title: Santos FC

text: In January 2021, Santos reached the Final of the 2020 Copa Libertadores, but lost to local rivals Palmeiras after a goal in the stoppage time. In the following month, Cuca announced his departure from the club, and Argentine Ariel Holan was hired on his place for the 2021 campaign.


title: Santos FC

text: Holan resigned in April 2021, after a poor campaign in the Campeonato Paulista, and Fernando Diniz was appointed manager in May; he was himself dismissed in September, as the club was threatened with relegation in the Série A, and Fábio Carille finished the season as manager, leading the club to a 10th place. Carille was sacked in February 2022, with Argentine manager Fabián Bustos being appointed in his place.


title: Santos FC

text: The first colors chosen for the new club were white, azure blue and golden lemon as an homage to Concórdia Club. But the difficulty to fabricate the colors on the uniform during those times forced a board meeting a year after the club's foundation. Pelúcio Paul suggested switching the official colors to white and black. According to Paul, the color white represents peace and black represents nobility. It received wide approval from the club members and the president of Santos, Raymundo Marques, based the club on the new colors.


title: Santos FC

text: Since the club's foundation, Santos have had eight main crests, though all underwent minor variations. In 1912, Santos adopted a black and white striped shield, with one of the early leather footballs in the middle and a diagonal band with the letters "SFBC". In order to pay homage to Concórdia Club (who let Santos use their headquarters to plan its foundation), the club used a crest that incorporated three golden lemon letters, the letters S, F and C, in the center of an azure blue circle. At the end of 1912, the crest was remade with a white band around the circle. The white band was surrounded by a golden lemon border. The letters were colored white with golden lemon serving as its outside borders. Due to the difficulty of creating these colors consistently, the crest was rebranded to a white badge with black borders and the letters 'SFC' colored black.


title: Santos FC

text: Later in 1913, the crest was redesigned as a badge inside a globe showing longitude and latitude lines as well as the equator. The badge had a black, diagonal band with "S.F.C." in white text. The top half above the band was white with a leather ball at the top left corner. The bottom half was a black and white striped background. Above the badge was a crown. During 1915, the club temporarily changed its name to União Futebol Clube and were forced to create a temporary crest for that year. The crest was an escutcheon with a white band that read 'União F.C.' and a black background. In 1925, the globe and crown were removed from the crest and it took its future form, only going through a remodelling in 2005.


title: Santos FC

text: Since 1979, Santos has had 38 different sponsors, with Rainha being the club's first kit manufacturer. Casas Bahia, a Brazilian retail chain which specializes in furniture and home appliances, became the first sponsor for the "Peixe". The club is currently primarily sponsored by kit manufacturers Umbro.


title: Santos FC

text: The team has also many sponsors that invest in the club as well. The current sponsors are Caixa (a Brazilian bank), Brahma (the second best-selling beer in Brazil), Semp and Algar Telecom (a Brazilian telecommunications company).


title: Santos FC

text: Soon after its foundation, Santos held their training in a field located in the district of Macuco. As the pitch did not meet the minimum size standards to host official matches, Santos played on the "Igreja Coração de Maria" pitch in Ana Costa Avenue. The field, however, was also used by other clubs in town. In 1915, the situation reached its breaking point, when Santos had constant conflicts with other city clubs on when the field could be used, forcing the club to reject several requests for international friendlies. To solve the problem, the leaders began searching for land in the city. On 31 May 1916, a general assembly approved the purchase of an area of 16,500 square meters, in the neighborhood of Vila Belmiro. On 12 October of that year, the inauguration of the "Vila Belmiro" sports park. The first game was held 10 days later, against Ypiranga for the 1916 Campeonato Paulista which Santos won 2–1. Adolpho Millon Jr. scored the first ever goal on that stadium.


title: Santos FC

text: The capacity has changed frequently, peaking at 32,989 in a 0–0 draw between Santos and Corinthians for the 1964 Campeonato Paulista. Since then, there have been a number of reductions due to modernizations. The last change was a new illumination system being installed on 27 January 1998, with an illumnination level of 1200 lux, more than the FIFA minimum recommendation. The Vila Belmiro was one of the venues of the 1949 Copa América, hosted the 1962 Copa Libertadores final and the 1998 Copa CONMEBOL final. It has also hosted a Copa do Brasil final in 2010. Due to its relative-low capacity, Santos has used other stadiums for high-profile matches such as the Estádio Palestra Itália, Pacaembu and Morumbi, all located in São Paulo, and the Maracanã in Rio de Janeiro. Current Santos President Luis Alvaro Ribeiro and other club directors are agreeing on building a stadium in a city nearby Santos called Cubatao, a stadium for 40,000 people which would become Santos' home field for almost 70% of the games during the season which would increase the team's profit.


title: Santos FC

text: In October 2005, the Centro de Treinamento Rei Pelé was inaugurated. Located in the Jabaquara neighborhood, the training ground, one of the most modern in Brazil, includes medical and training facilities for the first team and a hotel, Recanto dos Alvinegros.


title: Santos FC

text: The "Centro de Treinamento Meninos da Vila", located in the Saboó neighborhood, constitutes two fields of equal size to the "Vila Belmiro" and it is intended for the training and development of players. The two fields are named in homage to the revelation of players Diego and Robinho. It was inaugurated in August 2006.


