombudsman of Ukraine, stated that the referendum would be illegal because "under Ukrainian law any issues over territory can only be resolved by a nationwide referendum". Later that day, the Kherson Oblast Council passed a resolution stating that the proposed referendum would be illegal.


title: Russian occupation of Kherson Oblast

text: On 13 March, "Ukrayinska Pravda", a Ukrainian newspaper, reported that several thousand people in Kherson took part in a protest. Russian soldiers dispersed the protest with gunfire, stun grenades, and rubber bullets, injuring several people.


title: Russian occupation of Kherson Oblast

text: On 22 March, the Ukrainian government warned Kherson was facing a "humanitarian catastrophe" as the city was running out of food and medical supplies and accused Russia of blocking evacuation of civilians to Ukraine-controlled territory. Russia countered by saying that its military helped deliver aid to the city's population. A local journalist stated that there was only a staged event, in which former prisoners from Crimea were brought in to act as locals welcoming the Russians and accepting their assistance. According to several media outlets, residents report intrusive checkpoints, abductions, and Russian looting of shops.


title: Russian occupation of Kherson Oblast

text: On 18 April, Igor Kastyukevich, a Russian politician and deputy of the 8th State Duma, was allegedly appointed by the Russian government as a "de facto" mayor for Russian forces on 2 March. Kastyukevich denied these reports.


title: Russian occupation of Kherson Oblast

text: On 25 April 2022, Ihor Kolykhaiev announced that Russian forces had taken control of the Kherson City Council building.


title: Russian occupation of Kherson Oblast

text: On 26 April, both local authorities and Russian state media reported that Russian troops had taken over the city's administration headquarters and had appointed a new mayor, former KGB agent Oleksandr Kobets, and a new civilian-military regional administrator, ex-mayor Volodymyr Saldo. The next day, Ukraine's Prosecutor General said that troops used tear gas and stun grenades to disperse a pro-Ukraine protest in the city centre.


title: Russian occupation of Kherson Oblast

text: In an indication of an intended split from Ukraine, on 28 April the new military-civilian administration announced that from May it would switch the region's currency to the Russian ruble. Additionally, citing unnamed reports that alleged discrimination against Russian speakers, its deputy head, Kirill Stremousov said that "reintegrating the Kherson region back into a Nazi Ukraine is out of the question".


title: Russian occupation of Kherson Oblast

text: On 27 April, the Legislative Assembly of Krasnoyarsk Krai in Siberia approved the expropriation of grain from the Kherson region. Agricultural machinery from the occupied Kherson region was also transported to remote Russian lands, including Chechnya. Lyudmila Denisova, the Ukrainian Parliament Commissioner for Human Rights, has compared this to repeating the Holodomor, a famine in Soviet Ukraine in 1932-1933 that killed millions of Ukrainians.


title: Russian occupation of Kherson Oblast

text: On 29 April, Saldo stated that the official languages of the Kherson Oblast would be both Ukrainian and Russian and that the International Settlements Bank from South Ossetia would open 200 branches in Kherson Oblast soon.


title: Russian occupation of Kherson Oblast

text: On 1 May, a four-month plan was adopted for a full transition to rubles. At the same time, the Ukrainian hryvnia was to remain the current currency along with the ruble for four months.


title: Russian occupation of Kherson Oblast

text: On 7 May, a new coat of arms was adopted, based on the 1803 coat of arms of Kherson of the Russian Empire.


title: Russian occupation of Kherson Oblast

text: On 9 May, an Immortal Regiment event took place in the city, celebrating Victory Day. Soviet-era victory flags and red banners were flown.


title: Russian occupation of Kherson Oblast

text: On 11 May 2022, Kirill Stremousov announced his readiness to send President Vladimir Putin with a request for Kherson Oblast to join the Russian Federation, noting that there would be no creation of the "Kherson People's Republic" or referendums regarding this matter. Commenting on these statements, Putin's press secretary Dmitry Peskov said that this issue should be decided by the inhabitants of the region and that "these fateful decisions must have an absolutely clear legal background, legal justification, be absolutely legitimate, as was the case with Crimea".


title: Russian occupation of Kherson Oblast

text: On 30 May, Russia claimed that it had started exporting last year's grain from Kherson to Russia. They were also working on exporting sunflower seeds. According to locals, Russian soldiers were being employed as strawberry pickers in Kherson Oblast.


