title: Harold Wilson

text: When Wilson entered office for the second time, he had privately admitted that he had lost his enthusiasm for the role, telling a close adviser in 1974 that "I have been around this racetrack so often that I cannot generate any more enthusiasm for jumping any more hurdles." On 16 March 1976, Wilson announced his resignation as prime minister (taking effect on 5 April). He claimed that he had always planned on resigning at the age of 60 and that he was physically and mentally exhausted. As early as the late 1960s he had been telling intimates, like his doctor Sir Joseph Stone (later Lord Stone of Hendon), that he did not intend to serve more than eight or nine years as prime minister. Roy Jenkins has suggested that Wilson may have been motivated partly by the distaste for politics felt by his loyal and long-suffering wife, Mary. His doctor had detected problems which would later be diagnosed as colon cancer, and Wilson had begun drinking brandy during the day to cope with stress. In addition, by 1976 he might already have been aware of the first stages of early-onset Alzheimer's disease, which was to cause both his formerly excellent memory and his powers of concentration to fail dramatically.


title: Harold Wilson

text: Wilson's Prime Minister's Resignation Honours included many businessmen and celebrities, along with his political supporters. His choice of appointments caused lasting damage to his reputation, worsened by the suggestion that the first draft of the list had been written by his political secretary Marcia Williams on lavender notepaper (it became known as the "Lavender List"). Roy Jenkins noted that Wilson's retirement "was disfigured by his, at best, eccentric resignation honours list, which gave peerages or knighthoods to some adventurous business gentlemen, several of whom were close neither to him nor to the Labour Party." Some of those whom Wilson honoured included Lord Kagan, the inventor of Gannex (Wilson's preferred raincoat), who was eventually imprisoned for fraud, and Sir Eric Miller, who later committed suicide while under police investigation for corruption.


title: Harold Wilson

text: The Labour Party held an election to replace Wilson as leader of the Party (and therefore prime minister). Six candidates stood in the first ballot; in order of votes they were: Michael Foot, James Callaghan, Roy Jenkins, Tony Benn, Denis Healey and Anthony Crosland. In the third ballot, on 5 April, Callaghan defeated Foot in a parliamentary vote of 176 to 137, thus becoming Wilson's successor as prime minister and leader of the Labour Party, and he continued to serve as prime minister until May 1979.


title: Harold Wilson

text: As Wilson wished to remain an MP after leaving office, he was not immediately given the peerage customarily offered to retired prime ministers, but instead was created a Knight of the Garter. Following his departure from the House of Commons before the 1983 general election, he was granted a life peerage as Baron Wilson of Rievaulx, of Kirklees in the County of West Yorkshire, after Rievaulx Abbey, in the north of his native Yorkshire, and Kirklees, the metropolitan borough which includes his hometown of Huddersfield.


title: Harold Wilson

text: He was appointed in 1976 to chair the Committee to Review the Functioning of Financial Institutions (the Wilson Committee) which reported in June 1980.


title: Harold Wilson

text: Shortly after resigning as prime minister, Wilson was signed by David Frost to host a series of interview/chat show programmes. The pilot episode proved to be a flop as Wilson appeared uncomfortable with the informality of the format. Wilson also hosted two editions of the BBC chat show "Friday Night, Saturday Morning". He famously floundered in the role, and in 2000, Channel 4 chose one of his appearances as one of the 100 Moments of TV Hell.


title: Harold Wilson

text: A lifelong Gilbert and Sullivan fan, in 1975, Wilson joined the Board of Trustees of the D'Oyly Carte Trust at the invitation of Sir Hugh Wontner, who was then the Lord Mayor of London. At Christmas 1978, Wilson appeared on the "Morecambe and Wise" Christmas Special. Eric Morecambe's habit of appearing not to recognise the guest stars was repaid by Wilson, who referred to him throughout as 'Morry-camby' (the mispronunciation of Morecambe's name made by Ed Sullivan when the pair appeared on his famous American television show). Wilson appeared on the show again in 1980.


title: Harold Wilson

text: Wilson was not especially active in the House of Lords, although he did initiate a debate on unemployment in May 1984. His last speech was in a debate on marine pilotage in 1986, when he commented as an elder brother of Trinity House. In the same year he played himself as prime minister in an Anglia Television drama, "Inside Story".


title: Harold Wilson

text: Wilson continued regularly attending the House of Lords until just over a year before his death; the last sitting he attended was on 27 April 1994. He had a picture taken with other Labour Lords on 15 June 1994, just under a year before his death. He died from colon cancer and Alzheimer's disease on 24 May 1995, aged 79. His death came five months before that of his predecessor Alec Douglas-Home.


title: Harold Wilson

text: Wilson's memorial service was held in Westminster Abbey on 13 July 1995. It was attended by the Prince of Wales, former Prime Ministers Edward Heath, James Callaghan, and Margaret Thatcher, incumbent Prime Minister John Major and also Tony Blair, then Leader of the Opposition and later Prime Minister. Wilson was buried at St Mary's Old Church, St Mary's, Isles of Scilly, on 6 June. His epitaph is "" ("Time the Commander of Things").


title: Harold Wilson

text: Wilson regarded himself as a "man of the people" and did much to promote this image, contrasting himself with the stereotypical aristocratic conservatives and other statesmen who had preceded him, as an example of social mobility. He largely retained his Yorkshire accent. Other features of this persona included his working man's Gannex raincoat, his pipe (the British Pipesmokers' Council voted him Pipe Smoker of the Year in 1965 and Pipeman of the Decade in 1976, though in private he preferred cigars), his love of simple cooking and fondness for popular British relish HP Sauce, and his support for his home town's football team, Huddersfield Town. His first general election victory relied heavily on associating these down-to-earth attributes with a sense that the UK urgently needed to modernise after "thirteen years of Tory mis-rule".


title: Harold Wilson

text: Wilson exhibited his populist touch in June 1965 when he had the Beatles honoured with the award of MBE (such awards are officially bestowed by the Queen but are nominated by the prime minister of the day). The award was popular with young people and contributed to a sense that the prime minister was "in touch" with the younger generation. There were some protests by conservatives and elderly members of the military who were earlier recipients of the award, but such protesters were in the minority. Critics claimed that Wilson acted to solicit votes for the next general election (which took place less than a year later), but defenders noted that, since the minimum voting age at that time was 21, this was hardly likely to impact many of the Beatles' fans who at that time were predominantly teenagers. It cemented Wilson's image as a modernistic leader and linked him to the burgeoning pride in the 'New Britain' typified by the Beatles. The Beatles mentioned Wilson rather negatively, naming both him and his opponent Edward Heath in George Harrison's song "Taxman", the opener to 1966's "Revolver"—recorded and released after the MBEs.


title: Harold Wilson

text: In 1967, Wilson had a different interaction with a musical ensemble. He sued the pop group the Move for libel after the band's manager Tony Secunda published a promotional postcard for the single "Flowers in the Rain", featuring a caricature depicting Wilson in bed with his female assistant, Marcia Williams. Gossip had hinted at an improper relationship, though these rumours were never substantiated. Wilson won the case, and all royalties from the song (composed by Move leader Roy Wood) were assigned in perpetuity to a charity of Wilson's choosing.


title: Harold Wilson

text: Wilson coined the term 'Selsdon Man' to refer to the free market policies of the Conservative leader Edward Heath, developed at a policy retreat held at the Selsdon Park Hotel in early 1970. This phrase, intended to evoke the 'primitive throwback' qualities of anthropological discoveries such as Piltdown Man and Swanscombe Man, was part of a British political tradition of referring to political trends by suffixing 'man'. Other memorable phrases attributed to Wilson include "the white heat of the [technological] revolution", and "a week is a long time in politics", meaning that political fortunes can change extremely rapidly. In his broadcast after the 1967 devaluation of the pound, Wilson said: "This does not mean that the pound here in Britain—in your pocket or purse—is worth any less" and the phrase "the pound in your pocket" subsequently took on a life of its own.


title: Harold Wilson

text: Despite his successes, Wilson's reputation took a long time to start a recovery from the low ebb reached immediately following his second premiership. The reinvention of the Labour Party would take the better part of two decades at the hands of Neil Kinnock, John Smith and, electorally and most conclusively, Tony Blair. Disillusion with Britain's weak economic performance and troubled industrial relations, combined with active spadework by figures such as Sir Keith Joseph, had helped to make a radical market programme politically feasible for Margaret Thatcher (which was, in turn, to influence the subsequent Labour leadership, especially under Blair). An opinion poll in September 2011 found that Wilson came in third place when respondents were asked to name the best post-war Labour Party leader. He was beaten only by John Smith and Tony Blair.


title: Harold Wilson

text: Much of the disillusionment with Harold Wilson as Labour's leader and prime minister was due to his perceived failure on the economic front. He pledged not to devalue sterling, but did exactly that in 1967; he promised to keep unemployment low, but had by 1970 accepted a higher rate of joblessness than the Conservatives had managed. Some of the elements in Labour's programme – the emphasis on steadier growth, for instance – were probably misguided. These problems and defeats have, however, obscured some of the real achievements of the period. Science and education spending grew very quickly; industrial investment rose; government was increasingly well informed and better advised about the performance of the economy. In an increasingly unstable and rapidly changing economic environment, this government's economic record is here shown to be, if not hugely impressive, then at least relatively creditable.


title: Harold Wilson

text: In 1963, Soviet defector Anatoliy Golitsyn is said to have secretly claimed that Wilson was a KGB agent. The majority of intelligence officers did not believe that Golitsyn was credible in this and various other claims, but a significant number did (most prominently James Jesus Angleton, Deputy Director of Operations for Counter-Intelligence at the U.S. Central Intelligence Agency) and factional strife broke out between the two groups. Former MI5 officer Peter Wright claimed in his memoirs, "Spycatcher", that 30 MI5 agents then collaborated in an attempt to undermine Wilson. He retracted that claim, saying there was only one man.


title: Harold Wilson

text: In March 1987, James Miller, a former agent, claimed that the Ulster Workers Council Strike of 1974 had been promoted by MI5 to help destabilise Wilson's government. In July 1987, Labour MP Ken Livingstone used his maiden speech to raise the 1975 allegations of a former Army Press officer in Northern Ireland, Colin Wallace, who also alleged a plot to destabilise Wilson. Chris Mullin MP, speaking on 23 November 1988, argued that sources other than Peter Wright supported claims of a long-standing attempt by MI5 to undermine Wilson's government.