title: Santos FC

text: The core strength of Santos's global brand is often attributed to Lula's success in leading "Os Santasticos", which drew worldwide acclaim. The iconic team included Gilmar, Mauro, Mengálvio, Coutinho, Pepe and Pelé. This attention often generates greater interest in off-the-field, with the popularity of the club and brand spanning five continents across the globe. Many domestic and international clubs were founded in homage to Santos. In Macapá, Santos Futebol Clube do Macapá was founded in 1973. In João Pessoa, Santos Futebol Clube do João Pessoa was founded in 1949. In Viana, Angola, Santos Futebol Clube de Angola was founded in 2002. In Porto Alegre, Santos Futebol Clube de Alegrete also took after its "Paulista" model. Santos F.C. from Providence, Guyana is another example of the popularity of the infamous brand of the club. Kingston's Santos Football Club, four times national champions of Jamaica, pays tribute not only to the club, by using its name and crest, but also to the Brazilian national team by replacing the white color on the badge with yellow. The "Santos FC Academy" in Oak Park, California is a youth soccer academy in the United States that uses the club's name in tribute. In Iwata, Japan, "Santos FC Soccer Academy Japan" has grown in popularity since ts creation in 1993, having categories from the ages of six to nineteen while the club expanded its brand to Cairo, Egypt in 2008. "Santos FC's Soccer Academy" in Orlando, Florida is another one of the club's international branches. In Hong Kong, Nene Leung created the group "Nene & The Santos Boys", a group of Chinese and Hong Kongers who dedicate themselves to watch Santos' matches.


title: Santos FC

text: Santos is one of Brazil's most economically powerful and richest football clubs; it had an annual turnover of US$45.1m (€31.5m) in 2011 and became one of the most valuable clubs, worth over $86.7m (€60.6m). That same year, Santos' squad became the most valued in South America, being worth over €82m, surpassing every club in the Dutch "Eredivisie" and the English Football League Championship, most of the clubs in Portugal's Primeira Liga, Ukraine's "Premyer-Liha", Turkey's "Süper Lig", Russia's Premier League and France's "Ligue 1", as well as over half the clubs in Germany's "Bundesliga", Italy's "Serie A", Spain's "La Liga" and England's Premier League. Konami's Pro Evolution Soccer, a secondary sponsor of the official Copa Libertadores video game, featured Santos in the video game Pro Evolution Soccer 2012. This is the first time that the club is being featured on a video game. The flamboyant, attacking style of play adopted by this team (in contrast to the physical-minded approach favoured by European, Uruguayan and Argentinian teams of the era) was a constant, worldwide exhibition that saw Santos travel in over 50 countries on every continent (except Antarctica). The club's focus on commercial and sporting success brought significant profits in an industry often characterised by chronic losses. The strength of the Santos' brand was bolstered by its FIFA World Cup winners, especially Pelé. Pelé is hailed as a national hero. He is known for his accomplishments and contributions to the game of football. He is also acknowledged for his vocal support of policies to improve the social conditions of the poor (when he scored his 1,000th goal with Santos he dedicated it to the poor children of Brazil). During his career, he became known as "The King of Football" ("O Rei do Futebol"), "The King Pelé" ("O Rei Pelé") or simply "The King" ("O Rei"). In 2013, Santos signed Pelé to a contract agreeing to make him its global ambassador, extending it to a lifetime contract in 2014, and will continue to use his image in its marketing campaigns.


title: Santos FC

text: Santos is one of the most popular clubs in Brazil. Santos has fans in all states of Brazil and fans in several different countries around the world. According to a survey conducted by the research firm Institute DataFolha in early 2006, Santos is the fourth most popular football club in Brazil. According to the results, Santos was preferred by 4% of the Brazilian population, which represents approximately 10 million fans in Brazil. It is estimated that Santos FC has nearly 20 million fans worldwide and admirers scattered throughout Africa, Europe, North America and Latin American countries.


title: Santos FC

text: There are also several Santos organized fan clubs of football factories, among them Torcida Jovem do Santos, Sangue Jovem, and Força Jovem Santos.


title: Santos FC

text: Santos is one of the clubs with the largest number of members in Brazil, currently has over 70,000 members.


title: Santos FC

text: As Santos have no close rival within its own city, historical rivalries have been with Corinthians, São Paulo, and Palmeiras, clubs from nearby São Paulo city. The biggest rivalry Corinthians is known as "Clássico Alvi-negro" (the Black and White Derby) because of the colors of both teams, the derby between Santos and São Paulo is known as "San-São" and the derby between Santos and Palmeiras is known as "Clássico da Saudade" (Nostalgia Derby).


title: Santos FC

text: The club has been featured in several documentary and semi-documentary films such as "Guadalajara 70," "Uma história de futebol," "Dogão calabresa," and "Boleiros." Former players have also been published, most notably Pelé, but others have appeared in films such as "Ginga." Santos was the featured club in the film "Asa Branca: Um Sonho Brasileiro," a story of a modest but talented soccer player for Santos who reaches stardom. Pelé appeared, alongside other footballers of the 1960s and 1970s, with Michael Caine, and Sylvester Stallone, in the 1981 film "Escape to Victory," about an attempted escape from a World War II German POW Camp. The club has become a symbol of "Jogo Bonito" (English: The Beautiful Game) in football culture. This was largely thanks to the "Peixe's" golden generation of the 1960s, the "Santásticos," considered by some the best club team of all times.


