title: Penny (The Big Bang Theory)

text: In an early episode, Penny talked to Raj about her sister having shot her brother-in-law. In another episode, Penny accompanied the men to the comic book store to shop for a gift for her 13-year-old nephew. In "The Boyfriend Complexity" (4–9), Wyatt (Penny's father) tells Leonard he wants grandchildren one day, "and I want them to grow up on a house without wheels". In "The Dumpling Paradox", Penny has an unwanted guest, Christy, staying with her who had slept with her brother while being engaged to her cousin, saying, "she's "kind" of family". Christy knows Penny from back in Omaha and, according to Penny, she slept with nearly every man in the city, earning her the nickname "Whore of Omaha". While staying with Penny, Christy sleeps with Howard.


title: Penny (The Big Bang Theory)

text: In the fifth-season episode "The Pulled Groin Extrapolation", after Penny quickly grabs and eats the last dumpling of a group dinner after a brief disagreement over who should get it, Sheldon makes the sarcastic comment, "I've seen pictures of your mother. Keep eating", a reference to Penny's mother's weight, that clearly unsettles her. In "The Flaming Spittoon Acquisition", Penny confesses to Bernadette that her mother smoked pot while she was pregnant with her.


title: Penny (The Big Bang Theory)

text: Penny has mentioned having a sister who appears to be the mother of her 13-year-old nephew mentioned in season two. In the sixth-season episode "The Parking Spot Escalation" Penny mentions to Bernadette and Amy that her sister gave her her first ever bikini wax using melted crayolas and duct tape. In "The Bachelor Party Corrosion", Penny tells Bernadette, Amy and viewers that at her sister's wedding she was heavily pregnant since she and their father started a father-daughter dance and then her water broke.


title: Penny (The Big Bang Theory)

text: Penny has mentioned having a brother on parole, who she says is ""kind" of a chemist". In "The Rhinitis Revelation" (5–6), she is more explicit in revealing that he is in the practice of cooking crystal meth. She mentions that he is back in prison for 12–18 months, depending on his behavior, in the seventh-season finale, "The Status Quo Combustion".


title: Penny (The Big Bang Theory)

text: Penny's mother Susan, who Penny has occasionally spoken with on the phone in prior episodes (usually about other family members), first appears in the tenth-season premiere "The Conjugal Conjecture", portrayed by Katey Sagal (who previously played Cuoco's mother in the sitcom "8 Simple Rules"). She is shown to be very embarrassed by her family's shortcomings: her son's criminal record and jailing, Wyatt's drinking, and their overall humble existence as a farming family. Although she has previously met Leonard and likes him, she is uncomfortable about meeting his academic parents, not wanting them to think of her family as "white trash". She goes to great lengths to present them in the best possible light, including buying dental implants for her son.


title: Penny (The Big Bang Theory)

text: Penny's full name is never officially revealed. In 2009, Co-creator Bill Prady stated that Penny's last name would be revealed eventually. In 2014, executive producer Steve Molaro stated that her last name would remain a secret. Nevertheless, clues to her full name had already been revealed in Season 2.


title: Penny (The Big Bang Theory)

text: In the second-season episode "The Barbarian Sublimation", when she becomes addicted to online gaming, she uses the gamertag "Queen Penelope", though whether Penelope is her actual full first name is never confirmed in the series.


title: Penny (The Big Bang Theory)

text: In the second-season episode "The Work Song Nanocluster", Penny receives a package addressed to "Penny Teller", an apparent reference to magicians Penn and Teller. The name on the address label is just barely (and fleetingly) visible, and is not referenced in dialogue. The producers of the show approved the name "Penny Teller" for use on the package, mistakenly believing it would not be visible in the finished episode. In another early episode a letter can be seen, addressed to Penny London. Producer Bill Prady maintains that the last name "Teller" is "not canon".


title: Penny (The Big Bang Theory)

text: Following her marriage to Leonard, Penny is occasionally referred to or addressed with the last name Hofstadter.


title: Penny (The Big Bang Theory)

text: Tom Jicha of the "South Florida Sun-Sentinel" praised Cuoco's portrayal of Penny, stating: "Her character had the potential to be a bimbo, but she [Cuoco] has developed it into a fully fleshed-out woman, who isn't as book-smart as the other characters but is wiser in so many ways. She's also a great straight person, who can get off zingers of her own".


title: Chip 'n Dale: Rescue Rangers (TV series)

text: Chip 'n Dale: Rescue Rangers is an American animated adventure comedy television series produced by Walt Disney Television Animation. Created by Tad Stones and Alan Zaslove, it featured established Disney characters Chip 'n' Dale in a new setting. The series premiered on The Disney Channel on March 4, 1989, after the episode "Catteries Not Included" aired on August 27, 1988, as a preview. The series continued in September with a two-hour special, "Rescue Rangers: To the Rescue", later divided into five parts to air as part of the weekday run. The final episode aired on November 19, 1990.


text: On September 18, 1989, the series entered national syndication. It aired afternoons along with and following "DuckTales" on a network that would become Fox before transferring to a new channel. "TaleSpin", a series based on characters from "The Jungle Book", was added to the lineup, just before The Disney Afternoon aired on this new channel, following Rescue Rangers. From 1990 to 1993, reruns were aired as a part of The Disney Afternoon. It was syndicated on Toon Disney upon launch in 1998 but were removed a decade later. The entire run became available (as one season) as part of Disney+ as of its launch on November 12, 2019, fully remastered in high definition. The series was initially released on Blu-ray on January 25, 2022, via Disney Movie Club, then everywhere else on February 15, 2022.


text: A live-action/animated metafictional was released on Disney+ on May 20, 2022. From May 19–20, 2022, Disney XD reran the show to promote the film.


text: Chip and Dale are two chipmunks who start a detective agency, Rescue Rangers, along with their friends Gadget Hackwrench, Monterey Jack, and Zipper. The pint-sized detectives deal with crimes that are often "too small" for the police to handle, usually with other animals as their clients. The gang frequently find themselves going up against two particular arch-villains: Mafia-style tabby cat Fat Cat and mad scientist Norton Nimnul.


text: Except for the five-part set of episodes made from the pilot movie, each 22-minute episode of the series was self-contained. Plot points introduced in each episode stayed in the episode and any character development did not appear to continue through to future episodes. Most of the episodes followed a similar format, wherein the next case was presented at the start of the episode, then the bulk of the episode had the sleuths gathering clues and investigating the situation. In the last few minutes of the episode, the case was resolved, usually in dramatic fashion and the final moments would have a humorous wrap-up scene between the Rangers.


text: "Rescue Rangers" was originally conceived as the first of three new companion shows to Disney's popular "DuckTales" series, which had more than doubled the ratings among child audiences in its time slots after its debut in the fall of 1987. Disney had originally invested $20 million in "DuckTales" and then invested $28 million in "Chip 'n Dale: Rescue Rangers".


text: It, along with "TaleSpin" and a third series, "Double-O Duck" (which ultimately became "Darkwing Duck"), would round out a programming block later known as "The Disney Afternoon" along with the previously established "Disney's Adventures of the Gummi Bears" to capitalize on "DuckTales"s success.


text: When Tad Stones first came up with the idea for the "Rescue Rangers" series, Chip and Dale were not part of the show. He initially pitched doing a TV series based on "The Rescuers", but Disney rejected that idea as a sequel to that film was already in production. He created a new concept with the working title of "Metro Mice". The original draft starred an Indiana Jones-type mouse named Kit Colby who sported a fedora and a fluffy collared leather jacket, and the rest of the team included a chameleon, an earlier version of Gadget and a character resembling Monterey Jack with a different name. When he proposed the show in a meeting with Michael Eisner and Jeffrey Katzenberg, the idea was well received except for the character of Kit. At Eisner's suggestion, they replaced him with the chipmunk duo to give the show some established Disney characters to work with. By late 1987, two years before its television debut, the show was announced under its original proposed title of ""Chip 'n Dale and the Rescue Rangers"".


text: While Chip and Dale were established characters, in order to bring them into the series only their general appearance and basic personality traits were kept. Unlike their appearances in Disney shorts, the "Rescue Rangers" features the chipmunk duo as very verbal, with Chip voiced by Tress MacNeille and Dale voiced by Corey Burton. Audio processing was used to speed up the voice recordings and give the voices a higher pitch, particularly Chip's. The pair were given clothes—Chip the clothing of the original-concept Kit, while the goofier Dale was reminiscent of, but not specifically modeled after, Thomas Magnum from "Magnum, P.I." with his Hawaiian shirt.


text: The series premiered in 1989 on The Disney Channel before moving into a regular slot in syndication the following fall. In 1990, the series premiered as part of the lineup known as The Disney Afternoon, where it ran until 1993. On October 2, 1995, "Chip 'n Dale: Rescue Rangers" began reruns on The Disney Channel as part of a two-hour programming block called "Block Party", airing weekdays in the late afternoon/early evening and which also included "Darkwing Duck", "TaleSpin" and "DuckTales".


text: The show's opening theme was written (listed in the end credits as "words & music") by Mark Mueller, an ASCAP Award-winning pop music songwriter who also wrote the popular "DuckTales" theme song, and produced by Alf Clausen. The song performed over the title credits is sung by Jeff Pescetto (who also performed the "DuckTales" theme song). A full-length theme song was recorded by The Jets, a Minnesota pop group, and released on The Disney Afternoon soundtrack.


text: On November 6, 1989, Walt Disney Home Video released episodes from the series on video, containing a pair of episodes each.


text: On February 22, 1991, Walt Disney Home Video released 10 episodes from the series on five VHS cassettes in North America, containing a pair of episodes each.


text: Additionally, on December 14, 1994, the episode "Ghost of a Chance" was released together with the "Goof Troop" episode "Hallow-Weenies" on one VHS cassette as a special release called "Boo-Busters". On September 3, 1996, the episode "Good Times, Bat Times" was released together with the "Darkwing Duck" episode "Ghoul of My Dreams" on one VHS cassette as a special release called "Witcheroo!"


text: Eleven VHS cassettes containing 23 episodes of the series were released in Australia and New Zealand.


text: Walt Disney Studios Home Entertainment has released some of the series on DVD-Video; two volumes have been released in Region 1 thus far, featuring the first 51 episodes of the series. The first was released on November 8, 2005 (containing episodes 1–27) and the second on November 14, 2006 (containing episodes 28–51). The episodes on the first volume are arranged in production order, while the episodes on the second volume are arranged by original air date. The sets were originally packaged in a box containing 3 slipcases, one for each disc. Both volumes were reissued in standard-sized DVD cases in 2013. There has yet to be any word from Disney regarding the release of a third volume set for episodes 52–65. In 2022, the complete show was released on Blu-ray.