title: Harold Wilson

text: On the BBC television programme "The Plot Against Harold Wilson", broadcast on 16 March 2006 on BBC2, it was claimed there were threats of a "coup d'état" against the Wilson government, which were corroborated by leading figures of the time on both the left and the right. Wilson told two BBC journalists, Barrie Penrose and Roger Courtiour, who recorded the meetings on a cassette tape recorder, that he feared he was being undermined by MI5. The first time was in the late 1960s after the Wilson Government devalued the pound sterling but the threat faded after Conservative leader Edward Heath won the election of 1970. However, after the 1972 British miners' strike Heath decided to hold an election to renew his mandate to govern in February 1974 but lost narrowly to Wilson. There was again talk of a military coup, with rumours of Lord Mountbatten as head of an interim administration after Wilson had been deposed. In 1974, the British Army occupied Heathrow Airport on the grounds of training for possible IRA terrorist action at the airport. Although the military stated that this was a planned military exercise, 10 Downing Street was not informed in advance, and Wilson himself interpreted it as a show of strength, or warning, being made by the army.


title: Harold Wilson

text: Historian Christopher Andrew's official history of MI5, "The Defence of the Realm: The Authorized History of MI5", included a chapter (section E part 4) specifically alluding to a conspiracy instead of a plot against Wilson in the 1970s.:


title: Harold Wilson

text: The Director-General of the Security Service assured Prime Minister Margaret Thatcher, and she told the House of Commons on 6 May 1987:


title: Harold Wilson

text: In 2009, "The Defence of the Realm" held that while MI5 kept a file on Wilson from 1945 when he became an MP—because communist civil servants claimed that he had similar political sympathies—there was no bugging of his home or office, and no conspiracy against him. In 2010 newspaper reports made detailed allegations that the Cabinet Office had required that the section on bugging of 10 Downing Street be omitted from the history for "wider public interest reasons". In 1963, on Macmillan's orders following the Profumo affair, MI5 bugged the Cabinet room, the waiting room, and the prime minister's study until the devices were removed in 1977 on Callaghan's orders. From the records, it is unclear if Wilson or Heath knew of the bugging, and no recorded conversations were retained by MI5 so possibly the bugs were never activated. Professor Andrew had previously recorded in the preface of the history that "One significant excision as a result of these [Cabinet Office] requirements (in the chapter on The Wilson Plot) is, I believe, hard to justify", giving credence to these new allegations.


title: Harold Wilson

text: As a result of his concerns about the danger to British parliamentary democracy from these activities, Wilson issued instructions that no agency should ever bug the telephones of any members of Parliament, a policy (still in place) which came to be known as the Wilson Doctrine.


title: Harold Wilson

text: A portrait of Harold Wilson, painted by the Scottish portrait artist Cowan Dobson, hangs today at University College, Oxford. Two statues of Harold Wilson stand in prominent places. The first, unveiled by the then Prime Minister Tony Blair in July 1999, stands outside Huddersfield railway station in St George's Square, Huddersfield. Costing £70,000, the statue, designed by sculptor Ian Walters, is based on photographs taken in 1964 and depicts Wilson in walking pose at the start of his first term as prime minister. His widow, Mary requested that the eight-foot-tall monument not show Wilson holding his famous pipe as she feared it would make the representation a caricature.


title: Harold Wilson

text: A block of high-rise flats owned by Kirklees Metropolitan District Council in Huddersfield is named after Wilson.


title: Harold Wilson

text: In September 2006, Tony Blair unveiled a second bronze statue of Wilson in the latter's former constituency of Huyton, near Liverpool. The statue was created by Liverpool sculptor, Tom Murphy, and Blair paid tribute to Wilson's legacy at the unveiling, including the Open University. He added: "He also brought in a whole new culture, a whole new country. He made the country very, very different".


title: Harold Wilson

text: Also in 2006, a street on a new housing development in Tividale, West Midlands, was named Wilson Drive in honour of Wilson. Along with neighbouring new development Callaghan Drive (named after James Callaghan), it formed part of a large housing estate developed since the 1960s where all streets were named after former prime ministers or senior parliamentary figures.


title: Shah Rukh Khan filmography

text: Shah Rukh Khan is an Indian actor, producer and television personality who works in Hindi films. He began his acting career by playing a soldier in the Doordarshan series "Fauji" (1988), a role that garnered him recognition and led to starring roles in more television shows. He soon started receiving film offers and had his first release with the romantic drama "Deewana" (1992), in which he played a supporting part. Khan subsequently played villainous roles in the 1993 thrillers "Baazigar" and "Darr", box office successes that established his career in Bollywood. In 1995, Khan starred opposite Kajol in Aditya Chopra's romance "Dilwale Dulhania Le Jayenge", that became the longest running Indian film of all time. He continued to establish a reputation in romantic roles by playing opposite Madhuri Dixit in "Dil To Pagal Hai" (1997), and Kajol in the Karan Johar-directed "Kuch Kuch Hota Hai" (1998) and "Kabhi Khushi Kabhie Gham..." (2001).


title: Shah Rukh Khan filmography

text: In 1999, Khan collaborated with Aziz Mirza and Juhi Chawla to start a production company, Dreamz Unlimited, whose first release was the comedy-drama "Phir Bhi Dil Hai Hindustani" (2000) starring Khan and Chawla. The film was a commercial failure as was their next production, "Aśoka" (2001), leading to a setback. His career prospects improved in 2002 when he starred alongside Dixit and Aishwarya Rai in "Devdas", a period romance that garnered him critical acclaim. In 2004, he collaborated with his wife Gauri Khan to launch another company, Red Chillies Entertainment, whose first feature was the box office hit "Main Hoon Na" (2004). Khan's popularity continued to increase in the 2000s as he played the romantic lead opposite younger actresses, most notably Rani Mukerji and Preity Zinta, in several top-grossing productions, including "Kal Ho Naa Ho" (2003), "Veer-Zaara" (2004) and "Kabhi Alvida Naa Kehna" (2006). He also played against type as a NASA scientist in the drama "Swades" (2004), a hockey coach in the sports film "Chak De! India" (2007), and an autistic man in the drama "My Name Is Khan" (2010).


title: Shah Rukh Khan filmography

text: From 2007 onwards, Khan began to star opposite a third generation of heroines, most notably Deepika Padukone in "Om Shanti Om" (2007) and Anushka Sharma in "Rab Ne Bana Di Jodi" (2008). He went on to co-star with Padukone in the action-comedies "Chennai Express" (2013) and "Happy New Year" (2014), and reunited with Kajol in "Dilwale" (2015), all of which grossed over to rank among the highest-grossing Indian films. He then starred alongside Sharma in "Jab Harry Met Sejal" (2017) and "Zero" (2018), both of which were commercially unsuccessful.


title: Shah Rukh Khan filmography

text: Seventeen of Khan's films have grossed over in global ticket sales. With eight Filmfare Awards for Best Actor, he shares the record for the most wins in the category with Dilip Kumar. Khan has also starred in several non-fiction films that have documented his popularity, including the documentary "The Inner and Outer World of Shah Rukh Khan" (2005). From 2003 onwards, he has hosted several award ceremonies, including ten Filmfare Awards and six Screen Awards. In addition, he has featured as the host of television game shows "Kaun Banega Crorepati" (2007) and the talk show "TED Talks India" (2017–2019).


title: Sepsis

text: Sepsis, formerly known as septicemia (septicaemia in British English) or blood poisoning, is a life-threatening condition that arises when the body's response to infection causes injury to its own tissues and organs. This initial stage is followed by suppression of the immune system. Common signs and symptoms include fever, increased heart rate, increased breathing rate, and confusion. There may also be symptoms related to a specific infection, such as a cough with pneumonia, or painful urination with a kidney infection. The very young, old, and people with a weakened immune system may have no symptoms of a specific infection, and the body temperature may be low or normal instead of having a fever. Severe sepsis causes poor organ function or blood flow. The presence of low blood pressure, high blood lactate, or low urine output may suggest poor blood flow. Septic shock is low blood pressure due to sepsis that does not improve after fluid replacement.


title: Sepsis

text: Sepsis is caused by many organisms including bacteria, viruses and fungi. Common locations for the primary infection include the lungs, brain, urinary tract, skin, and abdominal organs. Risk factors include being very young or old, a weakened immune system from conditions such as cancer or diabetes, major trauma, and burns. Previously, a sepsis diagnosis required the presence of at least two systemic inflammatory response syndrome (SIRS) criteria in the setting of presumed infection. In 2016, a shortened sequential organ failure assessment score (SOFA score), known as the quick SOFA score (qSOFA), replaced the SIRS system of diagnosis. qSOFA criteria for sepsis include at least two of the following three: increased breathing rate, change in the level of consciousness, and low blood pressure. Sepsis guidelines recommend obtaining blood cultures before starting antibiotics; however, the diagnosis does not require the blood to be infected. Medical imaging is helpful when looking for the possible location of the infection. Other potential causes of similar signs and symptoms include anaphylaxis, adrenal insufficiency, low blood volume, heart failure, and pulmonary embolism.


title: Sepsis

text: Sepsis requires immediate treatment with intravenous fluids and antimicrobials. Ongoing care often continues in an intensive care unit. If an adequate trial of fluid replacement is not enough to maintain blood pressure, then the use of medications that raise blood pressure becomes necessary. Mechanical ventilation and dialysis may be needed to support the function of the lungs and kidneys, respectively. A central venous catheter and an arterial catheter may be placed for access to the bloodstream and to guide treatment. Other helpful measurements include cardiac output and superior vena cava oxygen saturation. People with sepsis need preventive measures for deep vein thrombosis, stress ulcers, and pressure ulcers unless other conditions prevent such interventions. Some people might benefit from tight control of blood sugar levels with insulin. The use of corticosteroids is controversial, with some reviews finding benefit, and others not.


title: Sepsis

text: Disease severity partly determines the outcome. The risk of death from sepsis is as high as 30%, while for severe sepsis it is as high as 50%, and septic shock 80%. Sepsis affected about 49 million people in 2017, with 11 million deaths (1 in 5 deaths worldwide). In the developed world, approximately 0.2 to 3 people per 1000 are affected by sepsis yearly, resulting in about a million cases per year in the United States. Rates of disease have been increasing. Some data indicate that sepsis is more common among males than females, however, other data show a greater prevalence of the disease among women. Descriptions of sepsis date back to the time of Hippocrates.


title: Sepsis

text: In addition to symptoms related to the actual cause, people with sepsis may have a fever, low body temperature, rapid breathing, a fast heart rate, confusion, and edema. Early signs include a rapid heart rate, decreased urination, and high blood sugar. Signs of established sepsis include confusion, metabolic acidosis (which may be accompanied by a faster breathing rate that leads to respiratory alkalosis), low blood pressure due to decreased systemic vascular resistance, higher cardiac output, and disorders in blood-clotting that may lead to organ failure. Fever is the most common presenting symptom in sepsis, but fever may be absent in some people such as the elderly or those who are immunocompromised.