title: Santos FC

text: The club has many local celebrities in its fan group, such as Brazilian singer Mariana Belém, current governor of São Paulo Geraldo Alckmin, current governor of Federal District (Brasília) Agnelo Queiroz, prosecutor Luiz Antônio Marrey, director, writer, actor and television hoster Marcelo Tas and Danielle Zangrando, gold and bronze judo medalist at the 2007 Pan American Games and 1995 World Judo Championships, respectively. Bob Marley, a famous Jamaican singer-songwriter and musician and the most widely known and revered performer of reggae music, played a practice match with Santos in 1980 along with the ska, rocksteady and reggae band Bob Marley & The Wailers. Bob Marley even wore the Santos uniform.


title: Santos FC

text: The Brazilian classical composer Gilberto Mendes, who was born and lived in the city of Santos, wrote in 1969 an oeuvre called "Santos Football Music," with audience interaction and a radio broadcast, previously recorded, of a sports commentator narrating a football game of the Santos FC, all forming a cluster with the orchestra.


title: Santos FC

text: "Santos 100 Anos de Futebol Arte" was a film released in 2012, year of the centenary of Santos FC, documenting the trajectory of the club during its 100 years of history.


title: Santos FC

text: Brazilian teams are limited to five players without Brazilian citizenship per match. The squad list includes only the principal nationality of each player; some players on the squad may have dual citizenship with another country.


title: Santos FC

text: Historically, Santos is Brazil's second most successful team, having won nine domestic trophies, and one of the most recognized football clubs in the world, having won eight international trophies, making them the sixth most successful team in South America (along with Olimpia for official international competitions won, all recognized by CONMEBOL); and the Intercontinental Champions' Supercup title.


title: Santos FC

text: Especially short competitions such as the Recopa Sudamericana, Intercontinental Cup (now defunct), or FIFA Club World Cup are not generally considered to contribute towards a Double or Treble.


title: Santos FC

text: Pelé holds the record for most Santos appearances, having played 1106 first-team matches from 1956 to 1974. Pepe is second, having played 750 times. The record for a goalkeeper is held by Agenor "Manga" Gomes, with 404 appearances. Five other players also have more than 500 appearances: Zito (727), Lima (696), Dorval (612), Edú (584) and Clodoaldo (510). Pelé is also Santos's all-time top goalscorer, with 1091 goals. Four other players have also scored over 200 goals for Santos: Pepe (405), Coutinho (370), Toninho Guerreiro (283) and Feitiço (216).


title: Santos FC

text: Borges holds the record for the most "Brasileirão" goals scored in one season for the club (23 in 2011). Feitiço's 31 goals in the 1931 Campeonato Paulista was the one-season record in the Campeonato Paulista, until it was surpassed by Pelé's 58 goals in 1958, whose record still stands. Officially, the highest home attendance for a Santos match is 132,728, in the Intercontinental Cup, in 1963. Santos has also set records in Brazilian football, most notably the most domestic titles (8 as of 2011) and the most seasons won in a row (5, from 1961 to 1965).


title: Santos FC

text: Santos is the joint-most successful Brazilian team in the Copa Libertadores, winning the 1962, 1963 and 2011 editions. Santos is Brazil's joint-second in Copa Libertadores semifinal appearances with seven in total. The club is also the first Brazilian side to win the Copa Libertadores without losing a single match, which it did in the 1963 season. In 1962, Santos won the Paulista, Taça Brasil, and the Copa Libertadores.


title: Osteoporosis

text: Osteoporosis is a systemic skeletal disorder characterized by low bone mass, micro-architectural deterioration of bone tissue leading to bone fragility, and consequent increase in fracture risk. It is the most common reason for a broken bone among the elderly. Bones that commonly break include the vertebrae in the spine, the bones of the forearm, and the hip. Until a broken bone occurs there are typically no symptoms. Bones may weaken to such a degree that a break may occur with minor stress or spontaneously. After the broken bone heals, the person may have chronic pain and a decreased ability to carry out normal activities.


title: Osteoporosis

text: Osteoporosis may be due to lower-than-normal maximum bone mass and greater-than-normal bone loss. Bone loss increases after the menopause due to lower levels of estrogen, and after Andropause due to lower levels of Testosterone. Osteoporosis may also occur due to a number of diseases or treatments, including alcoholism, anorexia, hyperthyroidism, kidney disease, and surgical removal of the ovaries. Certain medications increase the rate of bone loss, including some antiseizure medications, chemotherapy, proton pump inhibitors, selective serotonin reuptake inhibitors, and glucocorticosteroids. Smoking, and too little exercise are also risk factors. Osteoporosis is defined as a bone density of 2.5 standard deviations below that of a young adult. This is typically measured by dual-energy X-ray absorptiometry (DXA or DEXA).