title: Russian occupation of Kherson Oblast

text: On 3 June, the EU stated that it wouldn't recognize any Russian passports issued to Ukrainian citizens in the Kherson and Zaporizhzhia regions. On 11 June, according to local officials, the first Russian passports were handed out to citizens in Kherson and Zaporizhzhia Region, including local officials such as Volodymyr Saldo.


title: Russian occupation of Kherson Oblast

text: On 21 July, it was reported that a then-recent Russian decree had extended Russian 2022 war censorship laws to the Kherson oblast, with deportation to Russia included as a punishment for infringement.


title: Russian occupation of Kherson Oblast

text: According to Ukrainian authorities, at the beginning of July, People's Deputy of Ukraine Oleksii Kovalov assumed the position of deputy head of the government of Kherson Oblast. Kovalov was shot dead in his own home on 29 August 2022.


title: Russian occupation of Kherson Oblast

text: Deputy head of the Kherson Military-Civilian Administration Kirill Stremousov died in a car crash near Henichesk on 9 November 2022.


title: Russian occupation of Kherson Oblast

text: After being reported missing by her husband, on 16 November 2022 Russian media reported that Ekaterina Gubareva, another deputy head of the administration, had been detained by the Russian police in relation to a corruption case involving embezzlement of public funds and suspended from her current position.


title: Russian occupation of Kherson Oblast

text: The military commander and the head of the administration are in charge of the administration, which includes:


title: Russian occupation of Kherson Oblast

text: According to the occupation administration, the Kherson Military-Civilian Administration is divided into 5 districts, 49 territorial municipalities, within which there are 298 settlements. Thus, the military-civilian administration includes Kherson Raion, Beryslav Raion, Skadovsk Raion, Kakhovka Raion and Henichesk Raion. In fact, the administrative division of the Kherson Oblast and the division of the military-civilian administration do not have any significant differences, and the military-civilian administration simply copied the division of Ukraine so it retained, among other things, the Ukrainian system of administrative divisions.


title: Russian occupation of Kherson Oblast

text: Dementiy Bilyi, head of the Kherson regional department of the Committee of Voters of Ukraine, claimed that the Russian security forces were "beating, torturing, and kidnapping" civilians in the Kherson Oblast of Ukraine. He added that eyewitnesses had described "dozens" of arbitrary searches and detentions, resulting in an unknown amount of abducted persons. At least 400 residents had gone missing by 16 March, with the mayor and deputy mayor of the town of Skadovsk being allegedly abducted by armed men. An allegedly leaked letter described Russian plans to unleash a "great terror" to suppress protests occurring in Kherson, stating that people would "have to be taken from their homes in the middle of the night".


title: Russian occupation of Kherson Oblast

text: Ukrainians who escaped from occupied Kherson into Ukrainian-controlled territory provided testimonies of torture, abuse and kidnapping by Russian forces in the region. One person, from Bilozerka in Kherson Oblast, provided physical evidence of being tortured by Russians and described beatings, electrocutions, mock executions, strangulations, threats to kill family members and other forms of torture.


title: Russian occupation of Kherson Oblast

text: An investigation by BBC News gathered evidence of torture, which in addition to beatings also included electrocution and burns on people's hands and feet. A doctor who treated victims of torture in the region reported: "Some of the worst were burn marks on genitals, a gunshot wound to the head of a girl who was raped and burns from an iron on a patient's back and stomach. A patient told me two wires from a car battery were attached to his groin and he was told to stand on a wet rag". In addition to the BBC, Human Rights Watch and the United Nations Human Rights Monitoring Mission in Ukraine have reported on torture and disappearances carried out by Russian occupation forces in the region. One resident stated: "In Kherson, now people go missing all the time (...) there is a war going on, only this part is without bombs."


title: Russian occupation of Kherson Oblast

text: Kherson's elected Ukrainian mayor compiled a list of more than 300 people who had been kidnapped by Russian forces as of 15 May 2022. According to "The Times", in the building housing the Russian occupation authorities, the screams of the tortured can be frequently heard throughout the corridors.


title: Russian occupation of Kherson Oblast

text: On 22 July 2022, Human Rights Watch reported that Russian forces had tortured, unlawfully detained, and forcibly disappeared civilians in the occupied areas of Kherson and Zaporizhzhia regions. The purpose of the abuse seemed to be to obtain information and to instil fear so that people would accept the occupation, as Russia seeks to assert sovereignty over occupied territory in violation of international law.