title: Sepsis

text: The drop in blood pressure seen in sepsis can cause lightheadedness and is part of the criteria for septic shock.


title: Sepsis

text: Oxidative stress is observed in septic shock, with circulating levels of copper and vitamin C being decreased.


title: Sepsis

text: Infections leading to sepsis are usually bacterial but may be fungal, parasitic or viral. Gram-positive bacteria were the primary cause of sepsis before the introduction of antibiotics in the 1950s. After the introduction of antibiotics, gram-negative bacteria became the predominant cause of sepsis from the 1960s to the 1980s. After the 1980s, gram-positive bacteria, most commonly staphylococci, are thought to cause more than 50% of cases of sepsis. Other commonly implicated bacteria include "Streptococcus pyogenes", "Escherichia coli", "Pseudomonas aeruginosa", and "Klebsiella" species. Fungal sepsis accounts for approximately 5% of severe sepsis and septic shock cases; the most common cause of fungal sepsis is an infection by "Candida" species of yeast, a frequent hospital-acquired infection. The most common causes for parasitic sepsis are "Plasmodium" (which leads to malaria), "Schistosoma" and "Echinococcus".


title: Sepsis

text: The most common sites of infection resulting in severe sepsis are the lungs, the abdomen, and the urinary tract. Typically, 50% of all sepsis cases start as an infection in the lungs. In one-third to one-half of cases, the source of infection is unclear.


title: Sepsis

text: Sepsis is caused by a combination of factors related to the particular invading pathogen(s) and to the status of the immune system of the host. The early phase of sepsis characterized by excessive inflammation (sometimes resulting in a cytokine storm) may be followed by a prolonged period of decreased functioning of the immune system. Either of these phases may prove fatal. On the other hand, systemic inflammatory response syndrome (SIRS) occurs in people without the presence of infection, for example, in those with burns, polytrauma, or the initial state in pancreatitis and chemical pneumonitis. However, sepsis also causes similar response to SIRS.


title: Sepsis

text: Bacterial virulence factors, such as glycocalyx and various adhesins, allow colonization, immune evasion, and establishment of disease in the host. Sepsis caused by gram-negative bacteria is thought to be largely due to a response by the host to the lipid A component of lipopolysaccharide, also called endotoxin. Sepsis caused by gram-positive bacteria may result from an immunological response to cell wall lipoteichoic acid. Bacterial exotoxins that act as superantigens also may cause sepsis. Superantigens simultaneously bind major histocompatibility complex and T-cell receptors in the absence of antigen presentation. This forced receptor interaction induces the production of pro-inflammatory chemical signals (cytokines) by T-cells.


title: Sepsis

text: There are a number of microbial factors that may cause the typical septic inflammatory cascade. An invading pathogen is recognized by its pathogen-associated molecular patterns (PAMPs). Examples of PAMPs include lipopolysaccharides and flagellin in gram-negative bacteria, muramyl dipeptide in the peptidoglycan of the gram-positive bacterial cell wall, and CpG bacterial DNA. These PAMPs are recognized by the pattern recognition receptors (PRRs) of the innate immune system, which may be membrane-bound or cytosolic. There are four families of PRRs: the toll-like receptors, the C-type lectin receptors, the NOD-like receptors, and the RIG-I-like receptors. Invariably, the association of a PAMP and a PRR will cause a series of intracellular signalling cascades. Consequentially, transcription factors such as nuclear factor-kappa B and activator protein-1, will up-regulate the expression of pro-inflammatory and anti-inflammatory cytokines.


title: Sepsis

text: Upon detection of microbial antigens, the host systemic immune system is activated. Immune cells not only recognise pathogen-associated molecular patterns but also damage-associated molecular patterns from damaged tissues. An uncontrolled immune response is then activated because leukocytes are not recruited to the specific site of infection, but instead they are recruited all over the body. Then, an immunosuppression state ensues when the proinflammatory T helper cell 1 (TH1) is shifted to TH2, mediated by interleukin 10, which is known as "compensatory anti-inflammatory response syndrome". The apoptosis (cell death) of lymphocytes further worsens the immunosuppression. Neutrophils, monocytes, macrophages, dendritic cells, CD4+ T cells, and B cells all undergo apoptosis, whereas regulatory T cells are more apoptosis resistant. Subsequently, multiple organ failure ensues because tissues are unable to use oxygen efficiently due to inhibition of cytochrome c oxidase.


title: Sepsis

text: Inflammatory responses cause multiple organ dysfunction syndrome through various mechanisms as described below. Increased permeability of the lung vessels causes leaking of fluids into alveoli, which results in pulmonary edema and acute respiratory distress syndrome (ARDS). Impaired utilization of oxygen in the liver impairs bile salt transport, causing jaundice (yellowish discoloration of the skin). In kidneys, inadequate oxygenation results in tubular epithelial cell injury (of the cells lining the kidney tubules), and thus causes acute kidney injury (AKI). Meanwhile, in the heart, impaired calcium transport, and low production of adenosine triphosphate (ATP), can cause myocardial depression, reducing cardiac contractility and causing heart failure. In the gastrointestinal tract, increased permeability of the mucosa alters the microflora, causing mucosal bleeding and paralytic ileus. In the central nervous system, direct damage of the brain cells and disturbances of neurotransmissions causes altered mental status. Cytokines such as tumor necrosis factor, interleukin 1, and interleukin 6 may activate procoagulation factors in the cells lining blood vessels, leading to endothelial damage. The damaged endothelial surface inhibits anticoagulant properties as well as increases antifibrinolysis, which may lead to intravascular clotting, the formation of blood clots in small blood vessels, and multiple organ failure.


title: Sepsis

text: The low blood pressure seen in those with sepsis is the result of various processes, including excessive production of chemicals that dilate blood vessels such as nitric oxide, a deficiency of chemicals that constrict blood vessels such as vasopressin, and activation of ATP-sensitive potassium channels. In those with severe sepsis and septic shock, this sequence of events leads to a type of circulatory shock known as distributive shock.


title: Sepsis

text: Early diagnosis is necessary to properly manage sepsis, as the initiation of rapid therapy is key to reducing deaths from severe sepsis. Some hospitals use alerts generated from electronic health records to bring attention to potential cases as early as possible.


title: Sepsis

text: Within the first three hours of suspected sepsis, diagnostic studies should include white blood cell counts, measuring serum lactate, and obtaining appropriate cultures before starting antibiotics, so long as this does not delay their use by more than 45 minutes. To identify the causative organism(s), at least two sets of blood cultures using bottles with media for aerobic and anaerobic organisms are necessary. At least one should be drawn through the skin and one through each vascular access device (such as an IV catheter) that has been in place more than 48 hours. Bacteria are present in the blood in only about 30% of cases. Another possible method of detection is by polymerase chain reaction. If other sources of infection are suspected, cultures of these sources, such as urine, cerebrospinal fluid, wounds, or respiratory secretions, also should be obtained, as long as this does not delay the use of antibiotics.


title: Sepsis

text: Within six hours, if blood pressure remains low despite initial fluid resuscitation of 30 mL/kg, or if initial lactate is ≥ four mmol/L (36 mg/dL), central venous pressure and central venous oxygen saturation should be measured. Lactate should be re-measured if the initial lactate was elevated. Evidence for point of care lactate measurement over usual methods of measurement, however, is poor.


title: Sepsis

text: Within twelve hours, it is essential to diagnose or exclude any source of infection that would require emergent source control, such as a necrotizing soft tissue infection, an infection causing inflammation of the abdominal cavity lining, an infection of the bile duct, or an intestinal infarction. A pierced internal organ (free air on an abdominal X-ray or CT scan), an abnormal chest X-ray consistent with pneumonia (with focal opacification), or petechiae, purpura, or purpura fulminans may indicate the presence of an infection.


title: Sepsis

text: Previously, SIRS criteria had been used to define sepsis. If the SIRS criteria are negative, it is very unlikely the person has sepsis; if it is positive, there is just a moderate probability that the person has sepsis. According to SIRS, there were different levels of sepsis: sepsis, severe sepsis, and septic shock. The definition of SIRS is shown below:


title: Sepsis

text: In 2016 a new consensus was reached to replace screening by systemic inflammatory response syndrome (SIRS) with the sequential organ failure assessment (SOFA score) and the abbreviated version (qSOFA). The three criteria for the qSOFA score include a respiratory rate greater than or equal to 22 breaths per minute, systolic blood pressure 100 mmHg or less and altered mental status. Sepsis is suspected when 2 of the qSOFA criteria are met. The SOFA score was intended to be used in the intensive care unit (ICU) where it is administered upon admission to the ICU and then repeated every 48 hours, whereas the qSOFA could be used outside the ICU. Some advantages of the qSOFA score are that it can be administered quickly and does not require labs. However, the American College of Chest Physicians (CHEST) raised concerns that qSOFA and SOFA criteria may lead to delayed diagnosis of serious infection, leading to delayed treatment. Although SIRS criteria can be too sensitive and not specific enough in identifying sepsis, SOFA also has its limitations and is not intended to replace the SIRS definition. qSOFA has also been found to be poorly sensitive though decently specific for the risk of death with SIRS possibly better for screening. NOTE - Surviving Sepsis Campaign 2021 Guidelines recommends "against using qSOFA compared with SIRS, NEWS, or MEWS as a single screening tool for sepsis or septic shock".


title: Sepsis

text: Consensus definitions, however, continue to evolve, with the latest expanding the list of signs and symptoms of sepsis to reflect clinical bedside experience.


title: Sepsis

text: Biomarkers can help diagnosis because they can point to the presence or severity of sepsis, although their exact role in the management of sepsis remains undefined. A 2013 review concluded moderate-quality evidence exists to support the use of the procalcitonin level as a method to distinguish sepsis from non-infectious causes of SIRS. The same review found the sensitivity of the test to be 77% and the specificity to be 79%. The authors suggested that procalcitonin may serve as a helpful diagnostic marker for sepsis, but cautioned that its level alone does not definitively make the diagnosis. A 2012 systematic review found that soluble urokinase-type plasminogen activator receptor (SuPAR) is a nonspecific marker of inflammation and does not accurately diagnose sepsis. This same review concluded, however, that SuPAR has prognostic value, as higher SuPAR levels are associated with an increased rate of death in those with sepsis. Serial measurement of lactate levels (approximately every 4 to 6 hours) may guide treatment and is associated with lower mortality in sepsis.