title: Osteoporosis

text: Prevention of osteoporosis includes a proper diet during childhood and efforts to avoid medications that increase the rate of bone loss. Efforts to prevent broken bones in those with osteoporosis include a good diet, exercise, and fall prevention. Lifestyle changes such as stopping smoking and not drinking alcohol may help. Bisphosphonate medications are useful to decrease future broken bones in those with previous broken bones due to osteoporosis. In those with osteoporosis but no previous broken bones, they are less effective. They do not appear to affect the risk of death.


title: Osteoporosis

text: Osteoporosis becomes more common with age. About 15% of Caucasians in their 50s and 70% of those over 80 are affected. It is more common in women than men. In the developed world, depending on the method of diagnosis, 2% to 8% of males and 9% to 38% of females are affected. Rates of disease in the developing world are unclear. About 22 million women and 5.5 million men in the European Union had osteoporosis in 2010. In the United States in 2010, about 8 million women and between 1 and 2 million men had osteoporosis. White and Asian people are at greater risk. The word "osteoporosis" is from the Greek terms for "porous bones".


title: Osteoporosis

text: Osteoporosis itself has no symptoms; its main consequence is the increased risk of bone fractures. Osteoporotic fractures occur in situations where healthy people would not normally break a bone; they are therefore regarded as fragility fractures. Typical fragility fractures occur in the vertebral column, rib, hip and wrist.


title: Osteoporosis

text: Fractures are a common symptom of osteoporosis and can result in disability. Acute and chronic pain in the elderly is often attributed to fractures from osteoporosis and can lead to further disability and early mortality. These fractures may also be asymptomatic. The most common osteoporotic fractures are of the wrist, spine, shoulder and hip. The symptoms of a vertebral collapse ("compression fracture") are sudden back pain, often with radicular pain (shooting pain due to nerve root compression) and rarely with spinal cord compression or cauda equina syndrome. Multiple vertebral fractures lead to a stooped posture, loss of height, and chronic pain with resultant reduction in mobility.


title: Osteoporosis

text: Fractures of the long bones acutely impair mobility and may require surgery. Hip fracture, in particular, usually requires prompt surgery, as serious risks are associated with it, such as deep vein thrombosis and pulmonary embolism, and increased mortality.


title: Osteoporosis

text: Fracture risk calculators assess the risk of fracture based upon several criteria, including bone mineral density, age, smoking, alcohol usage, weight, and gender. Recognized calculators include FRAX, the Garvan FRC calculator and QFracture as well as the open access FREM tool. The FRAX tool can also be applied in a modification adapted to routinely collected health data.


title: Osteoporosis

text: The term "established osteoporosis" is used when a broken bone due to osteoporosis has occurred. Osteoporosis is a part of frailty syndrome.


title: Osteoporosis

text: There is an increased risk of falls associated with aging. These falls can lead to skeletal damage at the wrist, spine, hip, knee, foot, and ankle. Part of the fall risk is because of impaired eyesight due to many causes, (e.g. glaucoma, macular degeneration), balance disorder, movement disorders (e.g. Parkinson's disease), dementia, and sarcopenia (age-related loss of skeletal muscle). Collapse (transient loss of postural tone with or without loss of consciousness). Causes of syncope are manifold, but may include cardiac arrhythmias (irregular heart beat), vasovagal syncope, orthostatic hypotension (abnormal drop in blood pressure on standing up), and seizures. Removal of obstacles and loose carpets in the living environment may substantially reduce falls. Those with previous falls, as well as those with gait or balance disorders, are most at risk.


title: Osteoporosis

text: As well as susceptibility to breaks and fractures, osteoporosis can lead to other complications. Bone fractures which are results from osteoporosis can lead to disability and even an increased chance of death after the injury.


title: Osteoporosis

text: Depression is considered to a complication of osteoporosis. People with osteoporosis lose independence and risk being isolated due to less physical activity. This will further hinder the ability to manage health issues.


title: Osteoporosis

text: Osteoporosis is also linked to respiratory and cardiovascular health issues, such as loss of lung capacity. Multiple fractures lead to a collapsed thoracic spine, which makes less air being able to move into the lungs. Every thoracic vertebral body collapsed results in the loss of nearly 10% of lung volume.


title: Osteoporosis

text: Risk factors for osteoporotic fracture can be split between nonmodifiable and (potentially) modifiable. In addition, osteoporosis is a recognized complication of specific diseases and disorders. Medication use is theoretically modifiable, although in many cases, the use of medication that increases osteoporosis risk may be unavoidable.


title: Osteoporosis

text: Many diseases and disorders have been associated with osteoporosis. For some, the underlying mechanism influencing the bone metabolism is straightforward, whereas for others the causes are multiple or unknown.


title: Osteoporosis

text: Certain medications have been associated with an increase in osteoporosis risk; only glucocorticosteroids and anticonvulsants are classically associated, but evidence is emerging with regard to other drugs.


title: Osteoporosis

text: Age-related bone loss is common among humans due to exhibiting less dense bones than other primate species. Because of the more porous bones of humans, frequency of severe osteoporosis and osteoporosis related fractures is higher. The human vulnerability to osteoporosis is an obvious cost but it can be justified by the advantage of bipedalism inferring that this vulnerability is the byproduct of such. It has been suggested that porous bones help to absorb the increased stress that we have on two surfaces compared to our primate counterparts who have four surfaces to disperse the force. In addition, the porosity allows for more flexibility and a lighter skeleton that is easier to support. One other consideration may be that diets today have much lower amounts of calcium than the diets of other primates or the tetrapedal ancestors to humans which may lead to higher likelihood to show signs of osteoporosis.