title: Russian occupation of Kherson Oblast

text: According to "Nezavisimaya Gazeta", the activities of the Russian-installed Salvation Committee for Peace and Order encounter constant resistance among the population, and a number of its members were killed by Chief Directorate of Intelligence (GUR) or Ukrainian partisans. "Newsweek" also reports that two local high-profile pro-Russian figures were shot dead in Kherson by the Ukrainian resistance.


title: Russian occupation of Kherson Oblast

text: On 5 March, residents of Kherson went to a rally with Ukrainian flags and chanted that the city is still Ukrainian and will never be Russian, despite Russian occupation. The Russian military opened warning fire against the protesters. At the same time, the National Police of Ukraine published a video where a Kherson police officer, holding a Ukrainian flag in his hands, jumped onto a Russian armored personnel carrier that was driving past the rally, and local residents supported his action with shouts and applause.


title: Russian occupation of Kherson Oblast

text: On 7 March, the Kherson Regional Prosecutor's Office of Ukraine, on the basis of Part 2 of Article 438 of the Criminal Code of Ukraine (violation of the laws and customs of war, associated with premeditated murder), opened a criminal case into the death of several protesters in Nova Kakhovka. According to the investigation, during a rally on 6 March, the Russian military opened fire on protesters indiscriminately "despite the fact that people were unarmed and did not pose any threat," resulting in at least one death and seven injuries.


title: Russian occupation of Kherson Oblast

text: On 20 March, protesters in Kherson confronted several Russian military vehicles and told them to "go home". New rallies against the occupation happened on 11 and 27 April, both of which were violently dispersed by Russian occupation forces and separatist militias, killing four people in the process. The Woodrow Wilson International Center for Scholars reports that medical workers in Kherson refused to go to work, in order to boycott Russian occupation forces and not treat their injured.


title: Russian occupation of Kherson Oblast

text: On 20 April, regional media from Odessa reported that pro-Russian blogger Valery Kuleshov had been killed by Ukrainian partisans in Kherson.


title: Russian occupation of Kherson Oblast

text: On 6 August, deputy head of the Russian administration in Nova Kakhovka, Vitaly Gura, was shot dead in his home. In September 2022, information emerged that Gura's assassination had been faked by the FSB.


title: Russian occupation of Kherson Oblast

text: On 23 April 2022, Ukraine's Ministry of Defence claimed a strike on a Russian 49th Combined Arms Army command post near Kherson, saying it killed two generals and critically injured one. The names of the generals were not released.


title: Russian occupation of Kherson Oblast

text: On 24 April 2022, the Ukrainian Operational Command South reported that the Ukrainian army had liberated eight settlements in Kherson Oblast.


title: Russian occupation of Kherson Oblast

text: On 27 April 2022, the Ukrainian Air Force struck the Kherson TV Tower with a missile temporarily forcing Russian television off-air.


title: Russian occupation of Kherson Oblast

text: On 10 July, Iryna Vereshchuk, the Deputy Prime Minister of Ukraine urged civilians in the Kherson region to evacuate ahead of a future Ukrainian counterattack.


title: Russian occupation of Kherson Oblast

text: On 27 July 2022 the surface of a section of the Antonivka Road Bridge was rendered unusable for heavy equipment, by M142 HIMARS attacks.


title: Russian occupation of Kherson Oblast

text: On 4 September 2022, president Zelenskyy announced the liberation of two villages in Kherson Oblast. Ukrainian authorities released a photo showing the raising of the Ukrainian flag in Vysokopillia by Ukrainian forces.


title: Russian occupation of Kherson Oblast

text: On 6 September 2022, Ukraine confirmed reports that the villages of Liubymivka and Novovoskresenske, southeast of Vysokopillia, had been recaptured by the AFU.


title: Russian occupation of Kherson Oblast

text: In early October 2022, the Russian defensive lines in the northern parts of the oblast collapsed, and Ukraine successfully recaptured about 1,200 km of territory.


title: Russian occupation of Kherson Oblast

text: In November 2022, Ukrainian forces took back the city of Kherson. Following the loss of Kherson in November 2022, the Russian occupation force moved its temporary administrative centre to Henichesk, whilst retaining its claim to Kherson as the official capital.