title: Sepsis

text: The differential diagnosis for sepsis is broad and has to examine (to exclude) the non-infectious conditions that may cause the systemic signs of SIRS: alcohol withdrawal, acute pancreatitis, burns, pulmonary embolism, thyrotoxicosis, anaphylaxis, adrenal insufficiency, and neurogenic shock. Hyperinflammatory syndromes such as hemophagocytic lymphohistiocytosis (HLH) may have similar symptoms and are on the differential diagnosis.


title: Sepsis

text: In common clinical usage, neonatal sepsis refers to a bacterial blood stream infection in the first month of life, such as meningitis, pneumonia, pyelonephritis, or gastroenteritis, but neonatal sepsis also may be due to infection with fungi, viruses, or parasites. Criteria with regard to hemodynamic compromise or respiratory failure are not useful because they present too late for intervention.


title: Sepsis

text: Early recognition and focused management may improve the outcomes in sepsis. Current professional recommendations include a number of actions ("bundles") to be followed as soon as possible after diagnosis. Within the first three hours, someone with sepsis should have received antibiotics and, intravenous fluids if there is evidence of either low blood pressure or other evidence for inadequate blood supply to organs (as evidenced by a raised level of lactate); blood cultures also should be obtained within this time period. After six hours the blood pressure should be adequate, close monitoring of blood pressure and blood supply to organs should be in place, and the lactate should be measured again if initially it was raised. A related bundle, the "Sepsis Six", is in widespread use in the United Kingdom; this requires the administration of antibiotics within an hour of recognition, blood cultures, lactate, and hemoglobin determination, urine output monitoring, high-flow oxygen, and intravenous fluids.


title: Sepsis

text: Apart from the timely administration of fluids and antibiotics, the management of sepsis also involves surgical drainage of infected fluid collections and appropriate support for organ dysfunction. This may include hemodialysis in kidney failure, mechanical ventilation in lung dysfunction, transfusion of blood products, and drug and fluid therapy for circulatory failure. Ensuring adequate nutrition—preferably by enteral feeding, but if necessary, by parenteral nutrition—is important during prolonged illness. Medication to prevent deep vein thrombosis and gastric ulcers also may be used.


title: Sepsis

text: Two sets of blood cultures (aerobic and anaerobic) are recommended without delaying the initiation of antibiotics. Cultures from other sites such as respiratory secretions, urine, wounds, cerebrospinal fluid, and catheter insertion sites (in-situ more than 48 hours) are recommended if infections from these sites are suspected. In severe sepsis and septic shock, broad-spectrum antibiotics (usually two, a β-lactam antibiotic with broad coverage, or broad-spectrum carbapenem combined with fluoroquinolones, macrolides, or aminoglycosides) are recommended. The choice of antibiotics is important in determining the survival of the person. Some recommend they be given within one hour of making the diagnosis, stating that for every hour of delay in the administration of antibiotics, there is an associated 6% rise in mortality. Others did not find a benefit with early administration.


title: Sepsis

text: Several factors determine the most appropriate choice for the initial antibiotic regimen. These factors include local patterns of bacterial sensitivity to antibiotics, whether the infection is thought to be a hospital or community-acquired infection, and which organ systems are thought to be infected. Antibiotic regimens should be reassessed daily and narrowed if appropriate. Treatment duration is typically 7–10 days with the type of antibiotic used directed by the results of cultures. If the culture result is negative, antibiotics should be de-escalated according to the person's clinical response or stopped altogether if an infection is not present to decrease the chances that the person is infected with multiple drug resistance organisms. In case of people having a high risk of being infected with multiple drug resistant organisms such as "Pseudomonas aeruginosa", "Acinetobacter baumannii", the addition of an antibiotic specific to the gram-negative organism is recommended. For methicillin-resistant "Staphylococcus aureus" (MRSA), vancomycin or teicoplanin is recommended. For "Legionella" infection, addition of macrolide or fluoroquinolone is chosen. If fungal infection is suspected, an echinocandin, such as caspofungin or micafungin, is chosen for people with severe sepsis, followed by triazole (fluconazole and itraconazole) for less ill people. Prolonged antibiotic prophylaxis is not recommended in people who has SIRS without any infectious origin such as acute pancreatitis and burns unless sepsis is suspected.


title: Sepsis

text: Once-daily dosing of aminoglycoside is sufficient to achieve peak plasma concentration for a clinical response without kidney toxicity. Meanwhile, for antibiotics with low volume distribution (vancomycin, teicoplanin, colistin), a loading dose is required to achieve an adequate therapeutic level to fight infections. Frequent infusions of beta-lactam antibiotics without exceeding total daily dose would help to keep the antibiotics level above minimum inhibitory concentration (MIC), thus providing a better clinical response. Giving beta-lactam antibiotics continuously may be better than giving them intermittently. Access to therapeutic drug monitoring is important to ensure adequate drug therapeutic level while at the same time preventing the drug from reaching toxic level.


title: Sepsis

text: The Surviving Sepsis Campaign has recommended 30 mL/kg of fluid to be given in adults in the first three hours followed by fluid titration according to blood pressure, urine output, respiratory rate, and oxygen saturation with a target mean arterial pressure (MAP) of 65 mmHg. In children an initial amount of 20 mL/kg is reasonable in shock. In cases of severe sepsis and septic shock where a central venous catheter is used to measure blood pressures dynamically, fluids should be administered until the central venous pressure reaches 8–12 mmHg. Once these goals are met, the central venous oxygen saturation (ScvO2), i.e., the oxygen saturation of venous blood as it returns to the heart as measured at the vena cava, is optimized. If the ScvO2 is less than 70%, blood may be given to reach a hemoglobin of 10 g/dL and then inotropes are added until the ScvO2 is optimized. In those with acute respiratory distress syndrome (ARDS) and sufficient tissue blood fluid, more fluids should be given carefully.


title: Sepsis

text: Crystalloid solution is recommended as the fluid of choice for resuscitation. Albumin can be used if a large amount of crystalloid is required for resuscitation. Crystalloid solutions shows little difference with hydroxyethyl starch in terms of risk of death. Starches also carry an increased risk of acute kidney injury, and need for blood transfusion. Various colloid solutions (such as modified gelatin) carry no advantage over crystalloid. Albumin also appears to be of no benefit over crystalloids.


title: Sepsis

text: The Surviving Sepsis Campaign recommended packed red blood cells transfusion for hemoglobin levels below 70 g/L if there is no myocardial ischemia, hypoxemia, or acute bleeding. In a 2014 trial, blood transfusions to keep target hemoglobin above 70 or 90 g/L did not make any difference to survival rates; meanwhile, those with a lower threshold of transfusion received fewer transfusions in total. Erythropoietin is not recommended in the treatment of anemia with septic shock because it may precipitate blood clotting events. Fresh frozen plasma transfusion usually does not correct the underlying clotting abnormalities before a planned surgical procedure. However, platelet transfusion is suggested for platelet counts below (10 × 10/L) without any risk of bleeding, or (20 × 10/L) with high risk of bleeding, or (50 × 10/L) with active bleeding, before a planned surgery or an invasive procedure. IV immunoglobulin is not recommended because its beneficial effects are uncertain. Monoclonal and polyclonal preparations of intravenous immunoglobulin (IVIG) do not lower the rate of death in newborns and adults with sepsis. Evidence for the use of IgM-enriched polyclonal preparations of IVIG is inconsistent. On the other hand, the use of antithrombin to treat disseminated intravascular coagulation is also not useful. Meanwhile, the blood purification technique (such as hemoperfusion, plasma filtration, and coupled plasma filtration adsorption) to remove inflammatory mediators and bacterial toxins from the blood also does not demonstrate any survival benefit for septic shock.


title: Sepsis

text: If the person has been sufficiently fluid resuscitated but the mean arterial pressure is not greater than 65 mmHg, vasopressors are recommended. Norepinephrine (noradrenaline) is recommended as the initial choice. Delaying initiation of vasopressor therapy during septic shock is associated with increased mortality.


title: Sepsis

text: Norepinephrine is often used as a first-line treatment for hypotensive septic shock because evidence shows that there is a relative deficiency of vasopressin when shock continues for 24 to 48 hours. Norepinephrine raises blood pressure through a vasoconstriction effect, with little effect on stroke volume and heart rate. In some people, the required dose of vasopressor needed to increase the mean arterial pressure can become exceedingly high that it becomes toxic. In order to reduce the required dose of vasopressor, epinephrine may be added. Epinephrine is not often used as a first-line treatment for hypotensive shock because it reduces blood flow to the abdominal organs and increases lactate levels. Vasopressin can be used in septic shock because studies have shown that there is a relative deficiency of vasopressin when shock continues for 24 to 48 hours. However, vasopressin reduces blood flow to the heart, finger/toes, and abdominal organs, resulting in a lack of oxygen supply to these tissues. Dopamine is typically not recommended. Although dopamine is useful to increase the stroke volume of the heart, it causes more abnormal heart rhythms than norepinephrine and also has an immunosuppressive effect. Dopamine is not proven to have protective properties on the kidneys. Dobutamine can also be used in hypotensive septic shock to increase cardiac output and correct blood flow to the tissues. Dobutamine is not used as often as epinephrine due to its associated side effects, which include reducing blood flow to the gut. Additionally, dobutamine increases the cardiac output by abnormally increasing the heart rate.


title: Sepsis

text: The use of steroids in sepsis is controversial. Studies do not give a clear picture as to whether and when glucocorticoids should be used. The 2016 Surviving Sepsis Campaign recommends low dose hydrocortisone only if both intravenous fluids and vasopressors are not able to adequately treat septic shock. The 2021 Surviving Sepsis Campaign recommends IV corticosteroids for adults with septic shock who have an ongoing requirement for vasopressor therapy. A 2019 Cochrane review found low-quality evidence of benefit, as did two 2019 reviews.


title: Sepsis

text: During critical illness, a state of adrenal insufficiency and tissue resistance to corticosteroids may occur. This has been termed critical illness–related corticosteroid insufficiency. Treatment with corticosteroids might be most beneficial in those with septic shock and early severe ARDS, whereas its role in others such as those with pancreatitis or severe pneumonia is unclear. However, the exact way of determining corticosteroid insufficiency remains problematic. It should be suspected in those poorly responding to resuscitation with fluids and vasopressors. Neither ACTH stimulation testing nor random cortisol levels are recommended to confirm the diagnosis. The method of stopping glucocorticoid drugs is variable, and it is unclear whether they should be slowly decreased or simply abruptly stopped. However, the 2016 Surviving Sepsis Campaign recommended to taper steroids when vasopressors are no longer needed.