text: In the United Kingdom, Disney released one Region 2 volume in 2007, titled "Chip 'n Dale - Rescue Rangers - First Collection". Despite the set being similar to the US version, it contained only 20 episodes, while having 6 language tracks: English, French, Dutch, German, Spanish and Italian. Several other similar releases were then made to other countries, but only going up to episode #20. On December 5, 2012, a second DVD set of the series was released in the UK, but as a Region 2 version of Volume 2, titled "Chip 'n Dale Rescue Rangers Season 2". Unlike the first DVD set, this 3-disc set includes a Fastplay mode and only two language tracks: English and German, but subtitles have not been added. As of yet, there are no announced plans to release the rest of the series, or the seven episodes missing between the first two sets.


text: The series was released on Amazon Video in 2013 and was free for Amazon Prime members. However, it was unavailable for some time. The series was brought back to Amazon Instant Video in the United States in 2016, being currently available for purchase in SD and HD.


text: The complete series is also currently available for purchase in SD and HD on iTunes and Google Play (Volume 2 on Google Play is only available in SD), also released in 2016.


text: The complete series was released alongside the release of Disney's streaming service Disney+ on November 12, 2019. There, it is cropped to 16:9 widescreen format, unlike the Blu-ray release (which retains its original aspect ratio).


text: Walt Disney Studios Home Entertainment has released the entire series on Blu-ray Disc in a 2022 multi-region, high definition six-disc set, keeping its original image ratio (1.33:1). All episodes have been scanned from the original negatives, except episode 32 of season 2 "Prehysterical Pet" whose negatives could not be located. They are not sorted in the original airing order, nor the intended chronological order (e.g., the pilot episodes "Rescue Rangers to the Rescue - parts 1-5" are on disc 4).


text: Hal Erickson, author of "Television Cartoon Shows, An Illustrated Encyclopedia" compared the show to "DuckTales", stating that it was "consummately produced and written" and its animation "succeeded in putting most other overseas output to shame." Emily Ashby of "Common Sense Media" rated the series 4 out of 5 stars, complimented the depiction of positive messages, citing teamwork and saying the series succeeds to depict a female character as a role model, while finding the show family-friendly and entertaining. In January 2009, "IGN" named "Chip 'n Dale: Rescue Rangers" as the 60th-best in the Top 100 Animated TV Shows. Jeremy Hayes of "BuzzFeed" ranked "Chip 'n Dale: Rescue Rangers" 4th in their "Best Cartoons From The '80s" list.


text: In fall of 1989, McDonald's produced a series of "Chip 'n Dale: Rescue Rangers" themed Happy Meal that included toy versions of the main characters riding small vehicles. Scenes from the series were incorporated into the TV commercials advertising the Happy Meals. Ice cream versions of Chip 'n Dale were made by Good Humor.


text: A monthly comic book based on the show was published by Disney Comics in 1990, that ran for 19 issues. Subsequent comic stories were printed in "Disney Adventures" from 1990 to 1995, as well as in the Disney Afternoon comic book published by Marvel Comics. They also had a series from Boom Studios that was published for 8 issues from December 2010 to June 2011.


text: From September 2010, "Chip 'n Dale: Rescue Rangers" was revived by comics publisher Boom! Studios, as an ongoing monthly series slated to begin in December of the same year. This choice was based on the extreme and unexpected popularity of "Darkwing Duck", another Disney Afternoon property which BOOM! revived earlier in 2010. The series featured comics writer Ian Brill, and artist Leonel Castellani.


text: Eight issues were published, collecting the two 4-part stories into two trade paperback books. The comic series was cancelled May 2011, to be replaced by the launch of "DuckTales".


text: The Boom! Studios series was reprinted in IDW Publishing's "Disney's Afternoon Giant" in October 2018.


text: A live-action CGI feature-length film directed by Akiva Schaffer; written by Dan Gregor and Doug Mand; produced by David Hoberman and Todd Lieberman; and starring John Mulaney and Andy Samberg as the voices of Chip and Dale was released on May 20, 2022, on Disney+. The film also stars Eric Bana and Dennis Haysbert as the voices of Monterey Jack and Zipper while both Tress MacNeille and Corey Burton reprise their roles of Gadget and Zipper as well as Chip and Dale for a brief scene.


title: Pharmaceutical industry

text: The pharmaceutical industry discovers, develops, produces, and markets drugs or pharmaceutical drugs for use as medications to be administered to patients (or self-administered), with the aim to cure them, vaccinate them, or alleviate symptoms. Pharmaceutical companies may deal in generic or brand medications and medical devices. They are subject to a variety of laws and regulations that govern the patenting, testing, safety, efficacy using drug testing and marketing of drugs. The global pharmaceuticals market produced treatments worth $1,228.45 billion in 2020 and showed a compound annual growth rate (CAGR) of 1.8%.


title: Pharmaceutical industry

text: The modern era of pharmaceutical industry began with local apothecaries that expanded from their traditional role of distributing botanical drugs such as morphine and quinine to wholesale manufacture in the mid-1800s, and from discoveries resulting from applied research. Intentional drug discovery from plants began with the isolation between 1803 and 1805 of morphine - an analgesic and sleep-inducing agent - from opium by the German apothecary assistant Friedrich Sertürner, who named this compound after the Greek god of dreams, Morpheus. By the late 1880s, German dye manufacturers had perfected the purification of individual organic compounds from tar and other mineral sources and had also established rudimentary methods in organic chemical synthesis. The development of synthetic chemical methods allowed scientists to systematically vary the structure of chemical substances, and growth in the emerging science of pharmacology expanded their ability to evaluate the biological effects of these structural changes.


title: Pharmaceutical industry

text: By the 1890s, the profound effect of adrenal extracts on many different tissue types had been discovered, setting off a search both for the mechanism of chemical signalling and efforts to exploit these observations for the development of new drugs. The blood pressure raising and vasoconstrictive effects of adrenal extracts were of particular interest to surgeons as hemostatic agents and as treatment for shock, and a number of companies developed products based on adrenal extracts containing varying purities of the active substance. In 1897, John Abel of Johns Hopkins University identified the active principle as epinephrine, which he isolated in an impure state as the sulfate salt. Industrial chemist Jōkichi Takamine later developed a method for obtaining epinephrine in a pure state, and licensed the technology to Parke-Davis. Parke-Davis marketed epinephrine under the trade name Adrenalin. Injected epinephrine proved to be especially efficacious for the acute treatment of asthma attacks, and an inhaled version was sold in the United States until 2011 (Primatene Mist). By 1929 epinephrine had been formulated into an inhaler for use in the treatment of nasal congestion.


title: Pharmaceutical industry

text: While highly effective, the requirement for injection limited the use of epinephrine and orally active derivatives were sought. A structurally similar compound, ephedrine, was identified by Japanese chemists in the "Ma Huang" plant and marketed by Eli Lilly as an oral treatment for asthma. Following the work of Henry Dale and George Barger at Burroughs-Wellcome, academic chemist Gordon Alles synthesized amphetamine and tested it in asthma patients in 1929. The drug proved to have only modest anti-asthma effects but produced sensations of exhilaration and palpitations. Amphetamine was developed by Smith, Kline and French as a nasal decongestant under the trade name Benzedrine Inhaler. Amphetamine was eventually developed for the treatment of narcolepsy, post-encephalitic parkinsonism, and mood elevation in depression and other psychiatric indications. It received approval as a New and Nonofficial Remedy from the American Medical Association for these uses in 1937, and remained in common use for depression until the development of tricyclic antidepressants in the 1960s.


title: Pharmaceutical industry

text: In 1903, Hermann Emil Fischer and Joseph von Mering disclosed their discovery that diethylbarbituric acid, formed from the reaction of acid, phosphorus oxychloride and urea, induces sleep in dogs. The discovery was patented and licensed to Bayer pharmaceuticals, which marketed the compound under the trade name Veronal as a sleep aid beginning in 1904. Systematic investigations of the effect of structural changes on potency and duration of action led to the discovery of phenobarbital at Bayer in 1911 and the discovery of its potent anti-epileptic activity in 1912. Phenobarbital was among the most widely used drugs for the treatment of epilepsy through the 1970s, and as of 2014, remains on the World Health Organizations list of essential medications. The 1950s and 1960s saw increased awareness of the addictive properties and abuse potential of barbiturates and amphetamines and led to increasing restrictions on their use and growing government oversight of prescribers. Today, amphetamine is largely restricted to use in the treatment of attention deficit disorder and phenobarbital in the treatment of epilepsy.


title: Pharmaceutical industry

text: In 1958, Leo Sternbach discovered the first benzodiazepine, chlordiazepoxide (Librium). Dozens of other benzodiazepines have been developed and are in use, some of the more popular drugs being diazepam (Valium), alprazolam (Xanax), clonazepam (Klonopin), and lorazepam (Ativan). Due to their far superior safety and therapeutic properties, benzodiazepines have largely replaced the use of barbiturates in medicine, except in certain special cases. When it was later discovered that benzodiazepines, like barbiturates, significantly lose their effectiveness and can have serious side effects when taken long-term, Heather Ashton researched benzodiazepine dependence and developed a protocol to discontinue their use.


title: Pharmaceutical industry

text: A series of experiments performed from the late 1800s to the early 1900s revealed that diabetes is caused by the absence of a substance normally produced by the pancreas. In 1869, Oskar Minkowski and Joseph von Mering found that diabetes could be induced in dogs by surgical removal of the pancreas. In 1921, Canadian professor Frederick Banting and his student Charles Best repeated this study and found that injections of pancreatic extract reversed the symptoms produced by pancreas removal. Soon, the extract was demonstrated to work in people, but development of insulin therapy as a routine medical procedure was delayed by difficulties in producing the material in sufficient quantity and with reproducible purity. The researchers sought assistance from industrial collaborators at Eli Lilly and Co. based on the company's experience with large scale purification of biological materials. Chemist George B. Walden of Eli Lilly and Company found that careful adjustment of the pH of the extract allowed a relatively pure grade of insulin to be produced. Under pressure from Toronto University and a potential patent challenge by academic scientists who had independently developed a similar purification method, an agreement was reached for non-exclusive production of insulin by multiple companies. Prior to the discovery and widespread availability of insulin therapy the life expectancy of diabetics was only a few months.