title: Singh

text: Singh (: ) is a title, middle name or surname that means "lion" in various South Asian and Southeast Asian communities. Traditionally used by the Hindu Kshatriya community, it eventually became a common surname adopted by different communities including Rajputs, Jats, Gurjars and Sikhs. It was later mandated in the late 17th century by Guru Gobind Singh (born Gobind Rai) for all male Sikhs as well, in part as a rejection of caste-based prejudice. It has also been adopted by several castes and communities. As a surname or a middle name, it is now found throughout the world across communities and religious groups, becoming more of a title than a surname.


title: Singh

text: The word "Singh" is derived from the Sanskrit word सिंह (IAST: siṃha) meaning "lion", and is used in the sense "hero" or "eminent person".


title: Singh

text: Originally, the Sanskrit word for lion, variously transliterated as Simha or Singh was used as a title by Kshatriya warriors in northern parts of India. The earliest recorded examples of the names ending with "Simha" are the names of the two sons of the Western Satraps ruler Rudraraman in the second century CE. Jayasimha, the first ruler of the Chalukya dynasty to bear the title Simha, ruled around 500 CE. The Vengi branch of the Chalukyas continued using Simha as the last name till the eleventh century. The Rajputs started using Singh in preference to the classical epithet of "Varman". Among the Rajputs, the use of the word Simha came into vogue among the Paramaras of Malwa in 10th century CE, among the Guhilots and the Kachwahas of Narwar in the 12th century CE, and the Rathores of Marwar after the 17th century.


title: Singh

text: By the sixteenth century, "Singh" had become a popular surname among Rajputs. It was adopted by the Sikhs in 1699, as per the instructions of Guru Gobind Singh in order to create a parallel system of aristocratic titles being used by the neighboring Rajput hill chiefs of Anandpur Sahib. Singh is used by all baptized male Sikhs, regardless of their geographical or cultural binding; the women use Kaur.


title: Singh

text: In the 18th century, several groups started using the title "Singh". These included the Brahmins, the Kayasthas and the Baniyas of what are now Uttar Pradesh and Bihar. In the 19th century, even the Bengal court peons of the lower castes adopted the title "Singh". Bhumihars, who originally used Brahmin surnames, also started affixing Singh to their names. In Bihar and Jharkhand, the surname came to be associated with power and authority, and was adopted by people of multiple castes, including Brahmin zamindars. Citing Kshatriya status, Ahirs (Yadavs), Kushwaha (Koeri) and Kurmis also use 'Singh' as part of their names. Many Muslim Shins also used the surname "Sing". Some Jains had also adopted "Singh" in addition to various Hindu castes.


title: Singh

text: People belonging to several other castes and communities have also used Singh as a title, middle name or a surname; these include non-Sikh Punjabis, Gujjars (e.g. Nirbhay Singh Gujjar), Brahmins (e.g.Lakshmeshwar Singh), Marathas (e.g. Pratap Singh Rao Gaekwad) and Hindu Jats, (e.g. Bhim Singh Rana), Sikh Jats,(e.g. Maharaja Ranjit Singh), Kushwaha (Maurya), (e.g. Babu Singh Kushwaha), and the Bhil people (an Adivasi ethnic group). The surname 'Singh' is used by many caste groups in Bihar. The name is also found among the Indian diaspora. For example, taking advantage of the fact that there was no reliable way to ascertain a person's caste, some of the low-caste Indian indentured labourers brought to British Guiana adopted the surname "Singh", claiming to be Kshatriyas.


title: Singh

text: "Singh" is generally used as a surname or as a middle name/title (e.g. Mahendra Singh Dhoni). When used as a middle name, it is generally followed by the caste, clan or family name.


title: Singh

text: Rajputs may have "Singh" as a middle name or last name (e.g. Manish Singh Parmar). Numerous Yadavs also use this as their middle name (e.g. Mulayam Singh Yadav). To stop the practice of caste system in Sikhism, some Sikhs append "Khalsa" to Singh (e.g. Harinder Singh Khalsa). Some Sikhs and Rajputs add the names of their native villages instead (e.g. Harcharan Singh Longowal, after Longowal, Pratap Singh Khachariyawas after Khachariyawas). In order to create a casteless society, many first generation Indians and Nepalis changed their surnames to "Singh", which is now a common, neutral and non caste specific surname.