title: Osteoporosis

text: In the absence of risk factors other than sex and age a BMD measurement using dual-energy X-ray absorptiometry (DXA) is recommended for women at age 65. For women with risk factors a clinical FRAX is advised at age 50.


title: Osteoporosis

text: The underlying mechanism in all cases of osteoporosis is an imbalance between bone resorption and bone formation. In normal bone, matrix remodeling of bone is constant; up to 10% of all bone mass may be undergoing remodeling at any point in time. The process takes place in bone multicellular units (BMUs) as first described by Frost & Thomas in 1963. Osteoclasts are assisted by transcription factor PU.1 to degrade the bone matrix, while osteoblasts rebuild the bone matrix. Low bone mass density can then occur when osteoclasts are degrading the bone matrix faster than the osteoblasts are rebuilding the bone.


title: Osteoporosis

text: The three main mechanisms by which osteoporosis develops are an inadequate peak bone mass (the skeleton develops insufficient mass and strength during growth), excessive bone resorption, and inadequate formation of new bone during remodeling, likely due to mesenchymal stem cells biasing away from the osteoblast and toward the marrow adipocyte lineage. An interplay of these three mechanisms underlies the development of fragile bone tissue. Hormonal factors strongly determine the rate of bone resorption; lack of estrogen (e.g. as a result of menopause) increases bone resorption, as well as decreasing the deposition of new bone that normally takes place in weight-bearing bones. The amount of estrogen needed to suppress this process is lower than that normally needed to stimulate the uterus and breast gland. The α-form of the estrogen receptor appears to be the most important in regulating bone turnover. In addition to estrogen, calcium metabolism plays a significant role in bone turnover, and deficiency of calcium and vitamin D leads to impaired bone deposition; in addition, the parathyroid glands react to low calcium levels by secreting parathyroid hormone (parathormone, PTH), which increases bone resorption to ensure sufficient calcium in the blood. The role of calcitonin, a hormone generated by the thyroid that increases bone deposition, is less clear and probably not as significant as that of PTH.


title: Osteoporosis

text: The activation of osteoclasts is regulated by various molecular signals, of which RANKL (receptor activator of nuclear factor kappa-B ligand) is one of the best-studied. This molecule is produced by osteoblasts and other cells (e.g. lymphocytes), and stimulates RANK (receptor activator of nuclear factor κB). Osteoprotegerin (OPG) binds RANKL before it has an opportunity to bind to RANK, and hence suppresses its ability to increase bone resorption. RANKL, RANK, and OPG are closely related to tumor necrosis factor and its receptors. The role of the Wnt signaling pathway is recognized, but less well understood. Local production of eicosanoids and interleukins is thought to participate in the regulation of bone turnover, and excess or reduced production of these mediators may underlie the development of osteoporosis. Osteoclast maturation and activity is also regulated by activation of colony stimulating factor 1 receptor (CSF1R). Menopause-associated increase production of TNF-α stimulates stromal cells to produce colony stimulating factor 1 (CSF-1) which activates CSF1R and stimulates osteoclasts to reabsorb bone.


title: Osteoporosis

text: Trabecular bone (or cancellous bone) is the sponge-like bone in the ends of long bones and vertebrae. Cortical bone is the hard outer shell of bones and the middle of long bones. Because osteoblasts and osteoclasts inhabit the surface of bones, trabecular bone is more active and is more subject to bone turnover and remodeling. Not only is bone density decreased, but the microarchitecture of bone is also disrupted. The weaker spicules of trabecular bone break ("microcracks"), and are replaced by weaker bone. Common osteoporotic fracture sites, the wrist, the hip, and the spine, have a relatively high trabecular bone to cortical bone ratio. These areas rely on the trabecular bone for strength, so the intense remodeling causes these areas to degenerate most when the remodeling is imbalanced. Around the ages of 30–35, cancellous or trabecular bone loss begins. Women may lose as much as 50%, while men lose about 30%.


title: Osteoporosis

text: Osteoporosis can be diagnosed using conventional radiography and by measuring the bone mineral density (BMD). The most popular method of measuring BMD is dual-energy X-ray absorptiometry.


title: Osteoporosis

text: In addition to the detection of abnormal BMD, the diagnosis of osteoporosis requires investigations into potentially modifiable underlying causes; this may be done with blood tests. Depending on the likelihood of an underlying problem, investigations for cancer with metastasis to the bone, multiple myeloma, Cushing's disease and other above-mentioned causes may be performed.


title: Osteoporosis

text: Conventional radiography is useful, both by itself and in conjunction with CT or MRI, for detecting complications of osteopenia (reduced bone mass; pre-osteoporosis), such as fractures; for differential diagnosis of osteopenia; or for follow-up examinations in specific clinical settings, such as soft tissue calcifications, secondary hyperparathyroidism, or osteomalacia in renal osteodystrophy. However, radiography is relatively insensitive to detection of early disease and requires a substantial amount of bone loss (about 30%) to be apparent on X-ray images.