title: Pharmaceutical industry

text: The development of drugs for the treatment of infectious diseases was a major focus of early research and development efforts; in 1900,pneumonia, tuberculosis, and diarrhea were the three leading causes of death in the United States and mortality in the first year of life exceeded 10%.


title: Pharmaceutical industry

text: In 1911 arsphenamine, the first synthetic anti-infective drug, was developed by Paul Ehrlich and chemist Alfred Bertheim of the Institute of Experimental Therapy in Berlin. The drug was given the commercial name Salvarsan. Ehrlich, noting both the general toxicity of arsenic and the selective absorption of certain dyes by bacteria, hypothesized that an arsenic-containing dye with similar selective absorption properties could be used to treat bacterial infections. Arsphenamine was prepared as part of a campaign to synthesize a series of such compounds and found to exhibit partially selective toxicity. Arsphenamine proved to be the first effective treatment for syphilis, a disease which prior to that time was incurable and led inexorably to severe skin ulceration, neurological damage, and death.


title: Pharmaceutical industry

text: Ehrlich's approach of systematically varying the chemical structure of synthetic compounds and measuring the effects of these changes on biological activity was pursued broadly by industrial scientists, including Bayer scientists Josef Klarer, Fritz Mietzsch, and Gerhard Domagk. This work, also based in the testing of compounds available from the German dye industry, led to the development of Prontosil, the first representative of the sulfonamide class of antibiotics. Compared to arsphenamine, the sulfonamides had a broader spectrum of activity and were far less toxic, rendering them useful for infections caused by pathogens such as streptococci. In 1939, Domagk received the Nobel Prize in Medicine for this discovery. Nonetheless, the dramatic decrease in deaths from infectious diseases that occurred prior to World War II was primarily the result of improved public health measures such as clean water and less crowded housing, and the impact of anti-infective drugs and vaccines was significant mainly after World War II.


title: Pharmaceutical industry

text: In 1928, Alexander Fleming discovered the antibacterial effects of penicillin, but its exploitation for the treatment of human disease awaited the development of methods for its large scale production and purification. These were developed by a U.S. and British government-led consortium of pharmaceutical companies during the Second World War.


title: Pharmaceutical industry

text: Early progress toward the development of vaccines occurred throughout this period, primarily in the form of academic and government-funded basic research directed toward the identification of the pathogens responsible for common communicable diseases. In 1885, Louis Pasteur and Pierre Paul Émile Roux created the first rabies vaccine. The first diphtheria vaccines were produced in 1914 from a mixture of diphtheria toxin and antitoxin (produced from the serum of an inoculated animal), but the safety of the inoculation was marginal and it was not widely used. The United States recorded 206,000 cases of diphtheria in 1921 resulting in 15,520 deaths. In 1923, parallel efforts by Gaston Ramon at the Pasteur Institute and Alexander Glenny at the Wellcome Research Laboratories (later part of GlaxoSmithKline) led to the discovery that a safer vaccine could be produced by treating diphtheria toxin with formaldehyde. In 1944, Maurice Hilleman of Squibb Pharmaceuticals developed the first vaccine against Japanese Encephalitis. Hilleman would later move to Merck where he would play a key role in the development of vaccines against measles, mumps, chickenpox, rubella, hepatitis A, hepatitis B, and meningitis.


title: Pharmaceutical industry

text: Prior to the 20th century, drugs were generally produced by small scale manufacturers with little regulatory control over manufacturing or claims of safety and efficacy. To the extent that such laws did exist, enforcement was lax. In the United States, increased regulation of vaccines and other biological drugs was spurred by tetanus outbreaks and deaths caused by the distribution of contaminated smallpox vaccine and diphtheria antitoxin. The Biologics Control Act of 1902 required that federal government grant premarket approval for every biological drug and for the process and facility producing such drugs. This was followed in 1906 by the Pure Food and Drugs Act, which forbade the interstate distribution of adulterated or misbranded foods and drugs. A drug was considered misbranded if it contained alcohol, morphine, opium, cocaine, or any of several other potentially dangerous or addictive drugs, and if its label failed to indicate the quantity or proportion of such drugs. The government's attempts to use the law to prosecute manufacturers for making unsupported claims of efficacy were undercut by a Supreme Court ruling restricting the federal government's enforcement powers to cases of incorrect specification of the drug's ingredients.


title: Pharmaceutical industry

text: In 1937 over 100 people died after ingesting "Elixir Sulfanilamide" manufactured by S.E. Massengill Company of Tennessee. The product was formulated in diethylene glycol, a highly toxic solvent that is now widely used as antifreeze. Under the laws extant at that time, prosecution of the manufacturer was possible only under the technicality that the product had been called an "elixir", which literally implied a solution in ethanol. In response to this episode, the U.S. Congress passed the Federal Food, Drug, and Cosmetic Act of 1938, which for the first time required pre-market demonstration of safety before a drug could be sold, and explicitly prohibited false therapeutic claims.


title: Pharmaceutical industry

text: The aftermath of World War II saw an explosion in the discovery of new classes of antibacterial drugs including the cephalosporins (developed by Eli Lilly based on the seminal work of Giuseppe Brotzu and Edward Abraham), streptomycin (discovered during a Merck-funded research program in Selman Waksman's laboratory), the tetracyclines (discovered at Lederle Laboratories, now a part of Pfizer), erythromycin (discovered at Eli Lilly and Co.) and their extension to an increasingly wide range of bacterial pathogens. Streptomycin, discovered during a Merck-funded research program in Selman Waksman's laboratory at Rutgers in 1943, became the first effective treatment for tuberculosis. At the time of its discovery, sanitoriums for the isolation of tuberculosis-infected people were an ubiquitous feature of cities in developed countries, with 50% dying within 5 years of admission.


title: Pharmaceutical industry

text: A Federal Trade Commission report issued in 1958 attempted to quantify the effect of antibiotic development on American public health. The report found that over the period 1946–1955, there was a 42% drop in the incidence of diseases for which antibiotics were effective and only a 20% drop in those for which antibiotics were not effective. The report concluded that "it appears that the use of antibiotics, early diagnosis, and other factors have limited the epidemic spread and thus the number of these diseases which have occurred". The study further examined mortality rates for eight common diseases for which antibiotics offered effective therapy (syphilis, tuberculosis, dysentery, scarlet fever, whooping cough, meningococcal infections, and pneumonia), and found a 56% decline over the same period. Notable among these was a 75% decline in deaths due to tuberculosis.


title: Pharmaceutical industry

text: During the years 1940–1955, the rate of decline in the U.S. death rate accelerated from 2% per year to 8% per year, then returned to the historical rate of 2% per year. The dramatic decline in the immediate post-war years has been attributed to the rapid development of new treatments and vaccines for infectious disease that occurred during these years.


title: Pharmaceutical industry

text: Vaccine development continued to accelerate, with the most notable achievement of the period being Jonas Salk's 1954 development of the polio vaccine under the funding of the non-profit National Foundation for Infantile Paralysis. The vaccine process was never patented but was instead given to pharmaceutical companies to manufacture as a low-cost generic. In 1960 Maurice Hilleman of Merck Sharp & Dohme identified the SV40 virus, which was later shown to cause tumors in many mammalian species. It was later determined that SV40 was present as a contaminant in polio vaccine lots that had been administered to 90% of the children in the United States. The contamination appears to have originated both in the original cell stock and in monkey tissue used for production. In 2004 the United States Cancer Institute announced that it had concluded that SV40 is not associated with cancer in people.


title: Pharmaceutical industry

text: Other notable new vaccines of the period include those for measles (1962, John Franklin Enders of Children's Medical Center Boston, later refined by Maurice Hilleman at Merck), Rubella (1969, Hilleman, Merck) and mumps (1967, Hilleman, Merck) The United States incidences of rubella, congenital rubella syndrome, measles, and mumps all fell by >95% in the immediate aftermath of widespread vaccination. The first 20 years of licensed measles vaccination in the U.S. prevented an estimated 52 million cases of the disease, 17,400 cases of mental retardation, and 5,200 deaths.


title: Pharmaceutical industry

text: Hypertension is a risk factor for atherosclerosis, heart failure, coronary artery disease, stroke, renal disease, and peripheral arterial disease, and is the most important risk factor for cardiovascular morbidity and mortality, in industrialized countries. Prior to 1940 approximately 23% of all deaths among persons over age 50 were attributed to hypertension. Severe cases of hypertension were treated by surgery.


title: Pharmaceutical industry

text: Early developments in the field of treating hypertension included quaternary ammonium ion sympathetic nervous system blocking agents, but these compounds were never widely used due to their severe side effects, because the long-term health consequences of high blood pressure had not yet been established, and because they had to be administered by injection.


title: Pharmaceutical industry

text: In 1952 researchers at Ciba discovered the first orally available vasodilator, hydralazine. A major shortcoming of hydralazine monotherapy was that it lost its effectiveness over time (tachyphylaxis). In the mid-1950s Karl H. Beyer, James M. Sprague, John E. Baer, and Frederick C. Novello of Merck and Co. discovered and developed chlorothiazide, which remains the most widely used antihypertensive drug today. This development was associated with a substantial decline in the mortality rate among people with hypertension. The inventors were recognized by a Public Health Lasker Award in 1975 for "the saving of untold thousands of lives and the alleviation of the suffering of millions of victims of hypertension".


title: Pharmaceutical industry

text: A 2009 Cochrane review concluded that thiazide antihypertensive drugs reduce the risk of death (RR 0.89), stroke (RR 0.63), coronary heart disease (RR 0.84), and cardiovascular events (RR 0.70) in people with high blood pressure. In the ensuring years other classes of antihypertensive drug were developed and found wide acceptance in combination therapy, including loop diuretics (Lasix/furosemide, Hoechst Pharmaceuticals, 1963), beta blockers (ICI Pharmaceuticals, 1964) ACE inhibitors, and angiotensin receptor blockers. ACE inhibitors reduce the risk of new onset kidney disease [RR 0.71] and death [RR 0.84] in diabetic patients, irrespective of whether they have hypertension.