title: Singh

text: Originally, a common practice among the Rajput men was to have "Singh" as their last name, while Rajput women had the last name 'Kanwar'. However, now, many Rajput women have Singh in their name (e.g. Prashanti Singh) as well.


title: Singh

text: A section of around a million adherents of Sikhism that live abroad in Western countries only keep Singh or Kaur as their last name. This has caused legal problems in immigration procedures, especially in Canada. For a decade, the Canadian High Commission in New Delhi stated in letters to its Sikh clients that "the names Kaur and Singh do not qualify for the purpose of immigration to Canada", requiring people with these surnames to adopt new ones. The ban was denounced by the Sikh community, after which the Citizenship and Immigration Canada announced it was dropping the policy, calling the whole issue a misunderstanding based on a "poorly worded" letter.


title: Clomipramine

text: Clomipramine, sold under the brand name Anafranil among others, is a tricyclic antidepressant (TCA). It is used for the treatment of obsessive–compulsive disorder, panic disorder, major depressive disorder, and chronic pain. It may increase the risk of suicide in those under the age of 25. It is primarily taken by mouth. It has also been used to treat premature ejaculation.


title: Clomipramine

text: Common side effects include dry mouth, constipation, loss of appetite, sleepiness, weight gain, sexual dysfunction, and trouble urinating. Serious side effects include an increased risk of suicidal behavior in those under the age of 25, seizures, mania, and liver problems. If stopped suddenly a withdrawal syndrome may occur with headaches, sweating, and dizziness. It is unclear if it is safe for use in pregnancy. Its mechanism of action is not entirely clear but is believed to involve increased levels of serotonin.


title: Clomipramine

text: Clomipramine was discovered in 1964 by the Swiss drug manufacturer Ciba-Geigy. It is on the World Health Organization's List of Essential Medicines. It is available as a generic medication.


title: Clomipramine

text: In a meta-analysis of various trials involving fluoxetine (Prozac), fluvoxamine (Luvox), and sertraline (Zoloft) to test their relative efficacies in treating OCD, clomipramine was found to be the most effective.


title: Clomipramine

text: Clomipramine use during pregnancy is associated with congenital heart defects in the newborn. It is also associated with reversible withdrawal effects in the newborn. Clomipramine is also distributed in breast milk and hence nursing while taking clomipramine is advised against.


title: Clomipramine

text: Withdrawal symptoms may occur during gradual or particularly abrupt withdrawal of tricyclic antidepressant drugs. Possible symptoms include: nausea, vomiting, abdominal pain, diarrhea, insomnia, headache, nervousness, anxiety, dizziness and worsening of psychiatric status. Differentiating between the return of the original psychiatric disorder and clomipramine withdrawal symptoms is important. Clomipramine withdrawal can be severe. Withdrawal symptoms can also occur in neonates when clomipramine is used during pregnancy. A major mechanism of withdrawal from tricyclic antidepressants is believed to be due to a rebound effect of excessive cholinergic activity due to neuroadaptations as a result of chronic inhibition of cholinergic receptors by tricyclic antidepressants. Restarting the antidepressant and slow tapering is the treatment of choice for tricyclic antidepressant withdrawal. Some withdrawal symptoms may respond to anticholinergics, such as atropine or benztropine mesylate.


title: Clomipramine

text: There is no specific antidote for overdose and all treatment is purely supportive and symptomatic. Treatment with activated charcoal may be used to limit absorption in cases of oral overdose. Anyone suspected of overdosing on clomipramine should be hospitalised and kept under close surveillance for at least 72 hours. Clomipramine has been reported as being less toxic in overdose than most other TCAs in one meta-analysis but this may well be due to the circumstances surrounding most overdoses as clomipramine is more frequently used to treat conditions for which the rate of suicide is not particularly high such as OCD. In another meta-analysis, however, clomipramine was associated with a significant degree of toxicity in overdose.