title: Osteoporosis

text: The main radiographic features of generalized osteoporosis are cortical thinning and increased radiolucency. Frequent complications of osteoporosis are vertebral fractures for which spinal radiography can help considerably in diagnosis and follow-up. Vertebral height measurements can objectively be made using plain-film X-rays by using several methods such as height loss together with area reduction, particularly when looking at vertical deformity in T4-L4, or by determining a spinal fracture index that takes into account the number of vertebrae involved. Involvement of multiple vertebral bodies leads to kyphosis of the thoracic spine, leading to what is known as dowager's hump.


title: Osteoporosis

text: Dual-energy X-ray absorptiometry (DEXA scan) is considered the gold standard for the diagnosis of osteoporosis. Osteoporosis is diagnosed when the bone mineral density is less than or equal to 2.5 standard deviations below that of a young (30–40-year-old), healthy adult women reference population. This is translated as a T-score. But because bone density decreases with age, more people become osteoporotic with increasing age. The World Health Organization has established the following diagnostic guidelines:


title: Osteoporosis

text: The International Society for Clinical Densitometry takes the position that a diagnosis of osteoporosis in men under 50 years of age should not be made on the basis of densitometric criteria alone. It also states, for premenopausal women, Z-scores (comparison with age group rather than peak bone mass) rather than T-scores should be used, and the diagnosis of osteoporosis in such women also should not be made on the basis of densitometric criteria alone.


title: Osteoporosis

text: Chemical biomarkers are a useful tool in detecting bone degradation. The enzyme cathepsin K breaks down type-I collagen, an important constituent in bones. Prepared antibodies can recognize the resulting fragment, called a neoepitope, as a way to diagnose osteoporosis. Increased urinary excretion of C-telopeptides, a type-I collagen breakdown product, also serves as a biomarker for osteoporosis.


title: Osteoporosis

text: Quantitative computed tomography (QCT) differs from DXA in that it gives separate estimates of BMD for trabecular and cortical bone and reports precise volumetric mineral density in mg/cm rather than BMD's relative Z-score. Among QCT's advantages: it can be performed at axial and peripheral sites, can be calculated from existing CT scans without a separate radiation dose, is sensitive to change over time, can analyze a region of any size or shape, excludes irrelevant tissue such as fat, muscle, and air, and does not require knowledge of the patient's subpopulation in order to create a clinical score (e.g. the Z-score of all females of a certain age). Among QCT's disadvantages: it requires a high radiation dose compared to DXA, CT scanners are large and expensive, and because its practice has been less standardized than BMD, its results are more operator-dependent. Peripheral QCT has been introduced to improve upon the limitations of DXA and QCT.


title: Osteoporosis

text: Quantitative ultrasound has many advantages in assessing osteoporosis. The modality is small, no ionizing radiation is involved, measurements can be made quickly and easily, and the cost of the device is low compared with DXA and QCT devices. The calcaneus is the most common skeletal site for quantitative ultrasound assessment because it has a high percentage of trabecular bone that is replaced more often than cortical bone, providing early evidence of metabolic change. Also, the calcaneus is fairly flat and parallel, reducing repositioning errors. The method can be applied to children, neonates, and preterm infants, just as well as to adults. Some ultrasound devices can be used on the tibia.


title: Osteoporosis

text: The U.S. Preventive Services Task Force (USPSTF) recommend that all women 65 years of age or older be screened by bone densitometry. Additionally they recommend screening younger women with risk factors. There is insufficient evidence to make recommendations about the intervals for repeated screening and the appropriate age to stop screening.


title: Osteoporosis

text: In men the harm versus benefit of screening for osteoporosis is unknown. Prescrire states that the need to test for osteoporosis in those who have not had a previous bone fracture is unclear. The International Society for Clinical Densitometry suggest BMD testing for men 70 or older, or those who are indicated for risk equal to that of a 70‑year‑old. A number of tools exist to help determine who is reasonable to test.


title: Osteoporosis

text: Lifestyle prevention of osteoporosis is in many aspects the inverse of the potentially modifiable risk factors. As tobacco smoking and high alcohol intake have been linked with osteoporosis, smoking cessation and moderation of alcohol intake are commonly recommended as ways to help prevent it.


title: Osteoporosis

text: In people with coeliac disease adherence to a gluten-free diet decreases the risk of developing osteoporosis and increases bone density. The diet must ensure optimal calcium intake (of at least one gram daily) and measuring vitamin D levels is recommended, and to take specific supplements if necessary.


title: Osteoporosis

text: Studies of the benefits of supplementation with calcium and vitamin D are conflicting, possibly because most studies did not have people with low dietary intakes. A 2018 review by the USPSTF found low-quality evidence that the routine use of calcium and vitamin D supplements (or both supplements together) did not reduce the risk of having an osteoporotic fracture in male and female adults living in the community who had no known history of vitamin D deficiency, osteoporosis, or a fracture. The USPSTF does not recommend low dose supplementation (less than 1 g of calcium and 400 IU of vitamin D) in postmenopausal women as there does not appear to be a difference in fracture risk. A 2015 review found little data that supplementation of calcium decreases the risk of fractures. While some meta-analyses have found a benefit of vitamin D supplements combined with calcium for fractures, they did not find a benefit of vitamin D supplements (800 IU/day or less) alone. While supplementation does not appear to affect the risk of death, an increased risk of myocardial infarctions kidney stones, and stomach problems is associated with calcium supplementation.