title: Pharmaceutical industry

text: Prior to the second world war, birth control was prohibited in many countries, and in the United States even the discussion of contraceptive methods sometimes led to prosecution under Comstock laws. The history of the development of oral contraceptives is thus closely tied to the birth control movement and the efforts of activists Margaret Sanger, Mary Dennett, and Emma Goldman. Based on fundamental research performed by Gregory Pincus and synthetic methods for progesterone developed by Carl Djerassi at Syntex and by Frank Colton at G.D. Searle & Co., the first oral contraceptive, Enovid, was developed by E.D. Searle and Co. and approved by the FDA in 1960. The original formulation incorporated vastly excessive doses of hormones, and caused severe side effects. Nonetheless, by 1962, 1.2 million American women were on the pill, and by 1965 the number had increased to 6.5 million. The availability of a convenient form of temporary contraceptive led to dramatic changes in social mores including expanding the range of lifestyle options available to women, reducing the reliance of women on men for contraceptive practice, encouraging the delay of marriage, and increasing pre-marital co-habitation.


title: Pharmaceutical industry

text: In the U.S., a push for revisions of the FD&C Act emerged from Congressional hearings led by Senator Estes Kefauver of Tennessee in 1959. The hearings covered a wide range of policy issues, including advertising abuses, questionable efficacy of drugs, and the need for greater regulation of the industry. While momentum for new legislation temporarily flagged under extended debate, a new tragedy emerged that underscored the need for more comprehensive regulation and provided the driving force for the passage of new laws.


title: Pharmaceutical industry

text: On 12 September 1960, an American licensee, the William S. Merrell Company of Cincinnati, submitted a new drug application for Kevadon (thalidomide), a sedative that had been marketed in Europe since 1956. The FDA medical officer in charge of reviewing the compound, Frances Kelsey, believed that the data supporting the safety of thalidomide was incomplete. The firm continued to pressure Kelsey and the FDA to approve the application until November 1961, when the drug was pulled off the German market because of its association with grave congenital abnormalities. Several thousand newborns in Europe and elsewhere suffered the teratogenic effects of thalidomide. Without approval from the FDA, the firm distributed Kevadon to over 1,000 physicians there under the guise of investigational use. Over 20,000 Americans received thalidomide in this "study," including 624 pregnant patients, and about 17 known newborns suffered the effects of the drug.


title: Pharmaceutical industry

text: The thalidomide tragedy resurrected Kefauver's bill to enhance drug regulation that had stalled in Congress, and the Kefauver-Harris Amendment became law on 10 October 1962. Manufacturers henceforth had to prove to FDA that their drugs were effective as well as safe before they could go on the US market. The FDA received authority to regulate advertising of prescription drugs and to establish good manufacturing practices. The law required that all drugs introduced between 1938 and 1962 had to be effective. An FDA - National Academy of Sciences collaborative study showed that nearly 40 percent of these products were not effective. A similarly comprehensive study of over-the-counter products began ten years later.


title: Pharmaceutical industry

text: In 1971, Akira Endo, a Japanese biochemist working for the pharmaceutical company Sankyo, identified mevastatin (ML-236B), a molecule produced by the fungus Penicillium citrinum, as an inhibitor of HMG-CoA reductase, a critical enzyme used by the body to produce cholesterol. Animal trials showed very good inhibitory effect as in clinical trials, however a long-term study in dogs found toxic effects at higher doses and as a result mevastatin was believed to be too toxic for human use. Mevastatin was never marketed, because of its adverse effects of tumors, muscle deterioration, and sometimes death in laboratory dogs.


title: Pharmaceutical industry

text: P. Roy Vagelos, chief scientist and later CEO of Merck & Co, was interested, and made several trips to Japan starting in 1975. By 1978, Merck had isolated lovastatin (mevinolin, MK803) from the fungus "Aspergillus terreus", first marketed in 1987 as Mevacor.


title: Pharmaceutical industry

text: In April 1994, the results of a Merck-sponsored study, the Scandinavian Simvastatin Survival Study, were announced. Researchers tested simvastatin, later sold by Merck as Zocor, on 4,444 patients with high cholesterol and heart disease. After five years, the study concluded the patients saw a 35% reduction in their cholesterol, and their chances of dying of a heart attack were reduced by 42%. In 1995, Zocor and Mevacor both made Merck over US$1 billion. Endo was awarded the 2006 Japan Prize, and the Lasker-DeBakey Clinical Medical Research Award in 2008. For his "pioneering research into a new class of molecules" for "lowering cholesterol,"


title: Pharmaceutical industry

text: Since several decades, biologics have been rising in importance in comparison with small molecules treatments. The biotech subsector, animal health and the Chinese pharmaceutical sector have also grown substantially. On the organisational side, big international pharma corporations have experienced a substantial decline of their value share. Also, the core generic sector (substitutions for off-patent brands) has been downvalued due to competition.


title: Pharmaceutical industry

text: Drug discovery is the process by which potential drugs are discovered or designed. In the past, most drugs have been discovered either by isolating the active ingredient from traditional remedies or by serendipitous discovery. Modern biotechnology often focuses on understanding the metabolic pathways related to a disease state or pathogen, and manipulating these pathways using molecular biology or biochemistry. A great deal of early-stage drug discovery has traditionally been carried out by universities and research institutions.


title: Pharmaceutical industry

text: Drug development refers to activities undertaken after a compound is identified as a potential drug in order to establish its suitability as a medication. Objectives of drug development are to determine appropriate formulation and dosing, as well as to establish safety. Research in these areas generally includes a combination of "in vitro" studies, "in vivo" studies, and clinical trials. The cost of late stage development has meant it is usually done by the larger pharmaceutical companies. The pharmaceuticals and biotechnology industry spends more than 15% of its net sales for Research & Development which is in comparison with other industries by far the highest share.


title: Pharmaceutical industry

text: Often, large multinational corporations exhibit vertical integration, participating in a broad range of drug discovery and development, manufacturing and quality control, marketing, sales, and distribution. Smaller organizations, on the other hand, often focus on a specific aspect such as discovering drug candidates or developing formulations. Often, collaborative agreements between research organizations and large pharmaceutical companies are formed to explore the potential of new drug substances. More recently, multi-nationals are increasingly relying on contract research organizations to manage drug development.


title: Pharmaceutical industry

text: Drug discovery and development are very expensive; of all compounds investigated for use in humans only a small fraction are eventually approved in most nations by government-appointed medical institutions or boards, who have to approve new drugs before they can be marketed in those countries. In 2010 18 NMEs (New Molecular Entities) were approved and three biologics by the FDA, or 21 in total, which is down from 26 in 2009 and 24 in 2008. On the other hand, there were only 18 approvals in total in 2007 and 22 back in 2006. Since 2001, the Center for Drug Evaluation and Research has averaged 22.9 approvals a year.


title: Pharmaceutical industry

text: This approval comes only after heavy investment in pre-clinical development and clinical trials, as well as a commitment to ongoing safety monitoring. Drugs which fail part-way through this process often incur large costs, while generating no revenue in return. If the cost of these failed drugs is taken into account, the cost of developing a successful new drug (new chemical entity, or NCE), has been estimated at US$1.3 billion (not including marketing expenses). Professors Light and Lexchin reported in 2012, however, that the rate of approval for new drugs has been a relatively stable average rate of 15 to 25 for decades.


title: Pharmaceutical industry

text: Industry-wide research and investment reached a record $65.3 billion in 2009. While the cost of research in the U.S. was about 34.2 billion between 1995 and 2010, revenues rose faster (revenues rose by 200.4 billion in that time).


title: Pharmaceutical industry

text: A study by the consulting firm Bain & Company reported that the cost for discovering, developing and launching (which factored in marketing and other business expenses) a new drug (along with the prospective drugs that fail) rose over a five-year period to nearly $1.7 billion in 2003. According to Forbes, by 2010 development costs were between $4 billion to $11 billion per drug.


title: Pharmaceutical industry

text: Some of these estimates also take into account the opportunity cost of investing capital many years before revenues are realized (see Time-value of money). Because of the very long time needed for discovery, development, and approval of pharmaceuticals, these costs can accumulate to nearly half the total expense. A direct consequence within the pharmaceutical industry value chain is that major pharmaceutical multinationals tend to increasingly outsource risks related to fundamental research, which somewhat reshapes the industry ecosystem with biotechnology companies playing an increasingly important role, and overall strategies being redefined accordingly. Some approved drugs, such as those based on re-formulation of an existing active ingredient (also referred to as Line-extensions) are much less expensive to develop.


title: Pharmaceutical industry

text: In the United States, new pharmaceutical products must be approved by the Food and Drug Administration (FDA) as being both safe and effective. This process generally involves submission of an Investigational New Drug filing with sufficient pre-clinical data to support proceeding with human trials. Following IND approval, three phases of progressively larger human clinical trials may be conducted. Phase I generally studies toxicity using healthy volunteers. Phase II can include pharmacokinetics and dosing in patients, and Phase III is a very large study of efficacy in the intended patient population. Following the successful completion of phase III testing, a New Drug Application is submitted to the FDA. The FDA reviews the data and if the product is seen as having a positive benefit-risk assessment, approval to market the product in the US is granted.


title: Pharmaceutical industry

text: A fourth phase of post-approval surveillance is also often required due to the fact that even the largest clinical trials cannot effectively predict the prevalence of rare side-effects. Postmarketing surveillance ensures that after marketing the safety of a drug is monitored closely. In certain instances, its indication may need to be limited to particular patient groups, and in others the substance is withdrawn from the market completely.


title: Pharmaceutical industry

text: In the UK, the Medicines and Healthcare products Regulatory Agency approves and evaluates drugs for use. Normally an approval in the UK and other European countries comes later than one in the USA. Then it is the National Institute for Health and Care Excellence (NICE), for England and Wales, who decides if and how the National Health Service (NHS) will allow (in the sense of paying for) their use. The British National Formulary is the core guide for pharmacists and clinicians.


title: Pharmaceutical industry

text: In many non-US western countries, a 'fourth hurdle' of cost effectiveness analysis has developed before new technologies can be provided. This focuses on the 'efficacy price tag' (in terms of, for example, the cost per QALY) of the technologies in question. In England and Wales NICE decides whether and in what circumstances drugs and technologies will be made available by the NHS, whilst similar arrangements exist with the Scottish Medicines Consortium in Scotland, and the Pharmaceutical Benefits Advisory Committee in Australia. A product must pass the threshold for cost-effectiveness if it is to be approved. Treatments must represent 'value for money' and a net benefit to society.


title: Pharmaceutical industry

text: There are special rules for certain rare diseases ("orphan diseases") in several major drug regulatory territories. For example, diseases involving fewer than 200,000 patients in the United States, or larger populations in certain circumstances are subject to the Orphan Drug Act. Because medical research and development of drugs to treat such diseases is financially disadvantageous, companies that do so are rewarded with tax reductions, fee waivers, and market exclusivity on that drug for a limited time (seven years), regardless of whether the drug is protected by patents.