title: Clomipramine

text: Clomipramine may interact with a number of different medications, including the monoamine oxidase inhibitors which include isocarboxazid, moclobemide, phenelzine, selegiline and tranylcypromine, antiarrhythmic agents (due to the effects of TCAs like clomipramine on cardiac conduction. There is also a potential pharmacokinetic interaction with quinidine due to the fact that clomipramine is metabolised by CYP2D6 "in vivo"), diuretics (due to the potential for hypokalaemia (low blood potassium) to develop which increases the risk for QT interval prolongation and torsades de pointes), the selective serotonin reuptake inhibitors (SSRIs; due to both potential additive serotonergic effects leading to serotonin syndrome and the potential for a pharmacokinetic interaction with the SSRIs that inhibit CYP2D6 [e.g. fluoxetine and paroxetine]) and serotonergic agents such as triptans, other tricyclic antidepressants, tramadol, etc. (due to the potential for serotonin syndrome). Its use is also advised against in those concurrently on CYP2D6 inhibitors due to the potential for increased plasma levels of clomipramine and the resulting potential for CNS and cardiotoxicity.


title: Clomipramine

text: Clomipramine is a reuptake inhibitor of serotonin and norepinephrine, or a serotonin–norepinephrine reuptake inhibitor (SNRI); that is, it blocks the reuptake of these neurotransmitters back into neurons by preventing them from interacting with their transporters, thereby increasing their extracellular concentrations in the synaptic cleft and resulting in increased serotonergic and noradrenergic neurotransmission. In addition, clomipramine also has antiadrenergic, antihistamine, antiserotonergic, antidopaminergic, and anticholinergic activities. It is specifically an antagonist of the α-adrenergic receptor, the histamine H receptor, the serotonin 5-HT, 5-HT, 5-HT, 5-HT, and 5-HT receptors, the dopamine D, D, and D receptors, and the muscarinic acetylcholine receptors (M–M). Like other TCAs, clomipramine weakly blocks voltage-dependent sodium channels as well.


title: Clomipramine

text: Although clomipramine shows around 100- to 200-fold preference in affinity for the serotonin transporter (SERT) over the norepinephrine transporter (NET), its major active metabolite, desmethylclomipramine (norclomipramine), binds to the NET with very high affinity (K = 0.32 nM) and with dramatically reduced affinity for the SERT (K = 31.6 nM). Moreover, desmethylclomipramine circulates at concentrations that are approximately twice those of clomipramine. In accordance, occupancy of both the SERT and the NET has been shown with clomipramine administration in positron emission tomography studies with humans and non-human primates. As such, clomipramine is in fact a fairly balanced SNRI rather than only a serotonin reuptake inhibitor (SRI).


title: Clomipramine

text: The antidepressant effects of clomipramine are thought to be due to reuptake inhibition of serotonin and norepinephrine, while serotonin reuptake inhibition only is thought to be responsible for the effectiveness of clomipramine in the treatment of OCD. Conversely, antagonism of the H, α-adrenergic, and muscarinic acetylcholine receptors is thought to contribute to its side effects. Blockade of the H receptor is specifically responsible for the antihistamine effects of clomipramine and side effects like sedation and somnolence (sleepiness). Antagonism of the α-adrenergic receptor is thought to cause orthostatic hypotension and dizziness. Inhibition of muscarinic acetylcholine receptors is responsible for the anticholinergic side effects of clomipramine like dry mouth, constipation, urinary retention, blurred vision, and cognitive/memory impairment. In overdose, sodium channel blockade in the brain is believed to cause the coma and seizures associated with TCAs while blockade of sodium channels in the heart is considered to cause cardiac arrhythmias, cardiac arrest, and death. On the other hand, sodium channel blockade is also thought to contribute to the analgesic effects of TCAs, for instance in the treatment of neuropathic pain.


title: Clomipramine

text: The exceptionally strong serotonin reuptake inhibition of clomipramine likely precludes the possibility of its antagonism of serotonin receptors (which it binds to with more than 100-fold lower affinity than the SERT) resulting in a net decrease in signaling by these receptors. In accordance, while serotonin receptor antagonists like cyproheptadine and chlorpromazine are effective as antidotes against serotonin syndrome, clomipramine is nonetheless capable of inducing this syndrome. In fact, while all TCAs are SRIs and serotonin receptor antagonists to varying extents, the only TCAs that are associated with serotonin syndrome are clomipramine and to a lesser extent its dechlorinated analogue imipramine, which are the two most potent SRIs of the TCAs (and in relation to this have the highest ratios of serotonin reuptake inhibition to serotonin receptor antagonism). As such, whereas other TCAs can be combined with monoamine oxidase inhibitors (with caution due to the risk of hypertensive crisis from NET inhibition; sometimes done in treatment-resistant depressives), clomipramine cannot be due to the risk of serotonin syndrome and death. Unlike the case of its serotonin receptor antagonism, orthostatic hypotension is a common side effect of clomipramine, suggesting that its blockade of the α-adrenergic receptor is strong enough to overcome the stimulatory effects on the α-adrenergic receptor of its NET inhibition.