title: Sepsis

text: A target tidal volume of 6 mL/kg of predicted body weight (PBW) and a plateau pressure less than 30 cm HO is recommended for those who require ventilation due to sepsis-induced severe ARDS. High positive end expiratory pressure (PEEP) is recommended for moderate to severe ARDS in sepsis as it opens more lung units for oxygen exchange. Predicted body weight is calculated based on sex and height, and tools for this are available. Recruitment maneuvers may be necessary for severe ARDS by briefly raising the transpulmonary pressure. It is recommended that the head of the bed be raised if possible to improve ventilation. However, β2 adrenergic receptor agonists are not recommended to treat ARDS because it may reduce survival rates and precipitate abnormal heart rhythms. A spontaneous breathing trial using continuous positive airway pressure (CPAP), T piece, or inspiratory pressure augmentation can be helpful in reducing the duration of ventilation. Minimizing intermittent or continuous sedation is helpful in reducing the duration of mechanical ventilation.


title: Sepsis

text: General anesthesia is recommended for people with sepsis who require surgical procedures to remove the infective source. Usually, inhalational and intravenous anesthetics are used. Requirements for anesthetics may be reduced in sepsis. Inhalational anesthetics can reduce the level of proinflammatory cytokines, altering leukocyte adhesion and proliferation, inducing apoptosis (cell death) of the lymphocytes, possibly with a toxic effect on mitochondrial function. Although etomidate has a minimal effect on the cardiovascular system, it is often not recommended as a medication to help with intubation in this situation due to concerns it may lead to poor adrenal function and an increased risk of death. The small amount of evidence there is, however, has not found a change in the risk of death with etomidate.


title: Sepsis

text: Paralytic agents are not suggested for use in sepsis cases in the absence of ARDS, as a growing body of evidence points to reduced durations of mechanical ventilation, ICU and hospital stays. However, paralytic use in ARDS cases remains controversial. When appropriately used, paralytics may aid successful mechanical ventilation, however, evidence has also suggested that mechanical ventilation in severe sepsis does not improve oxygen consumption and delivery.


title: Sepsis

text: Source control refers to physical interventions to control a focus of infection and reduce conditions favorable to microorganism growth or host defense impairment, such as drainage of pus from an abscess. It is one of the oldest procedures for control of infections, giving rise to the Latin phrase "Ubi pus, ibi evacua", and remains important despite the emergence of more modern treatments.


title: Sepsis

text: Early goal directed therapy (EGDT) is an approach to the management of severe sepsis during the initial 6 hours after diagnosis. It is a step-wise approach, with the physiologic goal of optimizing cardiac preload, afterload, and contractility. It includes giving early antibiotics. EGDT also involves monitoring of hemodynamic parameters and specific interventions to achieve key resuscitation targets which include maintaining a central venous pressure between 8–12 mmHg, a mean arterial pressure of between 65 and 90 mmHg, a central venous oxygen saturation (ScvO) greater than 70% and a urine output of greater than 0.5 mL/kg/hour. The goal is to optimize oxygen delivery to tissues and achieve a balance between systemic oxygen delivery and demand. An appropriate decrease in serum lactate may be equivalent to ScvO and easier to obtain.


title: Sepsis

text: In the original trial, early goal-directed therapy was found to reduce mortality from 46.5% to 30.5% in those with sepsis, and the Surviving Sepsis Campaign has been recommending its use. However, three more recent large randomized control trials (ProCESS, ARISE, and ProMISe), did not demonstrate a 90-day mortality benefit of early goal-directed therapy when compared to standard therapy in severe sepsis. It is likely that some parts of EGDT are more important than others. Following these trials the use of EGDT is still considered reasonable.


title: Sepsis

text: Neonatal sepsis can be difficult to diagnose as newborns may be asymptomatic. If a newborn shows signs and symptoms suggestive of sepsis, antibiotics are immediately started and are either changed to target a specific organism identified by diagnostic testing or discontinued after an infectious cause for the symptoms has been ruled out. Despite early intervention, death occurs in 13% of children who develop septic shock, with the risk partly based on other health problems. Those without multiple organ system failures or who require only one inotropic agent mortality is low.


title: Sepsis

text: Treating fever in sepsis, including people in septic shock, has not been associated with any improvement in mortality over a period of 28 days. Treatment of fever still occurs for other reasons.


title: Sepsis

text: A 2012 Cochrane review concluded that N-acetylcysteine does not reduce mortality in those with SIRS or sepsis and may even be harmful.


title: Sepsis

text: Recombinant activated protein C (drotrecogin alpha) was originally introduced for severe sepsis (as identified by a high APACHE II score), where it was thought to confer a survival benefit. However, subsequent studies showed that it increased adverse events—bleeding risk in particular—and did not decrease mortality. It was removed from sale in 2011. Another medication known as eritoran also has not shown benefit.


title: Sepsis

text: In those with high blood sugar levels, insulin to bring it down to 7.8–10 mmol/L (140–180 mg/dL) is recommended with lower levels potentially worsening outcomes. Glucose levels taken from capillary blood should be interpreted with care because such measurements may not be accurate. If a person has an arterial catheter, arterial blood is recommended for blood glucose testing.


title: Sepsis

text: Intermittent or continuous renal replacement therapy may be used if indicated. However, sodium bicarbonate is not recommended for a person with lactic acidosis secondary to hypoperfusion. Low-molecular-weight heparin (LMWH), unfractionated heparin (UFH), and mechanical prophylaxis with intermittent pneumatic compression devices are recommended for any person with sepsis at moderate to high risk of venous thromboembolism. Stress ulcer prevention with proton-pump inhibitor (PPI) and H2 antagonist are useful in a person with risk factors of developing upper gastrointestinal bleeding (UGIB) such as on mechanical ventilation for more than 48 hours, coagulation disorders, liver disease, and renal replacement therapy. Achieving partial or full enteral feeding (delivery of nutrients through a feeding tube) is chosen as the best approach to provide nutrition for a person who is contraindicated for oral intake or unable to tolerate orally in the first seven days of sepsis when compared to intravenous nutrition. However, omega-3 fatty acids are not recommended as immune supplements for a person with sepsis or septic shock. The usage of prokinetic agents such as metoclopramide, domperidone, and erythromycin are recommended for those who are septic and unable to tolerate enteral feeding. However, these agents may precipitate prolongation of the QT interval and consequently provoke a ventricular arrhythmia such as torsades de pointes. The usage of prokinetic agents should be reassessed daily and stopped if no longer indicated.


title: Sepsis

text: Sepsis will prove fatal in approximately 24.4% of people, and septic shock will prove fatal in 34.7% of people within 30 days (32.2% and 38.5% after 90 days).


title: Sepsis

text: Lactate is a useful method of determining prognosis, with those who have a level greater than 4 mmol/L having a mortality of 40% and those with a level of less than 2 mmol/L having a mortality of less than 15%.


title: Sepsis

text: There are a number of prognostic stratification systems, such as APACHE II and Mortality in Emergency Department Sepsis. APACHE II factors in the person's age, underlying condition, and various physiologic variables to yield estimates of the risk of dying of severe sepsis. Of the individual covariates, the severity of the underlying disease most strongly influences the risk of death. Septic shock is also a strong predictor of short- and long-term mortality. Case-fatality rates are similar for culture-positive and culture-negative severe sepsis. The Mortality in Emergency Department Sepsis (MEDS) score is simpler and useful in the emergency department environment.


title: Sepsis

text: Some people may experience severe long-term cognitive decline following an episode of severe sepsis, but the absence of baseline neuropsychological data in most people with sepsis makes the incidence of this difficult to quantify or to study.


title: Sepsis

text: Sepsis causes millions of deaths globally each year and is the most common cause of death in people who have been hospitalized. The number of new cases worldwide of sepsis is estimated to be 18 million cases per year. In the United States sepsis affects approximately 3 in 1,000 people, and severe sepsis contributes to more than 200,000 deaths per year.


title: Sepsis

text: Sepsis occurs in 1–2% of all hospitalizations and accounts for as much as 25% of ICU bed utilization. Due to it rarely being reported as a primary diagnosis (often being a complication of cancer or other illness), the incidence, mortality, and morbidity rates of sepsis are likely underestimated. A study of U.S. states found approximately 651 hospital stays per 100,000 population with a sepsis diagnosis in 2010. It is the second-leading cause of death in non-coronary intensive care unit (ICU) and the tenth-most-common cause of death overall (the first being heart disease). Children under 12 months of age and elderly people have the highest incidence of severe sepsis. Among people from the U.S. who had multiple sepsis hospital admissions in 2010, those who were discharged to a skilled nursing facility or long-term care following the initial hospitalization were more likely to be readmitted than those discharged to another form of care. A study of 18 U.S. states found that, amongst people with Medicare in 2011, sepsis was the second most common principal reason for readmission within 30 days.


title: Sepsis

text: Several medical conditions increase a person's susceptibility to infection and developing sepsis. Common sepsis risk factors include age (especially the very young and old); conditions that weaken the immune system such as cancer, diabetes, or the absence of a spleen; and major trauma and burns.


title: Sepsis

text: From 1979 to 2000, data from the United States National Hospital Discharge Survey showed that the incidence of sepsis increased fourfold, to 240 cases per 100,000 population, with a higher incidence in men when compared to women. However, the global prevalence of sepsis has been estimated to be higher in women. During the same time frame, the in-hospital case fatality rate was reduced from 28% to 18%. However, according to the nationwide inpatient sample from the United States, the incidence of severe sepsis increased from 200 per 10,000 population in 2003 to 300 cases in 2007 for population aged more than 18 years. The incidence rate is particularly high among infants, with an incidence of 500 cases per 100,000 population. Mortality related to sepsis increases with age, from less than 10% in the age group of 3 to 5 years to 60% by sixth decade of life. The increase in the average age of the population, alongside the presence of more people with chronic diseases or on immunosuppressive medications, and also the increase in the number of invasive procedures being performed, has led to an increased rate of sepsis.


title: Sepsis

text: The term "σήψις" (sepsis) was introduced by Hippocrates in the fourth century BC, and it meant the process of decay or decomposition of organic matter. In the eleventh century, Avicenna used the term "blood rot" for diseases linked to severe purulent process. Though severe systemic toxicity had already been observed, it was only in the 19th century that the specific term – sepsis – was used for this condition.


title: Sepsis

text: The terms "septicemia", also spelled "septicaemia", and "blood poisoning" referred to the microorganisms or their toxins in the blood. The International Statistical Classification of Diseases and Related Health Problems (ICD) version 9, which was in use in the US until 2013, used the term septicemia with numerous modifiers for different diagnoses, such as "Streptococcal septicemia". All those diagnoses have been converted to sepsis, again with modifiers, in ICD-10, such as "Sepsis due to streptococcus".