title: Osteoporosis

text: Vitamin K deficiency is also a risk factor for osteoporotic fractures. The gene gamma-glutamyl carboxylase (GGCX) is dependent on vitamin K. Functional polymorphisms in the gene could attribute to variation in bone metabolism and BMD. Vitamin K2 is also used as a means of treatment for osteoporosis and the polymorphisms of GGCX could explain the individual variation in the response to treatment of vitamin K.


title: Osteoporosis

text: Dietary sources of calcium include dairy products, leafy greens, legumes, and beans. There has been conflicting evidence about whether or not dairy is an adequate source of calcium to prevent fractures. The National Academy of Sciences recommends 1,000 mg of calcium for those aged 19–50, and 1,200 mg for those aged 50 and above. A review of the evidence shows no adverse effect of higher protein intake on bone health.


title: Osteoporosis

text: There is limited evidence indicating that exercise is helpful in promoting bone health. There is some evidence that physical exercise may be beneficial for bone density in postmenopausal women and lead to a slightly reduced risk of a bone fracture (absolute difference 4%). A position statement concluded that increased bone activity and weight-bearing exercises at a young age prevent bone fragility in adults. Bicycling and swimming are not considered weight-bearing exercise. Neither contribute to slowing bone loss with age, and professional bicycle racing has a negative effect on bone density.


title: Osteoporosis

text: Low-quality evidence suggests that exercise may improve pain and quality of life of people with vertebral fractures and there is moderate-quality evidence that exercise will likely improve physical performance in individuals with vertebral fractures.


title: Osteoporosis

text: People with osteoporosis are at higher risk of falls due to poor postural control, muscle weakness, and overall deconditioning. Postural control is important to maintaining functional movements such as walking and standing. Physical therapy may be an effective way to address postural weakness that may result from vertebral fractures, which are common in people with osteoporosis. Physical therapy treatment plans for people with vertebral fractures include balance training, postural correction, trunk and lower extremity muscle strengthening exercises, and moderate-intensity aerobic physical activity. The goal of these interventions are to regain normal spine curvatures, increase spine stability, and improve functional performance. Physical therapy interventions were also designed to slow the rate of bone loss through home exercise programs.


title: Osteoporosis

text: Whole body vibration therapy has also been suggested as a physical therapy intervention. Moderate to low-quality evidence indicates that whole body vibration therapy may reduce the risk of falls. There are conflicting reviews as to whether vibration therapy improves bone mineral density.


title: Osteoporosis

text: Physical therapy can aid in overall prevention in the development of osteoporosis through therapeutic exercise. Prescribed amounts of mechanical loading or increased forces on the bones promote bone formation and vascularization in various ways, therefore offering a preventative measure that is not reliant on drugs. Specific exercise interacts with the body's hormones and signaling pathways which encourages the maintenance of a healthy skeleton.


title: Osteoporosis

text: Weight-bearing endurance exercise and/or exercises to strengthen muscles improve bone strength in those with osteoporosis. Aerobics, weight bearing, and resistance exercises all maintain or increase BMD in postmenopausal women. Fall prevention can help prevent osteoporosis complications. There is some evidence for hip protectors specifically among those who are in care homes.


title: Osteoporosis

text: The US National Osteoporosis Foundation recommends pharmacologic treatment for patients with hip of spine fracture thought to be related to osteoporosis, those with BMD 2.5 SD or more below the young normal mean (T-score -2.5 or below), and those with BMD between 1 and 2.5 SD below normal mean whose 10-year risk, using FRAX, for hip fracture is equal or more than 3%.


title: Osteoporosis

text: Bisphosphonates are useful in decreasing the risk of future fractures in those who have already sustained a fracture due to osteoporosis. This benefit is present when taken for three to four years. They do not appear to change the overall risk of death. Tentative evidence does not support the use of bisphosphonates as a standard treatment for secondary osteoporosis in children. Different bisphosphonates have not been directly compared, therefore it is unknown if one is better than another. Fracture risk reduction is between 25 and 70% depending on the bone involved. There are concerns of atypical femoral fractures and osteonecrosis of the jaw with long-term use, but these risks are low. With evidence of little benefit when used for more than three to five years and in light of the potential adverse events, it may be appropriate to stop treatment after this time. One medical organization recommends that after five years of medications by mouth or three years of intravenous medication among those at low risk, bisphosphonate treatment can be stopped. In those at higher risk they recommend up to ten years of medication by mouth or six years of intravenous treatment.


title: Osteoporosis

text: The goal of osteoporosis management is to prevent osteoporotic fractures, but for those who have sustained one already it is more urgent to prevent a secondary fracture. That is because patients with a fracture are more likely to experience a recurrent fracture, with marker increase in morbidity and mortality compared. Among the five bisphosphonates, no significant differences were found for a secondary fracture for all fracture endpoints combined. That being said, alendronate was identified as the most efficacious for secondary prevention of vertebral and hip fractures while zoledronate showed better performance for nonvertebral non-hip fracture prevention. There is concern that many people do not receive appropriate pharmacological therapy after a low-impact fracture.