title: Clomipramine

text: Clomipramine is a very strong SRI. Its affinity for the SERT was reported in one study using human tissues to be 0.14 nM, which is considerably higher than that of other TCAs. For example, the TCAs with the next highest affinities for the SERT in the study were imipramine, amitriptyline, and dosulepin (dothiepin), with K values of 1.4 nM, 4.3 nM, and 8.3 nM, respectively. In addition, clomipramine has a terminal half-life that is around twice as long as that of amitriptyline and imipramine. In spite of these differences however, clomipramine is used clinically at the same usual dosages as other serotonergic TCAs (100–200 mg/day). It achieves typical circulating concentrations that are similar in range to those of other TCAs but with an upper limit that is around twice that of amitriptyline and imipramine. For these reasons, clomipramine is the most potent SRI among the TCAs and is far stronger as an SRI than other TCAs at typical clinical dosages. In addition, clomipramine is more potent as an SRI than any selective serotonin reuptake inhibitors (SSRIs), it is more potent than paroxetine, which is the strongest SSRI.


title: Clomipramine

text: A positron emission tomography study found that a single low dose of 10 mg clomipramine to healthy volunteers resulted in 81.1% occupancy of the SERT, which was comparable to the 84.9% SERT occupancy by 50 mg fluvoxamine. In the study, single doses of 5 to 50 mg clomipramine resulted in 67.2 to 94.0% SERT occupancy while single doses of 12.5 to 50 mg fluvoxamine resulted in 28.4 to 84.9% SERT occupancy. Chronic treatment with higher doses was able to achieve up to 100.0% SERT occupancy with clomipramine and up to 93.6% SERT occupancy with fluvoxamine. Other studies have found 83% SERT occupancy with 20 mg/day paroxetine and 77% SERT occupancy with 20 mg/day citalopram. These results indicate that very low doses of clomipramine are able to substantially occupy the SERT and that clomipramine achieves higher occupancy of the SERT than SSRIs at comparable doses. Moreover, clomipramine may be able to achieve more complete occupancy of the SERT at high doses, at least relative to fluvoxamine.


title: Clomipramine

text: If the ratios of the 80% SERT occupancy dosage and the approved clinical dosage range are calculated and compared for SSRIs, SNRIs, and clomipramine, it can be deduced that clomipramine is by far the strongest SRI used medically. The lowest approved dosage of clomipramine can be estimated to be roughly comparable in SERT occupancy to the maximum approved dosages of the strongest SSRIs and SNRIs. Because their mechanism of action was originally not known and dose-ranging studies were never conducted, first-generation antipsychotics were dramatically overdosed in patients. It has been suggested that the same may have been true for clomipramine and other TCAs.


title: Clomipramine

text: Clomipramine was the first drug that was investigated for and found to be effective in the treatment of OCD. In addition, it was the first drug to be approved by the in the United States for the treatment of OCD. The effectiveness of clomipramine in the treatment of OCD is far greater than that of other TCAs, which are comparatively weak SRIs; a meta-analysis found pre- versus post-treatment effect sizes of 1.55 for clomipramine relative to a range of 0.67 for imipramine and 0.11 for desipramine. In contrast to other TCAs, studies have found that clomipramine and SSRIs, which are more potent SRIs, have similar effectiveness in the treatment of OCD. However, multiple meta-analyses have found that clomipramine nonetheless retains a significant effectiveness advantage relative to SSRIs; in the same meta-analysis mentioned previously, the effect sizes of SSRIs in the treatment of OCD ranged from 0.81 for fluoxetine to 1.36 for sertraline (relative to 1.55 for clomipramine). However, the effectiveness advantage for clomipramine has not been apparent in head-to-head comparisons of clomipramine versus SSRIs for OCD. The differences in effectiveness findings could be due to differences in methodologies across non-head-to-head studies.