title: Sepsis

text: The current terms are dependent on the microorganism that is present: bacteremia if bacteria are present in the blood at abnormal levels and are the causative issue, viremia for viruses, and fungemia for a fungus.


title: Sepsis

text: By the end of the 19th century, it was widely believed that microbes produced substances that could injure the mammalian host and that soluble toxins released during infection caused the fever and shock that were commonplace during severe infections. Pfeiffer coined the term endotoxin at the beginning of the 20th century to denote the pyrogenic principle associated with "Vibrio cholerae". It was soon realized that endotoxins were expressed by most and perhaps all gram-negative bacteria. The lipopolysaccharide character of enteric endotoxins was elucidated in 1944 by Shear. The molecular character of this material was determined by Luderitz et al. in 1973.


title: Sepsis

text: It was discovered in 1965 that a strain of C3H/HeJ mouse was immune to the endotoxin-induced shock. The genetic locus for this effect was dubbed "Lps". These mice were also found to be hyper susceptible to infection by gram-negative bacteria. These observations were finally linked in 1998 by the discovery of the toll-like receptor gene 4 (TLR 4). Genetic mapping work, performed over a period of five years, showed that TLR4 was the sole candidate locus within the Lps critical region; this strongly implied that a mutation within TLR4 must account for the lipopolysaccharide resistance phenotype. The defect in the TLR4 gene that led to the endotoxin resistant phenotype was discovered to be due to a mutation in the cytoplasm.


title: Sepsis

text: Controversy occurred in the scientific community over the use of mouse models in research into sepsis in 2013 when scientists published a review of the mouse immune system compared to the human immune system and showed that on a systems level, the two worked very differently; the authors noted that as of the date of their article over 150 clinical trials of sepsis had been conducted in humans, almost all of them supported by promising data in mice and that all of them had failed. The authors called for abandoning the use of mouse models in sepsis research; others rejected that but called for more caution in interpreting the results of mouse studies, and more careful design of preclinical studies. One approach is to rely more on studying biopsies and clinical data from people who have had sepsis, to try to identify biomarkers and drug targets for intervention.


title: Sepsis

text: Sepsis was the most expensive condition treated in United States' hospital stays in 2013, at an aggregate cost of $23.6 billion for nearly 1.3 million hospitalizations. Costs for sepsis hospital stays more than quadrupled since 1997 with an 11.5 percent annual increase. By payer, it was the most costly condition billed to Medicare and the uninsured, the second-most costly billed to Medicaid, and the fourth-most costly billed to private insurance.


title: Sepsis

text: A large international collaboration entitled the "Surviving Sepsis Campaign" was established in 2002 to educate people about sepsis and to improve outcomes with sepsis. The Campaign has published an evidence-based review of management strategies for severe sepsis, with the aim to publish a complete set of guidelines in subsequent years. The guidelines were updated in 2016 and again in 2021.


title: Sepsis

text: Sepsis Alliance is a charitable organization that was created to raise sepsis awareness among both the general public and healthcare professionals.


title: Sepsis

text: Some authors suggest that initiating sepsis by the normally mutualistic (or neutral) members of the microbiome may not always be an accidental side effect of the deteriorating host immune system. Rather it is often an adaptive microbial response to a sudden decline of host survival chances. Under this scenario, the microbe species provoking sepsis benefit from monopolizing the future cadaver, utilizing its biomass as decomposers, and then transmitted through soil or water to establish mutualistic relations with new individuals. The bacteria "Streptococcus pneumoniae", "Escherichia coli", "Proteus" spp., "Pseudomonas aeruginosa", "Staphylococcus aureus", "Klebsiella" spp., "Clostridium" spp., "Lactobacillus" spp., "Bacteroides" spp. and the fungi "Candida" spp. are all capable of such a high level of phenotypic plasticity. Evidently, not all cases of sepsis arise through such adaptive microbial strategy switches.


title: Sepsis

text: Paul E. Marik's "Marik protocol", also known as the "HAT" protocol, proposed a combination of hydrocortisone, vitamin C, and thiamine as a treatment for preventing sepsis for people in intensive care. Marik's own initial research, published in 2017, showed a dramatic evidence of benefit, leading to the protocol becoming popular among intensive care physicians, especially after the protocol received attention on social media and National Public Radio, leading to criticism of science by press conference from the wider medical community. Subsequent independent research failed to replicate Marik's positive results, indicating the possibility that they had been compromised by bias. A systematic review of trials in 2021 found that the claimed benefits of the protocol could not be confirmed. Another more recent review found that "HAT therapy significantly reduced the duration of vasopressor use and improved the SOFA score but appeared not to have significant benefits in other outcomes for patients with sepsis."


title: Darren Aronofsky

text: Darren Aronofsky (born February 12, 1969) is an American film director, producer, and screenwriter. His films are noted for their surrealistic, melodramatic, and sometimes disturbing elements, often in the form of psychological fiction.


title: Darren Aronofsky

text: Aronofsky attended Harvard University, where he studied film and social anthropology, and then the American Film Institute where he studied directing. He won several film awards after completing his senior thesis film, "Supermarket Sweep", which became a National Student Academy Award finalist. In 1997, he founded the film and TV production company Protozoa Pictures. His feature debut, the surrealist psychological thriller "Pi" (1998), was produced for $60,000 and grossed over $3 million; It won Aronofsky the Directing Award at the Sundance Film Festival and an Independent Spirit Award for Best First Screenplay.


title: Darren Aronofsky

text: Aronofsky's follow-up, the psychological drama "Requiem for a Dream" (2000), was based on the novel of the same name by Hubert Selby Jr. The film garnered strong reviews and received an Academy Award nomination for Ellen Burstyn's performance. After writing the World War II horror film "Below" (2002), Aronofsky began production on his third film, the romantic fantasy sci-fi drama "The Fountain" (2006). The film received mixed reviews and performed poorly at the box-office, but has since garnered a cult following.


title: Darren Aronofsky

text: His fourth film, the sports drama "The Wrestler" (2008), was released to critical acclaim and both of the film's stars, Mickey Rourke and Marisa Tomei, received Academy Award nominations. His next film, the psychological horror film "Black Swan" (2010), received further critical acclaim and many accolades, with five Academy Awards nominations, including Best Picture and Best Director, and a Best Actress win for Natalie Portman. Aronofsky's sixth feature film, the biblically–inspired epic "Noah" (2014), became his first film to open at No. 1 at the box office despite its mixed reception from critics and audiences. His seventh and eighth films, "mother!" (2017) and "The Whale" (2022), sparked controversy upon release and polarized both critics and audiences.


title: Darren Aronofsky

text: Aronofsky was born in the Brooklyn borough of New York City, the son of teachers Charlotte and Abraham Aronofsky, and grew up in the borough's Manhattan Beach neighborhood. He said he was "raised culturally Jewish, but there was very little spiritual attendance in temple. It was a cultural thing—celebrating the holidays, knowing where you came from, knowing your history, having respect for what your people have been through." He graduated from Edward R. Murrow High School. He has one sister, Patti, who attended a professional ballet school through high school. His parents would often take him to Broadway theatre performances, which sparked his keen interest in show business.


title: Darren Aronofsky

text: During his youth, he trained as a field biologist with The School for Field Studies in Kenya in 1985 and Alaska in 1986. He attended school in Kenya to pursue an interest in learning about ungulates. He later said, "[T]he School for Field Studies changed the way I perceived the world". Aronofsky's interest in the outdoors led him to backpack his way through Europe and the Middle East. At the age of 18, he entered Harvard University, where he majored in social anthropology and studied filmmaking; he graduated in 1991.


title: Darren Aronofsky

text: He became seriously interested in film while attending Harvard after befriending Dan Schrecker, an aspiring animator, and Sean Gullette, who would go on to star in Aronofsky's first film, "Pi". His cinematic influences included Akira Kurosawa, Roman Polanski, Terry Gilliam, Shinya Tsukamoto, Hubert Selby Jr. Spike Lee, Satoshi Kon, and Jim Jarmusch.


title: Darren Aronofsky

text: Aronofsky's senior thesis film, "Supermarket Sweep", was a finalist in the 1991 Student Academy Awards. In 1992, Aronofsky received his MFA degree in directing from the AFI Conservatory, where his classmates included Todd Field, Doug Ellin, Scott Silver and Mark Waters. He won the institute's Franklin J. Schaffner Alumni Medal.


title: Darren Aronofsky

text: Aronofsky's debut feature, titled "Pi"—sometimes stylized as "π"—was shot in November 1997. The film was financed in part from $100 donations from 600 of his friends and family. In return, he promised to pay each back $150 if the film made money, and they would at least get screen credit if the film lost money. Producing the film with an initial budget of $60,000, Aronofsky premiered "Pi" at the 1998 Sundance Film Festival, where he won the Best Director award. The film itself was nominated for a special Jury Award. Artisan Entertainment bought distribution rights for $1 million. The film was released to the public later that year to critical acclaim and it grossed a total of $3,221,152 at the box-office. "Pi" was the first film to be made available for download on the Internet.


title: Darren Aronofsky

text: Aronofsky followed his debut with "Requiem for a Dream", a film based on Hubert Selby Jr.'s novel of the same name. He was paid $50,000, and worked for three years with nearly the same production team as his previous film. Following the financial breakout of "Pi", he was capable of hiring established actors, including Ellen Burstyn and Jared Leto, and received a budget of $3,500,000 to produce the film. Production of the film occurred over the period of one year, with the film being released in October 2000. The film went on to gross $7,390,108 worldwide. Aronofsky received acclaim for his stylish direction, and was nominated for another Independent Spirit Award, this time for Best Director. The film itself was nominated for five awards in total, winning two, for Best Actress and Cinematography. Clint Mansell's soundtrack for the film was also well-regarded, and since their first collaboration in 1996, Mansell has composed the music to every Aronofsky film, (except for "Mother!", 2017). Ellen Burstyn was nominated for numerous awards, including for an Academy Award for Best Actress, and won the Independent Spirit Award. Aronofsky was awarded the PRISM Award from the Robert Wood Johnson Foundation with the National Institute on Drug Abuse for the film's depiction of drug abuse.