title: Pharmaceutical industry

text: In 2011, global spending on prescription drugs topped $954 billion, even as growth slowed somewhat in Europe and North America. The United States accounts for more than a third of the global pharmaceutical market, with $340 billion in annual sales followed by the EU and Japan. Emerging markets such as China, Russia, South Korea and Mexico outpaced that market, growing a huge 81 percent.


title: Pharmaceutical industry

text: The top ten best-selling drugs of 2013 totaled $75.6 billion in sales, with the anti-inflammatory drug Humira being the best-selling drug worldwide at $10.7 billion in sales. The second and third best selling were Enbrel and Remicade, respectively. The top three best-selling drugs in the United States in 2013 were Abilify ($6.3 billion,) Nexium ($6 billion) and Humira ($5.4 billion). The best-selling drug ever, Lipitor, averaged $13 billion annually and netted $141 billion total over its lifetime before Pfizer's patent expired in November 2011.


title: Pharmaceutical industry

text: IMS Health publishes an analysis of trends expected in the pharmaceutical industry in 2007, including increasing profits in most sectors despite loss of some patents, and new 'blockbuster' drugs on the horizon.


title: Pharmaceutical industry

text: Depending on a number of considerations, a company may apply for and be granted a patent for the drug, or the process of producing the drug, granting exclusivity rights typically for about 20 years. However, only after rigorous study and testing, which takes 10 to 15 years on average, will governmental authorities grant permission for the company to market and sell the drug. Patent protection enables the owner of the patent to recover the costs of research and development through high profit margins for the branded drug. When the patent protection for the drug expires, a generic drug is usually developed and sold by a competing company. The development and approval of generics is less expensive, allowing them to be sold at a lower price. Often the owner of the branded drug will introduce a generic version before the patent expires in order to get a head start in the generic market. Restructuring has therefore become routine, driven by the patent expiration of products launched during the industry's "golden era" in the 1990s and companies' failure to develop sufficient new blockbuster products to replace lost revenues.


title: Pharmaceutical industry

text: In the U.S., the value of prescriptions increased over the period of 1995 to 2005 by 3.4 billion annually, a 61 percent increase. Retail sales of prescription drugs jumped 250 percent from $72 billion to $250 billion, while the average price of prescriptions more than doubled from $30 to $68.


title: Pharmaceutical industry

text: Advertising is common in healthcare journals as well as through more mainstream media routes. In some countries, notably the US, they are allowed to advertise directly to the general public. Pharmaceutical companies generally employ salespeople (often called 'drug reps' or, an older term, 'detail men') to market directly and personally to physicians and other healthcare providers. In some countries, notably the US, pharmaceutical companies also employ lobbyists to influence politicians. Marketing of prescription drugs in the US is regulated by the federal Prescription Drug Marketing Act of 1987. The pharmaceutical marketing plan incorporates the spending plans, channels, and thoughts which will take the drug association, and its items and administrations, forward in the current scene.


title: Pharmaceutical industry

text: The book "Bad Pharma" also discusses the influence of drug representatives, how ghostwriters are employed by the drug companies to write papers for academics to publish, how independent the academic journals really are, how the drug companies finance doctors' continuing education, and how patients' groups are often funded by industry.


title: Pharmaceutical industry

text: Since the 1980s, new methods of marketing for prescription drugs to consumers have become important. Direct-to-consumer media advertising was legalised in the FDA Guidance for Industry on Consumer-Directed Broadcast Advertisements.


title: Pharmaceutical industry

text: There has been increasing controversy surrounding pharmaceutical marketing and influence. There have been accusations and findings of influence on doctors and other health professionals through drug reps including the constant provision of marketing 'gifts' and biased information to health professionals; highly prevalent advertising in journals and conferences; funding independent healthcare organizations and health promotion campaigns; lobbying physicians and politicians (more than any other industry in the US); sponsorship of medical schools or nurse training; sponsorship of continuing educational events, with influence on the curriculum; and hiring physicians as paid consultants on medical advisory boards.


title: Pharmaceutical industry

text: Some advocacy groups, such as No Free Lunch and AllTrials, have criticized the effect of drug marketing to physicians because they say it biases physicians to prescribe the marketed drugs even when others might be cheaper or better for the patient.


title: Pharmaceutical industry

text: There have been related accusations of disease mongering (over-medicalising) to expand the market for medications. An inaugural conference on that subject took place in Australia in 2006. In 2009, the Government-funded National Prescribing Service launched the "Finding Evidence – Recognising Hype" program, aimed at educating GPs on methods for independent drug analysis.


title: Pharmaceutical industry

text: Meta-analyses have shown that psychiatric studies sponsored by pharmaceutical companies are several times more likely to report positive results, and if a drug company employee is involved the effect is even larger. Influence has also extended to the training of doctors and nurses in medical schools, which is being fought.


title: Pharmaceutical industry

text: It has been argued that the design of the Diagnostic and Statistical Manual of Mental Disorders and the expansion of the criteria represents an increasing medicalization of human nature, or "disease mongering", driven by drug company influence on psychiatry. The potential for direct conflict of interest has been raised, partly because roughly half the authors who selected and defined the DSM-IV psychiatric disorders had or previously had financial relationships with the pharmaceutical industry.


title: Pharmaceutical industry

text: In the US, starting in 2013, under the Physician Financial Transparency Reports (part of the Sunshine Act), the Centers for Medicare & Medicaid Services has to collect information from applicable manufacturers and group purchasing organizations in order to report information about their financial relationships with physicians and hospitals. Data are made public in the Centers for Medicare & Medicaid Services website. The expectation is that relationship between doctors and Pharmaceutical industry will become fully transparent.


title: Pharmaceutical industry

text: In a report conducted by OpenSecrets, there were more than 1,100 lobbyists working in some capacity for the pharmaceutical business in 2017. In the first quarter of 2017, the health products and pharmaceutical industry spent $78 million on lobbying members of the United States Congress.


title: Pharmaceutical industry

text: It has been argued that the pricing of pharmaceuticals is becoming a major challenge for health systems.


title: Pharmaceutical industry

text: Ben Goldacre has argued that regulators – such as the Medicines and Healthcare products Regulatory Agency (MHRA) in the UK, or the Food and Drug Administration (FDA) in the United States – advance the interests of the drug companies rather than the interests of the public due to revolving door exchange of employees between the regulator and the companies and friendships develop between regulator and company employees. He argues that regulators do not require that new drugs offer an improvement over what is already available, or even that they be particularly effective.


title: Pharmaceutical industry

text: Others have argued that excessive regulation suppresses therapeutic innovation and that the current cost of regulator-required clinical trials prevents the full exploitation of new genetic and biological knowledge for the treatment of human disease. A 2012 report by the President's Council of Advisors on Science and Technology made several key recommendations to reduce regulatory burdens to new drug development, including 1) expanding the FDA's use of accelerated approval processes, 2) creating an expedited approval pathway for drugs intended for use in narrowly defined populations, and 3) undertaking pilot projects designed to evaluate the feasibility of a new, adaptive drug approval process.


title: Pharmaceutical industry

text: Pharmaceutical fraud involves deceptions which bring financial gain to a pharmaceutical company. It affects individuals and public and private insurers. There are several different schemes used to defraud the health care system which are particular to the pharmaceutical industry. These include: Good Manufacturing Practice (GMP) Violations, Off Label Marketing, Best Price Fraud, CME Fraud, Medicaid Price Reporting, and Manufactured Compound Drugs. Of this amount $2.5 billion was recovered through "False Claims Act" cases in FY 2010. Examples of fraud cases include the GlaxoSmithKline $3 billion settlement, Pfizer $2.3 billion settlement and Merck & Co. $650 million settlement. Damages from fraud can be recovered by use of the False Claims Act, most commonly under the "qui tam" provisions which rewards an individual for being a "whistleblower", or relator (law).


title: Pharmaceutical industry

text: Every major company selling atypical antipsychotics—Bristol-Myers Squibb, Eli Lilly and Company, Pfizer, AstraZeneca and Johnson & Johnson—has either settled recent government cases, under the False Claims Act, for hundreds of millions of dollars or is currently under investigation for possible health care fraud. Following charges of illegal marketing, two of the settlements set records in 2009 for the largest criminal fines ever imposed on corporations. One involved Eli Lilly's antipsychotic Zyprexa, and the other involved Bextra, an anti-inflammatory medication used for arthritis. In the Bextra case, the government also charged Pfizer with illegally marketing another antipsychotic, Geodon; Pfizer settled that part of the claim for $301 million, without admitting any wrongdoing.


title: Pharmaceutical industry

text: On 2 July 2012, GlaxoSmithKline pleaded guilty to criminal charges and agreed to a $3 billion settlement of the largest health-care fraud case in the U.S. and the largest payment by a drug company. The settlement is related to the company's illegal promotion of prescription drugs, its failure to report safety data, bribing doctors, and promoting medicines for uses for which they were not licensed. The drugs involved were Paxil, Wellbutrin, Advair, Lamictal, and Zofran for off-label, non-covered uses. Those and the drugs Imitrex, Lotronex, Flovent, and Valtrex were involved in the kickback scheme.


title: Pharmaceutical industry

text: The following is a list of the four largest settlements reached with pharmaceutical companies from 1991 to 2012, rank ordered by the size of the total settlement. Legal claims against the pharmaceutical industry have varied widely over the past two decades, including Medicare and Medicaid fraud, off-label promotion, and inadequate manufacturing practices.


title: Pharmaceutical industry

text: In May 2015, the New England Journal of Medicine emphasized the importance of pharmaceutical industry-physician interactions for the development of novel treatments, and argued that moral outrage over industry malfeasance had unjustifiably led many to overemphasize the problems created by financial conflicts of interest. The article noted that major healthcare organizations, such as National Center for Advancing Translational Sciences of the National Institutes of Health, the President's Council of Advisors on Science and Technology, the World Economic Forum, the Gates Foundation, the Wellcome Trust, and the Food and Drug Administration had encouraged greater interactions between physicians and industry in order to improve benefits to patients.


title: Pharmaceutical industry

text: In November 2020 several pharmaceutical companies announced successful trials of COVID-19 vaccines, with efficacy


title: Pharmaceutical industry

text: of 90 to 95% in preventing infection. Per company announcements and data reviewed by external analysts, these vaccines are priced at $3 to $37 per dose. The Wall Street Journal ran an editorial calling for this achievement to be recognized with a Nobel Peace Prize.