title: Clomipramine

text: Relatively high doses of SSRIs are needed for effectiveness in the treatment of OCD. Studies have found that high dosages of SSRIs above the normally recommended maximums are significantly more effective in OCD treatment than lower dosages (e.g., 250 to 400 mg/day sertraline versus 200 mg/day sertraline). In addition, the combination of clomipramine and SSRIs has also been found to be significantly more effective in alleviating OCD symptoms, and clomipramine is commonly used to augment SSRIs for this reason. Studies have found that intravenous clomipramine, which is associated with very high circulating concentrations of the drug and a much higher ratio of clomipramine to its metabolite desmethylclomipramine, is more effective than oral clomipramine in the treatment of OCD. There is a case report of complete remission from OCD for approximately one month following a massive overdose of fluoxetine, an SSRI with a uniquely long duration of action. Taken together, stronger serotonin reuptake inhibition has consistently been associated with greater alleviation of OCD symptoms, and since clomipramine, at the clinical dosages in which it is employed, is effectively the strongest SRI used medically (see table above), this may underlie its unique effectiveness in the treatment of OCD.


title: Clomipramine

text: In addition to serotonin reuptake inhibition, clomipramine is also a mild but clinically significant antagonist of the dopamine D, D, and D receptors at high concentrations. Addition of antipsychotics, which are potent dopamine receptor antagonists, to SSRIs, has been found to significantly augment their effectiveness in the treatment of OCD. As such, besides strong serotonin reuptake inhibition, clomipramine at high doses might also block dopamine receptors to treat OCD symptoms, and this could additionally or alternatively be involved in its possible effectiveness advantage over SSRIs.


title: Clomipramine

text: Although clomipramine is probably more effective in the treatment of OCD compared to SSRIs, it is greatly inferior to them in terms of tolerability and safety due to its lack of selectivity for the SERT and promiscuous pharmacological activity. In addition, clomipramine has high toxicity in overdose and can potentially result in death, whereas death rarely, if ever, occurs with overdose of SSRIs. It is for these reasons that clomipramine, in spite of potentially superior effectiveness to SSRIs, is now rarely used as a first-line agent in the treatment of OCD, with SSRIs being used as first-line therapies instead and clomipramine generally being reserved for more severe cases and as a second-line agent.


title: Clomipramine

text: The oral bioavailability of clomipramine is approximately 50%. Peak plasma concentrations occur around 2–6 hours (with an average of 4.7 hours) after taking clomipramine orally and are in the range of 56–154 ng/mL (178–489 nmol/L). Steady-state concentrations of clomipramine are around 134–532 ng/mL (426–1,690 nmol/L), with an average of 218 ng/mL (692 nmol/L), and are reached after 7 to 14 days of repeated dosing. Steady-state concentrations of the active metabolite, desmethylclomipramine, are around 230–550 ng/mL (730–1,750 nmol/L). The volume of distribution (V) of clomipramine is approximately 17 L/kg. It binds approximately 97–98% to plasma proteins, primarily to albumin. Clomipramine is metabolized in the liver mainly by CYP2D6. It has a terminal half-life of 32 hours, and its N-desmethyl metabolite, desmethylclomipramine, has a terminal half-life of approximately 69 hours. Clomipramine is mostly excreted in urine (60%) and feces (32%).


title: Clomipramine

text: Clomipramine is a tricyclic compound, specifically a dibenzazepine, and possesses three rings fused together with a side chain attached in its chemical structure. Other dibenzazepine TCAs include imipramine, desipramine, and trimipramine. Clomipramine is a derivative of imipramine with a chlorine atom added to one of its rings and is also known as 3-chloroimipramine. It is a tertiary amine TCA, with its side chain-demethylated metabolite desmethylclomipramine being a secondary amine. Other tertiary amine TCAs include amitriptyline, imipramine, dosulepin (dothiepin), doxepin, and trimipramine. The chemical name of clomipramine is 3-(3-chloro-10,11-dihydro-5"H"-dibenzo["b,f"]azepin-5-yl)-"N,N"-dimethylpropan-1-amine and its free base form has a chemical formula of CHClN with a molecular weight of 314.857 g/mol. The drug is used commercially almost exclusively as the hydrochloride salt; the free base has been used rarely. The CAS Registry Number of the free base is 303-49-1 and of the hydrochloride is 17321-77-6.