title: Darren Aronofsky

text: In May 2000, Aronofsky was briefly attached to make an adaptation of David Wiesner's 1999 children's book "Sector 7" for Nickelodeon Movies, the project remains unmade. In mid-2000, Warner Bros. hired Aronofsky to write and direct "Batman: Year One", which was to be the fifth film in the Batman franchise. Aronofsky, who collaborated with Frank Miller on an unproduced script for "Ronin", brought Miller to co-write "Year One" with him, intending to reboot the series. "It's "somewhat" based on the comic book", Aronofsky later said. "Toss out everything you can imagine about Batman! Everything! We're starting completely anew", who intended to re-imagine the titular character in a darker, adult-oriented and grounded style, with his adaptation aiming for an R-rating. Regular Aronofsky collaborator Matthew Libatique was set as cinematographer, and Aronofsky had also approached Christian Bale for the role of Batman. Bale was ultimately cast in the role for "Batman Begins". After that project failed to develop, Aronofsky declined the opportunity to direct a film in the "Batman" franchise. In March 2001, he helped write the screenplay to the horror film "Below", which he also produced.


title: Darren Aronofsky

text: In April 2001, Aronofsky entered negotiations with Warner Bros. and Village Roadshow to direct a then-untitled science fiction film, with Brad Pitt in the lead role. In June 2001, actress Cate Blanchett entered talks to join the film, which Aronofsky, wanting the title to remain secret, had given the working title of "The Last Man". Production was postponed to wait for a pregnant Blanchett to give birth to her child in December 2001. Production was ultimately set for late October 2002 in Queensland and Sydney.


title: Darren Aronofsky

text: By now officially titled "The Fountain", the film had a budget of $70 million, co-financed by Warner Bros. and New Regency, which had filled the gap after Village Roadshow withdrew. Pitt left the project seven weeks before the first day of shooting, halting production. In February 2004, Warner Bros. resurrected it on a $35 million budget with Hugh Jackman in the lead role. In August, actress Rachel Weisz filled the vacancy left by Blanchett. "The Fountain" was released on November 22, 2006, a day before the American Thanksgiving holiday; ultimately it grossed $15,978,422 in theaters worldwide. Audiences and critics were divided in their responses to it.


title: Darren Aronofsky

text: In 2007, Aronofsky hired writer Scott Silver to develop "The Fighter" with him. Aronofsky approached Bale to star in the film, but Aronofsky dropped out because of its similarities to "The Wrestler" and to work on MGM's "RoboCop" remake. In July 2010, Aronofsky had left the project due to uncertainty over the financially distressed studio's future. When asked about the film, he said, "I think I'm still attached. I don't know. I haven't heard from anyone in a while". Later during 2007, Aronofsky said he was planning to film a movie about Noah's Ark.


title: Darren Aronofsky

text: Aronofsky had the idea for "The Wrestler" for over a decade. He hired Robert Siegel (filmmaker) to turn his idea into a script. The actor Nicolas Cage entered negotiations in October 2007 to star as Randy, the film's protagonist. The following month Cage left the project, and Mickey Rourke replaced him in the lead role. Aronofsky said that Cage pulled out of the movie because Aronofsky wanted Rourke to star; Aronofsky said, stating that Cage was "a complete gentleman, and he understood that my heart was with Mickey and he stepped aside. I have so much respect for Nic Cage as an actor and I think it really could have worked with Nic but, you know, Nic was incredibly supportive of Mickey and he is old friends with Mickey and really wanted to help with this opportunity, so he pulled himself out of the race." Cage responded, "I wasn't quote 'dropped' from the movie. I resigned from the movie because I didn't think I had enough time to achieve the look of the wrestler who was on steroids, which I would never do". The roughly 40-day shoot began in January 2008.


title: Darren Aronofsky

text: "The Wrestler" premiered at the 65th Venice International Film Festival. Initially receiving little attention, the film wound up winning the Golden Lion, the highest award at the world's oldest film festival. "The Wrestler" received critical acclaim, and both Rourke and co-star Marisa Tomei received Academy Award, Golden Globe, SAG, and BAFTA nominations for their performances. Rourke won a Golden Globe, as did Bruce Springsteen for his original song written for the film. "The Wrestler" grossed $44,674,354 worldwide on a budget of $6,000,000 making it Aronofsky's highest-grossing film to that point.


title: Darren Aronofsky

text: Aronofsky's next film was "Black Swan", which had been in development since 2001, a psychological thriller horror film about a New York City ballerina. The film starred actress Natalie Portman, whom Aronofsky had known since 2000. She introduced Aronofsky to Mila Kunis, who joined the cast in 2009. "Black Swan" had its world premiere as the opening film at the 67th Venice Film Festival in September 2010. It received a standing ovation whose length "Variety" said made it "one of the strongest Venice openers in recent memory".


title: Darren Aronofsky

text: "Black Swan" has received high praise from film critics, and received a record 12 Broadcast Film Critics Association nominations, four Independent Spirit Award nominations, four Golden Globe nominations, three SAG nominations, and many more accolades. Aronofsky received a Golden Globe nomination for Best Director. The film broke limited-release box-office records and grossed an unexpectedly high $329,398,046. On January 25, 2011, the film was nominated for a total of five Academy Awards; Best Picture, Best Director, Best Actress, Best Cinematography and Best Film Editing. On February 27, 2011, Portman won for Best Actress. The film was awarded the PRISM Award from the Substance Abuse & Mental Health Services Administration for its depiction of mental health issues. Aronofsky served as an executive producer on "The Fighter", which was also nominated for Best Picture at the Oscars and won two for Best Supporting Actor and Best Supporting Actress for Christian Bale and Melissa Leo.


title: Darren Aronofsky

text: Aronofsky was attached to "The Wolverine," which was scheduled to begin production in March 2011, but he left the project due to scheduling issues. The film was set to be sixth entry of the "X-Men" film series, featuring a story revolving around Wolverine's adventures in Japan. In December 2011, Aronofsky directed the music video for Lou Reed and Metallica's "The View" from their album "Lulu".


title: Darren Aronofsky

text: Aronofsky was set to direct an HBO series pilot called "Hobgoblin". Announced on June 16, 2011, the series would have depicted a group of magicians and con artists who use their powers of deception to defeat Hitler during World War II. He was set to work on the project with Pulitzer Prize winning author Michael Chabon and his wife Ayelet Waldman. In June 2013, it was announced that HBO had dropped the show and Aronofsky had pulled out, as well.


title: Darren Aronofsky

text: In 2011, Aronofsky tried to launch production on "Noah", a retelling of the Bible story of Noah's Ark, projected for a $115 million budget. By the following year, the film had secured funding and distribution from New Regency and Paramount Pictures, with Russell Crowe hired for the title role. The film was adapted into a serialized graphic novel written by Aronofsky and Ari Handel, published in French in October 2011 by the Belgian publisher Le Lombard. By July 2012, Aronofsky's crews were building an ark set in Oyster Bay, Long Island, New York. Aronofsky announced the start of filming on "Noah" on Twitter in the same month, tweeting shots of the filming in Iceland. The film featured Emma Watson, Anthony Hopkins, Logan Lerman, and Jennifer Connelly, with the latter having also starred in "Requiem for a Dream". During its opening weekend, "Noah" held the largest non-sequel opening within Russia and Brazil, and the fourth-largest opening of all time. Aronofsky did not use live animals for the film, saying in a PETA video that "There's really no reason to do it anymore because the technology has arrived". The HSUS gave him their inaugural Humane Filmmaker Award in honor of his use of computer-generated animals.


title: Darren Aronofsky

text: Aronofsky's next film, "mother!", was released by Paramount Pictures on September 15, 2017. It stars Jennifer Lawrence, Javier Bardem, Michelle Pfeiffer, Domhnall Gleeson, Ed Harris and Kristen Wiig. The film sparked controversy upon release for its depiction of violence, and, though it received generally positive reviews, it polarized audiences, becoming one of few films to receive a "F" CinemaScore grade. On review aggregator Rotten Tomatoes, the film has an approval rating of 69% based on 278 reviews, and an average rating of 6.8/10. The site's critical consensus reads, "There's no denying that "mother!" is the thought-provoking product of a singularly ambitious artistic vision, though it may be too unwieldy for mainstream tastes."


title: Darren Aronofsky

text: His next film would be "A courtroom drama of Artificial intelligence", in which he would cooperate again with Paramount Pictures, having doing so in "mother!". In 2018, he was the co-executive producer of "", a virtual reality journey through the universe, that was acquired in a seven figure deal at the 2018 Sundance Film Festival. In January 2021, his next film was announced to be "The Whale", a film adaptation of Samuel D. Hunter's play of the same name, starring Brendan Fraser.


title: Darren Aronofsky

text: In 2018, Aronofsky executive produced One Strange Rock for NatGeo. This 10-part cinematic event series explores the fragility and wonder of planet Earth—one of the most peculiar, unique places in the universe. Host Will Smith guides viewers on an unprecedented exploration, bolstered by an elite group of eight astronauts who provide unique perspectives and relate personal memoirs of the planet seen from a distance. Hourlong episodes delve into monumental events such as genesis, cosmic violence, human intelligence and alien life, oxygen, and survival vs. destruction. The series is now available on Disney Plus. A second season, titled "Welcome to Earth" is currently in production and expected to premiere this year. Aronofsky is also producing Limitless for NatGeo. This upcoming series features Chris Hemsworth as it delves into the science of longevity and how to live better longer.


title: Darren Aronofsky

text: In 2020, Aronofsky produced director Lance Oppenheim's debut feature documentary, Some Kind of Heaven. Set in The Villages retirement community in Florida, the film follows four residents who struggle to fit into the community's prepackaged paradise. The film premiered at the Sundance Film Festival before being released by Magnolia Pictures in 2021. It's now available on Hulu.


title: Darren Aronofsky

text: Aronofsky's first two films, "Pi" and "Requiem for a Dream", were low budget and used montages of extremely short shots, also known as hip hop montages. While an average 100-minute film has 600 to 700 cuts "Requiem for a Dream" features more than 2,000. Split-screen is used extensively, along with extremely tight closeups. Long tracking shots, including those shot with an apparatus strapping a camera to an actor, called the Snorricam, and time-lapse photography are also prominent stylistic devices. Often with his films, Aronofsky alternates between extreme closeups and extreme wide shots to create a sense of isolation.


title: Darren Aronofsky

text: With "The Fountain", Aronofsky restricted the use of computer-generated imagery. Henrik Fett, the visual effects supervisor of Look Effects, said, "Darren was quite clear on what he wanted and his intent to greatly minimize the use of computer graphics ... and I think the results are outstanding." He used more subtle directing in "The Wrestler" and "Black Swan," in which a less-visceral directing style better showcases the acting and narratives. Aronofsky filmed both works with a muted palette and a grainy style. Part of this consistent style involves collaborations with frequent partners cinematographer Matthew Libatique, editor Andrew Weisblum and composer Clint Mansell. Mansell's music is often an important element of the films.