title: Pharmaceutical industry

text: Doctors Without Borders warned that high prices and monopolies on medicines, tests, and vaccines would prolong the pandemic and cost lives. They urged governments to prevent profiteering, using compulsory licenses as needed, as had already been done by Canada, Chile, Ecuador, Germany, and Israel.


title: Pharmaceutical industry

text: On 20 February, 46 US lawmakers called for the US government not to grant monopoly rights when giving out taxpayer development money for any coronavirus vaccines and treatments, to avoid giving exclusive control of prices and availability to private manufacturers.


title: Pharmaceutical industry

text: In the United States the government signed agreements in which research and development and/or the building of manufacturing plants for potential COVID-19 therapeutics was subsidized. Typically, the agreement involved the government taking ownership of a certain number of doses of the product without further payment. For example, under the auspices of Operation Warp Speed in the United States, the government subsidized research related to COVID-19 vaccines and therapeutics at Regeneron, Johnson and Johnson, Moderna, AstraZeneca, Novavax, Pfizer, and GSK. Typical terms involved research subsidies of $400 million to $2 billion, and included government ownership of the first 100 million doses of any COVID-19 vaccine successfully developed.


title: Pharmaceutical industry

text: American pharmaceutical company Gilead sought and obtained orphan drug status for remdesivir from the US Food and Drug Administration (FDA) on 23 March 2020. This provision is intended to encourage the development of drugs affecting fewer than 200,000 Americans by granting strengthened and extended legal monopoly rights to the manufacturer, along with waivers on taxes and government fees. Remdesivir is a candidate for treating COVID-19; at the time the status was granted, fewer than 200,000 Americans had COVID-19, but numbers were climbing rapidly as the COVID-19 pandemic reached the US, and crossing the threshold soon was considered inevitable. Remdesivir was developed by Gilead with over $79 million in U.S. government funding. In May 2020, Gilead announced that it would provide the first 940,000 doses of remdesivir to the federal government free of charge. After facing strong public reactions, Gilead gave up the "orphan drug" status for remdesivir on 25 March. Gilead retains 20-year remdesivir patents in more than 70 countries. In May 2020, the company further announced that it was in discussions with several generics companies to provide rights to produce remdesivir for developing countries, and with the Medicines Patent Pool to provide broader generic access.


title: Pharmaceutical industry

text: Patents have been criticized in the developing world, as they are thought to reduce access to existing medicines. Reconciling patents and universal access to medicine would require an efficient international policy of price discrimination. Moreover, under the TRIPS agreement of the World Trade Organization, countries must allow pharmaceutical products to be patented. In 2001, the WTO adopted the Doha Declaration, which indicates that the TRIPS agreement should be read with the goals of public health in mind, and allows some methods for circumventing pharmaceutical monopolies: via compulsory licensing or parallel imports, even before patent expiration.


title: Pharmaceutical industry

text: In March 2001, 40 multi-national pharmaceutical companies brought litigation against South Africa for its Medicines Act, which allowed the generic production of antiretroviral drugs (ARVs) for treating HIV, despite the fact that these drugs were on-patent. HIV was and is an epidemic in South Africa, and ARVs at the time cost between US$10,000 and US$15,000 per patient per year. This was unaffordable for most South African citizens, and so the South African government committed to providing ARVs at prices closer to what people could afford. To do so, they would need to ignore the patents on drugs and produce generics within the country (using a compulsory license), or import them from abroad. After international protest in favour of public health rights (including the collection of 250,000 signatures by Médecins Sans Frontières), the governments of several developed countries (including The Netherlands, Germany, France, and later the US) backed the South African government, and the case was dropped in April of that year.


title: Pharmaceutical industry

text: In 2016, GlaxoSmithKline (the world's sixth largest pharmaceutical company) announced that it would be dropping its patents in poor countries so as to allow independent companies to make and sell versions of its drugs in those areas, thereby widening the public access to them. GlaxoSmithKline published a list of 50 countries they would no longer hold patents in, affecting one billion people worldwide.


title: Pharmaceutical industry

text: In 2011 four of the top 20 corporate charitable donations and eight of the top 30 corporate charitable donations came from pharmaceutical manufacturers. The bulk of corporate charitable donations (69% as of 2012) comes by way of non-cash charitable donations, the majority of which again were donations contributed by pharmaceutical companies.


title: Hell's Kitchen (American season 20)

text: The twentieth season of the American competitive reality television series "Hell's Kitchen" (subtitled as Hell's Kitchen: Young Guns) premiered on Fox on May 31, 2021. Gordon Ramsay returned as host and head chef, while season 10 winner Christina Wilson returned to serve as red team sous-chef and season seven runner-up Jason Santos returned to serve as blue team sous-chef.


title: Hell's Kitchen (American season 20)

text: The season was won by executive chef Trenton Garvey, with line cook Megan Gill finishing second and head chef Kiya Willhelm placing third.


title: Hell's Kitchen (American season 20)

text: On February 26, 2019, it was announced that the series had been renewed for a nineteenth and twentieth season. Both seasons were filmed in 2019 (prior to the COVID-19 pandemic) at a television studio a short distance from the actual Hell's Kitchen restaurant in Las Vegas, Nevada. On April 7, 2021, it was announced that the twentieth season would premiere on May 31, 2021.


title: Mia Tyler

text: Mia Abagale Tallarico (born December 22, 1978), better known as Mia Tyler, is an American actress, model, media personality and socialite.


title: Mia Tyler

text: Tyler is the daughter of rock singer Steven Tyler of the band Aerosmith and actress Cyrinda Foxe. She was born at Alice Peck Day Hospital in Lebanon, New Hampshire, and raised nearby, primarily by Lake Sunapee. She is the paternal half-sister of actress Liv Tyler (whose mother is model and singer Bebe Buell). In 1979, Steven Tyler wrote a song titled after Mia, which was released on the Aerosmith album "Night in the Ruts".


title: Mia Tyler

text: Tyler's parents divorced in 1987, and by 1990 she and her mother relocated from New Hampshire to New York City. Her mother died in 2002 of a brain tumor (diagnosed in 1997).


title: Mia Tyler

text: At age 17, Tyler appeared as a VJ on the MTV show "House of Style". Primarily a fashion model, she has been represented by the modeling agency Wilhelmina Models. She has appeared in such elite magazines as "Seventeen", "Teen", "Teen People", "Mode", "Us", "Jump", "YM", "Moxie Girl", "Vogue" and on the cover of "Flare". She modeled for H&M, MXM], Penningtons and Lane Bryant. She has also appeared on the runways of New York and Paris.


title: Mia Tyler

text: In 2005 Tyler was a member of the VH1 reality show "Celebrity Fit Club", and featured in "Really Rich Real Estate", also on VH1, in 2006. In March 2009, Tyler was a judge on "Pretty Wicked", a reality show that airs on the Oxygen network.


title: Mia Tyler

text: She has had a few acting roles, including Marsha in "Rush Hour 3", and in "A Little Bit of Lipstick".


title: Mia Tyler

text: Tyler along with Steven both appeared in the Season 13 episode of "Hell's Kitchen" as chef's table guests in the red kitchen.


title: Mia Tyler

text: In 2002, Tyler married ex-Papa Roach drummer Dave Buckner in Sacramento, California; the two were divorced in 2005. She was also engaged to guitarist Brian Harrah, but the couple broke up in 2008. Mia gave birth on May 10, 2017, to Axton Joseph Tallarico, who is the son of her boyfriend Dan Halen.


title: Matilda (novel)

text: Matilda is a children's novel written by British writer Roald Dahl and illustrated by Quentin Blake. It was published in 1988 by Jonathan Cape. The story features Matilda Wormwood, a precocious child with uncaring parents, and her time in school run by the tyrannical headmistress Miss Trunchbull.


title: Matilda (novel)

text: The book has been adapted in various media, including as an audio reading by actress Kate Winslet, a 1996 feature film directed by Danny DeVito, a two-part BBC Radio 4 programme, and a 2010 musical which has run on the West End in London, Broadway in New York, and around the world. A film adaptation of the musical was released in 2022.


title: Matilda (novel)

text: In 2003, "Matilda" was listed at number 74 in "The Big Read", a BBC survey of the British public of the top 200 novels of all time. In 2012, "Matilda" was ranked number 30 among all-time best children's novels in a survey published by "School Library Journal", a US monthly. "Time" magazine named "Matilda" in its list of the 100 Best Young-Adult Books of All Time. In 2012, Matilda Wormwood appeared on a Royal Mail commemorative postage stamp.


title: Matilda (novel)

text: In a small Buckinghamshire village forty minutes by bus away from Reading and 8 miles from Aylesbury, Matilda Wormwood is born to Mr and Mrs Wormwood. She immediately shows amazing precocity, learning to speak at age one and to read at age three and a half, perusing all the children's books in the library by the age of four and three months and moving on to longer classics such as "Great Expectations" and "Jane Eyre". However, her parents emotionally abuse her and completely refuse to acknowledge her abilities; to keep from getting frustrated, Matilda finds herself forced to pull pranks on them, such as gluing her father's hat to his head, sticking a parrot in the chimney to simulate a burglar or ghost, and bleaching her father's hair with peroxide.


title: Matilda (novel)

text: At the age of five and a half, Matilda enters school and befriends her teacher Jennifer Honey, who is astonished by her intellectual abilities. Miss Honey tries to move Matilda into a higher class, but the tyrannical headmistress, Miss Agatha Trunchbull, refuses. Miss Honey also tries to talk to Mr and Mrs Wormwood about their daughter's intelligence, but they ignore her, with the mother contending "brainy-ness" is an undesirable trait in a little girl.


title: Matilda (novel)

text: Miss Trunchbull later confronts a girl called Amanda Thripp for wearing pigtails (the headmistress repeatedly displays a dislike of long hair throughout the book) and does a hammer throw with the girl over the playground fence. A boy called Bruce Bogtrotter is later caught by the cook stealing a piece of Miss Trunchbull's cake; the headmistress makes him attempt to eat an 18 in (45 cm) wide cake in front of the assembly, then smashes the platter over his head in rage after he unexpectedly succeeds.


title: Matilda (novel)

text: Matilda quickly develops a particularly strong bond with Miss Honey and watches as Trunchbull terrorises her students with deliberately creative, over-the-top punishments to prevent parents from believing them, such as throwing them in a dark closet dubbed "The Chokey", which is lined with nails and broken glass. When Matilda's friend Lavender plays a practical joke on Trunchbull by placing a newt in her jug of water, Matilda is blamed; in anger, she uses an unexpected power of telekinesis to tip the glass of water containing the newt onto Trunchbull.


title: Matilda (novel)

text: Matilda reveals her new powers to Miss Honey, who confides that after her wealthy father, Dr Magnus Honey, suspiciously died, she was raised by an abusive aunt, revealed to be Miss Trunchbull. Trunchbull appears, among other misdeeds, to be withholding her niece's inheritance; Miss Honey has to live in poverty in a derelict farm cottage, and her salary is being paid into Miss Trunchbull's bank account for the first 10 years of her teaching career while she is restricted to £1 per week in pocket money. Preparing to avenge Miss Honey, Matilda practises her telekinesis at home. Later, during a sadistic lesson that Miss Trunchbull is teaching, Matilda telekinetically raises a piece of chalk to the blackboard and begins to use it to write, posing as the spirit of Magnus Honey. Addressing Miss Trunchbull using her first name (Agatha), "Magnus" demands that Miss Trunchbull hand over Miss Honey's house and wages and leave the school, causing Miss Trunchbull to faint.


title: Matilda (novel)

text: The next day, the school's deputy headmaster, Mr Trilby, visits Trunchbull's house and finds it empty, except for signs of Trunchbull's hasty exit. She is never seen again, and the next day Miss Honey receives a letter from a local solicitor's office, telling her that her father's lifetime savings were safe in her bank and the property she lived in as a child was left to her. Trilby becomes the new headmaster, proving himself to be capable and good-natured, overwhelmingly improving the school's atmosphere and curriculum, and quickly moving Matilda into the top-form class with the 11-year-olds. Rather to Matilda's relief, she soon is no longer capable of telekinesis. Miss Honey theorises this is because Matilda is using her brainpower on a more challenging curriculum, leaving less of her brain's enormous energy free.


title: Matilda (novel)

text: Matilda continues to visit Miss Honey at her house regularly, returning home one day to find her parents and her older brother Michael hastily packing to leave for Spain. Miss Honey explains this is because the police found out Mr Wormwood has been selling stolen cars. Matilda asks permission to live with Miss Honey, to which her parents rather distractedly agree. Matilda and Miss Honey find their happy ending, as the Wormwoods drive away, never to be seen again.


title: Matilda (novel)

text: In 2003, "Matilda" was listed at number 74 in "The Big Read", a BBC poll of the British public of the top 200 novels of all time. In 2012 "Matilda" was ranked number 30 on a list of the top 100 children's novels published by "School Library Journal", a monthly with primarily US audience. It was the first of four books by Dahl among the Top 100, more than any other writer. "Time" magazine included "Matilda" in its list of the 100 Best Young-Adult Books of All Time. Worldwide sales have reached 17 million, and since 2016 sales have spiked to the extent that it outsells Dahl's other works.


title: Matilda (novel)

text: The "mean and loathsome" Mrs Pratchett, owner of the sweet shop Dahl frequented as a boy in Cardiff, inspired Dahl's creation of Miss Trunchbull. Mr Wormwood was based on a real-life character from Dahl's home village of Great Missenden in Buckinghamshire. The library in Great Missenden was the inspiration for Mrs Phelps's library, where Matilda devours classic literature by the age of four and three months.


title: Matilda (novel)

text: The novel was made into the film "Matilda" in 1996. It starred Mara Wilson as Matilda, and was directed by Danny DeVito, who also portrayed Mr Wormwood and narrated the story. The film changed the setting and nationality of every character (except Trunchbull who is played by Welsh actress Pam Ferris) from British to American. Although not a commercial success, it received critical acclaim at the time of its release, and on Rotten Tomatoes has a score of 90% based on reviews from 21 critics.


title: Matilda (novel)

text: The English actress Kate Winslet provides the English-language audiobook recording of "Matilda". In 2014, the American Library Association shortlisted her for an Odyssey Award for her audiobook performance.


title: Matilda (novel)

text: In 1990, the Redgrave Theatre in Farnham produced a musical version, adapted by Rony Robinson with music by Ken Howard and Alan Blaikley, which toured the UK. It starred Annabelle Lanyon as Matilda and Jonathan Linsley as Miss Trunchbull and had mixed reviews.


title: Matilda (novel)

text: A second musical version of the novel, "Matilda the Musical", written by Dennis Kelly and Tim Minchin and commissioned by the Royal Shakespeare Company, premiered in November 2010. It opened at the Cambridge Theatre in the West End on 24 November 2011. It opened on Broadway on 11 April 2013 at the Shubert Theatre. The musical has since done a US tour and opened in July 2015 in Australia. The stage version has become hugely popular with audiences and praised by critics, and won multiple Olivier Awards in the UK and Tony Awards in the US. One critic called it "the best British musical since "Billy Elliot"".


title: Matilda (novel)

text: In December 2009, BBC Radio 4's "Classic Serial" broadcast a two-part adaptation by Charlotte Jones of the novel with Lenny Henry as the Narrator, Lauren Mote as Matilda, Nichola McAuliffe as Miss Trunchbull, Emerald O'Hanrahan as Miss Honey, Claire Rushbrook as Mrs. Wormwood and John Biggins as Mr. Wormwood.


title: Matilda (novel)

text: On 27 November 2018, Netflix was revealed to be adapting "Matilda" as an animated series, which will be part of an "animated event series" along with other Roald Dahl books such as "The BFG", "The Twits", and "Charlie and the Chocolate Factory". A film adaptation of the musical was released by Sony Pictures Releasing and Netflix in 2022. It stars Alisha Weir as Matilda and Emma Thompson as Miss Trunchbull. It is directed by Matthew Warchus.


title: Matilda (novel)

text: Celebrating 30 years of the book's publication in October 2018, original illustrator Quentin Blake imagined what Matilda might be doing as a grown-up woman today. He drew images of her undertaking three possible roles: an explorer, an astrophysicist, and a librarian at the British Library.


title: Matilda (novel)

text: One of Miss Trunchbull's punishments is to force an overweight child, Bruce Bogtrotter, to eat an enormous chocolate cake, which makes him so full that he cannot move. The cook had caught him stealing a piece of cake from the kitchen. In "Roald Dahl's Revolting Recipes" one of the recipes is based on that cake; whereas Bruce is a more sympathetic variation of Augustus Gloop (from "Charlie and the Chocolate Factory") and similar gluttons, and made something of a hero by finishing the cake without suffering nausea. The short story "The Magic Finger" by Roald Dahl, released in 1966, may have been a precursor to "Matilda". A young girl has power within her finger to do things to other people when she gets emotional about a cause she feels strongly about.


title: Francis I, Holy Roman Emperor

text: Francis I (Francis Stephen; ; ; 8 December 1708 – 18 August 1765) was Holy Roman Emperor, Archduke of Austria, Duke of Lorraine and Bar, and Grand Duke of Tuscany. He became the ruler of the Holy Roman Empire, Austria, and Tuscany through his marriage to Maria Theresa, daughter of Emperor Charles VI. Francis was the last non-Habsburg monarch of both the Empire and Austria, which were effectively governed by Maria Theresa. The couple were the founders of the Habsburg-Lorraine dynasty, and their marriage produced sixteen children.


title: Francis I, Holy Roman Emperor

text: Francis was the fourth (but oldest surviving) son of Leopold, Duke of Lorraine, and the French princess Élisabeth Charlotte d'Orléans. Duke Leopold died in 1729, and was succeeded by his son. In 1736, Francis married Maria Theresa. In 1738, he left the Duchy of Lorraine and Bar for the deposed Polish king Stanisław Leszczyński in exchange for the Grand Duchy of Tuscany, as one of the terms ending the War of the Polish Succession. Following the death of his father-in-law Charles VI in 1740, Francis and his wife became the rulers of the Habsburg domains. Maria Theresa gave her husband responsibility for the empire's financial affairs, which he handled well. Francis' death in 1765 left Maria Theresa as sole ruler.


title: Francis I, Holy Roman Emperor

text: Francis was born in Nancy, Lorraine (now in France), the oldest surviving son of Leopold, Duke of Lorraine, and his wife Princess Élisabeth Charlotte d'Orléans. He was connected with the Habsburgs through his grandmother Eleonore, daughter of Emperor Ferdinand III. He was very close to his brother Charles and sister Anne Charlotte.


title: Francis I, Holy Roman Emperor

text: Emperor Charles VI favoured the family, who, besides being his cousins, had served the house of Austria with distinction. He had designed to marry his daughter Maria Theresa to Francis' older brother Leopold Clement. On Leopold Clement's death, Charles adopted the younger brother as his future son-in-law. Francis was brought up in Vienna with Maria Theresa with the understanding that they were to be married, and a real affection arose between them.


title: Francis I, Holy Roman Emperor

text: At the age of 15, when he was brought to Vienna, he was established in the Silesian Duchy of Teschen, which had been mediatised and granted to his father by the emperor in 1722. Francis succeeded his father as Duke of Lorraine in 1729. In 1731 he was initiated into freemasonry (Grand Lodge of England) by John Theophilus Desaguliers at a specially convened lodge in The Hague at the house of the British Ambassador, Philip Stanhope, 4th Earl of Chesterfield. During a subsequent visit to England, Francis was made a Master Mason at another specially convened lodge at Houghton Hall, the Norfolk estate of British Prime Minister Robert Walpole.


title: Francis I, Holy Roman Emperor

text: Maria Theresa arranged for Francis to become "Lord Lieutenant" (locumtenens) of Hungary in 1732. He was not excited about this position, but Maria Theresa wanted him closer to her. In June 1732 he agreed to go to the Hungarian capital, Pressburg (today's Bratislava).


title: Francis I, Holy Roman Emperor

text: When the War of the Polish Succession broke out in 1733, France used it as an opportunity to seize Lorraine, since France's prime minister, Cardinal Fleury, was concerned that, as a Habsburg possession, it would bring Austrian power too close to France.


title: Francis I, Holy Roman Emperor

text: A preliminary peace was concluded in October 1735 and ratified in the Treaty of Vienna in November 1738. Under its terms, Stanisław I, the father-in-law of King Louis XV and the losing claimant to the Polish throne, received Lorraine, while Francis, in compensation for his loss, was made heir to the Grand Duchy of Tuscany, which he would inherit in 1737.