title: Darren Aronofsky

text: "Pi" features several references to mathematics and mathematical theories. In a 1998 interview, Aronofsky acknowledged several influences for "Pi": "I'm a big fan of Kurosawa and Fellini. In this film in particular I think there's a lot of Roman Polanski influence and Terry Gilliam influence as well as a Japanese director named Shinya Tsukamoto—he directed ""." The visual style of "Pi" and "Requiem for a Dream" features numerous similarities to "Tetsuo: The Iron Man".


title: Darren Aronofsky

text: The majority of reviewers characterized "Requiem for a Dream" in the genre of "drug movies", along with films like "The Basketball Diaries", "Trainspotting", "Spun", and "Fear and Loathing in Las Vegas". But, Aronofsky placed his movie in a wider context, saying:


title: Darren Aronofsky

text: With his friend Ari Handel, Aronofsky developed the plot for "The Fountain"; the director wrote the screenplay. In 1999, Aronofsky thought that "The Matrix" redefined the science fiction genre in film. He sought to make a science fiction film that explored new territory, as did "The Matrix" and its predecessors "Star Wars" and "". He wanted to go beyond science fiction films with plots driven by technology and science.


title: Darren Aronofsky

text: In the Toronto International Film Festival interview conducted by James Rocchi, Aronofsky credited the 1957 Charles Mingus song "The Clown" as a major influence on "The Wrestler". It is an instrumental piece, with a poem read over the music about a clown who accidentally discovers the bloodlust of the crowds and eventually kills himself in performance.


title: Darren Aronofsky

text: Aronofsky called "Black Swan" a companion piece to "The Wrestler", recalling one of his early projects about a love affair between a wrestler and a ballerina. He eventually separated the wrestling and the ballet worlds, considering them as "too much for one movie". He compared the two films: "Wrestling some consider the lowest art—if they would even call it art—and ballet some people consider the highest art. But what was amazing to me was how similar the performers in both of these worlds are. They both make incredible use of their bodies to express themselves." About the psychological thriller nature of "Black Swan", actress Natalie Portman compared the film's tone to Polanski's 1968 film "Rosemary's Baby", while Aronofsky said Polanski's "Repulsion" (1965) and "The Tenant" (1976) were "big influences" on the final film. Actor Vincent Cassel also compared "Black Swan" to Polanski's early films, commenting that it was also influenced by Alejandro Jodorowsky's movies and David Cronenberg's early work.


title: Darren Aronofsky

text: "Requiem for a Dream" was originally set for release in 2000, but it was met with controversy in the United States, being rated NC-17 by the MPAA due to a graphic sex scene. Aronofsky appealed the rating, claiming that cutting any portion of the film would dilute its message. The appeal was denied and the film's distributor Artisan Entertainment decided to release the film unrated.


title: Darren Aronofsky

text: The question of who had designed 40 ballet costumes for Portman and the dancers in "Black Swan" was one publicized controversy related to the film. The media gave substantial coverage to the dance double controversy: how much credit for the dancing in the film was being given to Portman and how much to her "dance double", Sarah Lane, an American Ballet Theatre soloist. Lane claimed to have danced more than she was credited. The director and Fox Searchlight disputed Lane's claim. Their released statements said, "We were fortunate to have Sarah there to cover the more complicated dance sequences and we have nothing but praise for the hard work she did. However, Natalie herself did most of the dancing featured in the final film."


title: Darren Aronofsky

text: While Aronofsky's other movies have evoked significant emotional response, they were surpassed by the controversy aroused by "Noah". It was screened for the first time on March 28, 2014, and despite its PG-13 rating, it has quickly been recognized by Box Office Mojo as one of the most controversial movies of the last 35 years along with such titles as "The Passion of the Christ" or "The Da Vinci Code". "Noah" has been banned in United Arab Emirates, Qatar, and Indonesia on religious grounds with other countries following suit.


title: Darren Aronofsky

text: Aronofsky's films have also been criticized for content and casting. His seventh film "mother!" (2017) sparked controversy upon release due to its graphic and disturbing content, polarizing both critics and audiences. His eighth film "The Whale" (2022) also received controversy for lead star Brendan Fraser wearing a prosthetic suit; and for casting the heterosexual Fraser as a homosexual character. Some critics labeled the film's messaging relating to its lead character's obesity as fatphobic. In preparing for the role, Fraser consulted the Obesity Action Coalition (OAC) and conversed with members of the group about their life experiences. The OAC recognized the controversial use of prosthetics in portraying obesity, but the organization supported its role in the film because rather than "demean or ridicule," it helped "realistically portray one person's story with obesity, something rarely seen in media."


title: Darren Aronofsky

text: Aronofsky began dating English actress Rachel Weisz in the summer of 2001, and in 2005 they were engaged. Their son was born on May 31, 2006, in New York City. The couple resided in the East Village in Manhattan. In November 2010, Weisz and Aronofsky announced that they had been apart for months, but were continuing to raise their son together in New York. In September 2016, he began dating actress Jennifer Lawrence, whom he met during the filming of "mother!". The relationship ended in November 2017.


title: Darren Aronofsky

text: In April 2011, Aronofsky was announced as the President of the Jury for the 68th Venice International Film Festival.


title: Darren Aronofsky

text: He said of his spiritual beliefs in 2014, "I think I definitely believe. My biggest expression of what I believe is in "The Fountain"."


title: Darren Aronofsky

text: In November 2014, Aronofsky was announced as the President of the Jury for the 65th Berlin International Film Festival, for February 2015.


title: Darren Aronofsky

text: Aronofsky is known for his environmental activism. A number of his films, notably "Noah" and "mother!", can be read as environmental parables. In 2014 he traveled to the Alberta Tar Sands with the Sierra Club's Michael Brune and Leonardo DiCaprio. In 2015, he traveled to Alaska's Arctic National Wildlife Refuge with Brune, Keri Russell, and the leaders of several veterans groups.


title: Darren Aronofsky

text: In 2015, he collaborated with the artist JR on "The Standing March", a public art installation in Paris encouraging diplomats at COP21 to take action against climate change.


title: Denis Villeneuve

text: Denis Villeneuve (; born October 3, 1967) is a Canadian filmmaker. He is a four-time recipient of the Canadian Screen Award (formerly Genie Award) for Best Direction, winning for "Maelström" in 2001, "Polytechnique" in 2009, "Incendies" in 2010 and "Enemy" in 2013. The first three of these films also won the Canadian Screen Award for Best Motion Picture, while the latter was awarded the prize for best Canadian film of the year by the Toronto Film Critics Association.


title: Denis Villeneuve

text: Internationally, he is known for directing several critically acclaimed films, including the thrillers "Prisoners" (2013) and "Sicario" (2015), as well as the science fiction films "Arrival" (2016) and "Blade Runner 2049" (2017). For his work on "Arrival", he received an Academy Award nomination for Best Director. He was awarded the prize of Director of the Decade by the Hollywood Critics Association in December 2019.


title: Denis Villeneuve

text: His latest film, "Dune" (2021), based on Frank Herbert's novel of the same name, premiered at the 78th Venice International Film Festival; the film received critical acclaim, was a commercial success at the box office internationally, and is his highest grossing film to date, and earned him Academy Award nominations for Best Adapted Screenplay and Best Picture, with the film itself winning a leading six Oscars at the 94th Academy Awards.


title: Denis Villeneuve

text: Villeneuve was born on October 3, 1967, in the village of Gentilly in Bécancour, Quebec, to Nicole Demers, a homemaker, and Jean Villeneuve, a notary. He is the eldest of four siblings. His younger brother, Martin, also became a filmmaker.


title: Denis Villeneuve

text: Villeneuve attended the Séminaire Saint-Joseph de Trois-Rivières and later studied science at the Cégep de Trois-Rivières. He studied cinema at the Université du Québec à Montréal.


title: Denis Villeneuve

text: Villeneuve began his career making short films and won Radio-Canada's youth film competition, "La Course Europe-Asie", in 1991.


title: Denis Villeneuve

text: Villeneuve cites Stanley Kubrick, Alfred Hitchcock, the Coen Brothers, Paul Thomas Anderson and Steven Spielberg as his main cinematic influences.


title: Denis Villeneuve

text: "August 32nd on Earth" (1998), Villeneuve's feature film directorial debut, premiered in the Un Certain Regard section at the 1998 Cannes Film Festival. Alexis Martin won the Prix Jutra for Best Actor. The film was selected as the Canadian entry for the Best Foreign Language Film at the 71st Academy Awards, but was not nominated.


title: Denis Villeneuve

text: His second film, "Maelström" (2000), attracted further attention and screened at festivals worldwide, ultimately winning eight Jutra Awards and the award for Best Canadian Film from the Toronto International Film Festival. He followed that up with the controversial, but critically acclaimed black and white film "Polytechnique" (2009) about the shootings that occurred at the University of Montreal in 1989. The film premiered at the Cannes Film Festival and received numerous honours, including nine Genie Awards, becoming Villeneuve's first film to win the Genie (now known as a Canadian Screen Award) for Best Motion Picture.


title: Denis Villeneuve

text: Villeneuve's fourth film "Incendies" (2010) garnered critical acclaim when it premiered at the Venice and Toronto International Film Festivals in 2010. "Incendies" was subsequently chosen to represent Canada at the 83rd Academy Awards in the category of Best Foreign Language Film and was eventually nominated for the award, though it did not win. The film went on to win eight awards at the 31st Genie Awards, including Best Motion Picture, Best Direction, Best Actress (Lubna Azabal), Best Adapted Screenplay, Cinematography, Editing, Overall Sound, and Sound Editing. "Incendies" was chosen by "The New York Times" as one of the top 10 best films of that year.


title: Denis Villeneuve

text: In January 2011, he was selected by "Variety" as one of the top ten filmmakers to watch. Also in 2011, Villeneuve won the National Arts Centre Award.


title: Denis Villeneuve

text: Villeneuve followed "Incendies" with the crime thriller film "Prisoners", starring Hugh Jackman and Jake Gyllenhaal. The film screened at festivals across the globe, won several awards, and was nominated for the Academy Award for Best Cinematography in 2014.


title: Denis Villeneuve

text: Following "Incendies" and "Prisoners", Villeneuve won Best Director for his sixth film, the psychological thriller "Enemy" (2014), at the 2nd Canadian Screen Awards. The film was awarded the $100,000 cash prize for best Canadian film of the year by the Toronto Film Critics Association in 2015.


title: Denis Villeneuve

text: Later that year, Villeneuve directed the crime thriller film "Sicario", scripted by Taylor Sheridan, and starring Emily Blunt, Benicio del Toro, Daniel Kaluuya, and Josh Brolin. The film competed for the Palme d'Or at the 2015 Cannes Film Festival, though it did not win. It screened at the Toronto International Film Festival in 2015 and went on to gross nearly $80 million worldwide.