title: Francis I, Holy Roman Emperor

text: Although fighting stopped after the preliminary peace, the final peace settlement had to wait until the death of the last Medici Grand Duke of Tuscany, Gian Gastone de' Medici in 1737, to allow the territorial exchanges provided for by the peace settlement to go into effect.


title: Francis I, Holy Roman Emperor

text: In March 1736 the Emperor persuaded Francis, his future son-in-law, to secretly exchange Lorraine for the Grand Duchy of Tuscany. France had demanded that Maria Theresa's fiancé surrender his ancestral Duchy of Lorraine to accommodate the deposed King of Poland. The Emperor considered other possibilities (such as marrying her to the future Charles III of Spain) before announcing the engagement of the couple. If something were to go wrong, Francis would become governor of the Austrian Netherlands.


title: Francis I, Holy Roman Emperor

text: Elisabeth of Parma had also wanted the Grand Duchy of Tuscany for her son Charles III of Spain; Gian Gastone de' Medici was childless and was related to Elisabeth via her great-grandmother Margherita de' Medici. As a result, Elisabeth's sons could claim by right of being a descendant of Margherita.


title: Francis I, Holy Roman Emperor

text: On 31 January 1736 Francis agreed to marry Maria Theresa. He hesitated three times (and laid down the feather before signing). Especially his mother Élisabeth Charlotte d'Orléans and his brother Prince Charles Alexander of Lorraine were against the loss of Lorraine. On 1 February, Maria Theresa sent Francis a letter: she would withdraw from her future reign, when a male successor for her father appeared.


title: Francis I, Holy Roman Emperor

text: They married on 12 February in the Augustinian Church, Vienna. The wedding was held on 14 February 1736. The (secret) treaty between the Emperor and Francis was signed on 4 May 1736. On 5 January 1737, instruments of cession were signed at Pontremoli between Spain and the Empire, with Spain ceding Parma, Piacenza and Tuscany to the Holy Roman Empire and the Empire recognizing Don Carlos of Spain as King of Naples and Sicily. On 10 January, the Spanish troops began their withdrawal from Tuscany, and were replaced by 6,000 Austrians. On 24 January 1737 Francis received Tuscany from his father-in-law. Until then, Maria Theresa was Duchess of Lorraine.


title: Francis I, Holy Roman Emperor

text: Gian Gastone de' Medici, who died on 9 July 1737, was the second cousin of Francis (Gian Gastone and Francis' father Leopold were both great-grandchildren of Francis II, Duke of Lorraine), who also had Medici blood through his maternal great-great-grandmother Marie de' Medici, Queen consort of France and Navarre. In June 1737 Francis went to Hungary again to fight against the Turks. In October 1738 he was back in Vienna. On 17 December 1738 the couple travelled south, accompanied by his brother Charles to visit Florence for three months. They arrived on 20 January 1739.


title: Francis I, Holy Roman Emperor

text: In 1744 Francis' brother Charles married a younger sister of Maria Theresa, Archduchess Maria Anna of Austria. In 1744 Charles became governor of the Austrian Netherlands, a post he held until his death in 1780.


title: Francis I, Holy Roman Emperor

text: In the Treaty of Füssen, Maria Theresa secured his election as Emperor, which took place on 13 September 1745. He succeeded Charles VII, and she made him co-regent of her hereditary dominions.


title: Francis I, Holy Roman Emperor

text: Francis was well content to leave the wielding of power to his able wife. He had a natural fund of good sense and brilliant business capacity and was a useful assistant to Maria Theresa in the laborious task of governing the complicated Austrian dominions, but he was not active in politics or diplomacy. However, his wife left him in charge of the financial affairs, which he managed well until his death. Heavily indebted and on the verge of bankruptcy at the end of the Seven Years' War, the Austrian Empire was in a better financial condition than France or Great Britain in the 1780s. He also took a great interest in the natural sciences.


title: Francis I, Holy Roman Emperor

text: Francis was a serial adulterer; many of his affairs well-known and indiscreet, notably one with Princess Maria Wilhelmina of Auersperg, who was thirty years his junior. This particular affair was remarked upon in the letters and journals of visitors to the court and in those of his children.


title: Francis I, Holy Roman Emperor

text: He died suddenly in his carriage while returning from the opera at Innsbruck on 18 August 1765. He is buried in tomb number 55 in the Imperial Crypt in Vienna.


title: Francis I, Holy Roman Emperor

text: Maria Theresa and Francis I had sixteen children, amongst them the last pre-revolutionary queen consort of France, their youngest daughter, Marie Antoinette (1755–1793). Francis was succeeded as Emperor by his eldest son, Joseph II, and as Grand Duke of Tuscany by his younger son, Peter Leopold (later Emperor Leopold II). Maria Theresa retained the government of her dominions until her own death in 1780.


title: Hectare

text: The hectare (; SI symbol: ha) is a non-SI metric unit of area equal to a square with 100-metre sides (1 hm), or 10,000 m, and is primarily used in the measurement of land. There are 100 hectares in one square kilometre. An acre is about and one hectare contains about .


title: Hectare

text: In 1795, when the metric system was introduced, the are was defined as 100 square metres, or one square decametre, and the hectare ("hecto-" + "are") was thus 100 "ares" or  km (10,000 square metres). When the metric system was further rationalised in 1960, resulting in the International System of Units (), the "are" was not included as a recognised unit. The hectare, however, remains as a non-SI unit accepted for use with the SI and whose use is "expected to continue indefinitely". Though the dekare/decare daa (1,000 m) and are (100 m) are not officially "accepted for use", they are still used in some contexts.


title: Hectare

text: The hectare (), although not a unit of SI, is the only named unit of area that is accepted for use with SI units. The name was coined in French, from the Latin "ārea". In practice the hectare is fully derived from the SI, being equivalent to a square hectometre. It is widely used throughout the world for the measurement of large areas of land, and it is the legal unit of measure in domains concerned with land ownership, planning, and management, including law (land deeds), agriculture, forestry, and town planning throughout the European Union and


title: Hectare

text: Some countries that underwent a general conversion from traditional measurements to metric measurements (e.g. Canada) required a resurvey when units of measure in legal descriptions relating to land were converted to metric units. Others, such as South Africa, published conversion factors which were to be used particularly "when preparing consolidation diagrams by compilation".


title: Hectare

text: In many countries, metrification redefined or clarified existing measures in terms of metric units. The following legacy units of area have been redefined as being equal to one hectare:


title: Hectare

text: The metric system of measurement was first given a legal basis in 1795 by the French Revolutionary government. The law of 18 Germinal, Year III (7 April 1795) defined five units of measure:


title: Hectare

text: In 1960, when the metric system was updated as the International System of Units (SI), the "are" did not receive international recognition. The International Committee for Weights and Measures () makes no mention of the "are" in the current (2006) definition of the SI, but classifies the hectare as a "Non-SI unit accepted for use with the International System of Units".


title: Hectare

text: In 1972, the European Economic Community (EEC) passed directive 71/354/EEC, which catalogued the units of measure that might be used within the Community. The units that were catalogued replicated the recommendations of the CGPM, supplemented by a few other units including the "are" (and implicitly the "hectare") whose use was limited to the measurement of land.


title: Hectare

text: The names "centiare", "deciare", "decare" and "hectare" are derived by adding the standard metric prefixes to the original base unit of area, the "are".


title: Hectare

text: The decimilliare (sometimes seen in cadastre area evaluation of real estate plots) is are or one square decimetre.


title: Hectare

text: The are ( or ) is a unit of area, equal to 100 square metres (), used for measuring land area. It was defined by older forms of the metric system, but is now outside the modern International System of Units (SI). It is still commonly used in speech to measure real estate, in particular in Indonesia, India, and in various European countries.


title: Hectare

text: In Russian and some other languages of the former Soviet Union, the "are" is called (: 'a hundred', i.e. 100 m or hectare). It is used to describe the size of suburban dacha or allotment garden plots or small city parks where the hectare would be too large. Many Russian dachas are 6 ares in size (in Russian, ).


title: Hectare

text: The decare or dekare () is derived from "deca" and "are", and is equal to 10 ares or 1000 square metres. It is used in Norway and in the former Ottoman areas of the Middle East and Bulgaria as a measure of land area. Instead of the name "decare", the names of traditional land measures are usually used, redefined as one decare:


title: Neutron bomb

text: A neutron bomb, officially defined as a type of enhanced radiation weapon (ERW), is a low-yield thermonuclear weapon designed to maximize lethal neutron radiation in the immediate vicinity of the blast while minimizing the physical power of the blast itself. The neutron release generated by a nuclear fusion reaction is intentionally allowed to escape the weapon, rather than being absorbed by its other components. The neutron burst, which is used as the primary destructive action of the warhead, is able to penetrate enemy armor more effectively than a conventional warhead, thus making it more lethal as a tactical weapon.


title: Neutron bomb

text: The concept was originally developed by the United States in the late 1950s and early 1960s. It was seen as a "cleaner" bomb for use against massed Soviet armored divisions. As these would be used over allied nations, notably West Germany, the reduced blast damage was seen as an important advantage.


title: Neutron bomb

text: ERWs were first operationally deployed for anti-ballistic missiles (ABMs). In this role the burst of neutrons would cause nearby warheads to undergo partial fission, preventing them from exploding properly. For this to work, the ABM would have to explode within approximately of its target. The first example of such a system was the W66, used on the Sprint missile used in the US Nike-X system. It is believed the Soviet equivalent, the A-135's 53T6 missile, uses a similar design.


title: Neutron bomb

text: The weapon was once again proposed for tactical use by the United States in the 1970s and 1980s, and production of the W70 began for the MGM-52 Lance in 1981. This time it led to protests as the growing anti-nuclear movement gained strength through this period. Opposition was so intense that European leaders refused to accept it on their territory. US President Ronald Reagan ordered the production of the W70-3, which remained in the US stockpile until they were retired in 1992. The last W70 was dismantled in February 1996.


title: Neutron bomb

text: In a standard thermonuclear design, a small fission bomb is placed close to a larger mass of thermonuclear fuel. The two components are then placed within a thick radiation case, usually made from uranium, lead or steel. The case traps the energy from the fission bomb for a brief period, allowing it to heat and compress the main thermonuclear fuel. The case is normally made of depleted uranium or natural uranium metal, because the thermonuclear reactions give off extraordinarily large numbers of high-energy neutrons that can cause fission reactions in the casing material. These can add considerable energy to the reaction; in a typical design as much as 50% of the total energy comes from fission events in the casing. For this reason, these weapons are technically known as fission-fusion-fission designs.