title: Osteoporosis

text: For those with osteoporosis but who have not had a fracture, evidence does not support a reduction in fracture risk with risedronate or etidronate. Alendronate decreases fractures of the spine but does not have any effect on other types of fractures. Half stop their medications within a year. When on treatment with bisphosphonates rechecking bone mineral density is not needed. There is tentative evidence of benefit in males with osteoporosis.


title: Osteoporosis

text: Fluoride supplementation does not appear to be effective in postmenopausal osteoporosis, as even though it increases bone density, it does not decrease the risk of fractures.


title: Osteoporosis

text: Teriparatide (a recombinant parathyroid hormone) has been shown to be effective in treatment of women with postmenopausal osteoporosis. Some evidence also indicates strontium ranelate is effective in decreasing the risk of vertebral and nonvertebral fractures in postmenopausal women with osteoporosis. Hormone replacement therapy, while effective for osteoporosis, is only recommended in women who also have menopausal symptoms. It is not recommended for osteoporosis by itself. Raloxifene, while effective in decreasing vertebral fractures, does not affect the risk of nonvertebral fracture. And while it reduces the risk of breast cancer, it increases the risk of blood clots and strokes. While denosumab is effective at preventing fractures in women, there is not clear evidence of benefit in males. In hypogonadal men, testosterone has been shown to improve bone quantity and quality, but, as of 2008, no studies evaluated its effect on fracture risk or in men with a normal testosterone levels. Calcitonin while once recommended is no longer due to the associated risk of cancer and questionable effect on fracture risk. Alendronic acid/colecalciferol can be taken to treat this condition in post-menopausal women.


title: Osteoporosis

text: Romosozumab (sold under the brand name Evenity) is a monoclonal antibody against sclerostin. Romosozumab is usually reserved for patients with very high fracture risk and is the only available drug therapy for osteoporosis that leads to simultaneous inhibition of bone resorption together with an anabolic effect.


title: Osteoporosis

text: Certain medications like alendronate, etidronate, risedronate, raloxifene, and strontium ranelate can help to prevent osteoporotic fragility fractures in postmenopausal women with osteoporosis. Tentative evidence suggests that Chinese herbal medicines may have potential benefits on bone mineral density.


title: Osteoporosis

text: Although people with osteoporosis have increased mortality due to the complications of fracture, the fracture itself is rarely lethal.


title: Osteoporosis

text: Hip fractures can lead to decreased mobility and additional risks of numerous complications (such as deep venous thrombosis and/or pulmonary embolism, and pneumonia). The six-month mortality rate for those aged 50 and above following hip fracture was found to be around 13.5%, with a substantial proportion (almost 13%) needing total assistance to mobilize after a hip fracture.


title: Osteoporosis

text: Vertebral fractures, while having a smaller impact on mortality, can lead to severe chronic pain of neurogenic origin, which can be hard to control, as well as deformity. Though rare, multiple vertebral fractures can lead to such severe hunchback (kyphosis), the resulting pressure on internal organs can impair one's ability to breathe.


title: Osteoporosis

text: Apart from risk of death and other complications, osteoporotic fractures are associated with a reduced health-related quality of life.


title: Osteoporosis

text: The condition is responsible for millions of fractures annually, mostly involving the lumbar vertebrae, hip, and wrist. Fragility fractures of ribs are also common in men.


title: Osteoporosis

text: Hip fractures are responsible for the most serious consequences of osteoporosis. In the United States, more than 250,000 hip fractures annually are attributable to osteoporosis. A 50-year-old white woman is estimated to have a 17.5% lifetime risk of fracture of the proximal femur. The incidence of hip fractures increases each decade from the sixth through the ninth for both women and men for all populations. The highest incidence is found among men and women ages 80 or older.


title: Osteoporosis

text: Between 35 and 50% of all women over 50 had at least one vertebral fracture. In the United States, 700,000 vertebral fractures occur annually, but only about a third are recognized. In a series of 9704 women aged 68.8 on average studied for 15 years, 324 had already sustained a vertebral fracture at entry into the study and 18.2% developed a vertebral fracture, but that risk rose to 41.4% in women who had a previous vertebral fracture.


title: Osteoporosis

text: In the United States, 250,000 wrist fractures annually are attributable to osteoporosis. Wrist fractures are the third most common type of osteoporotic fractures. The lifetime risk of sustaining a Colles' fracture is about 16% for white women. By the time women reach age 70, about 20% have had at least one wrist fracture.


title: Osteoporosis

text: Fragility fractures of the ribs are common in men as young as age 35. These are often overlooked as signs of osteoporosis, as these men are often physically active and develop the fracture in the course of physical activity, such as falling while water skiing or jet skiing.


title: Osteoporosis

text: It is estimated that 200 million people have osteoporosis. Osteoporosis becomes more common with age. About 15% of Caucasians in their 50s and 70% of those over 80 are affected. It is more common in women than men. In the developed world, depending on the method of diagnosis, 2% to 8% of males and 9% to 38% of females are affected. Rates of disease in the developing world are unclear.


title: Osteoporosis

text: Postmenopausal women have a higher rate of osteoporosis and fractures than older men. Postmenopausal women have decreased estrogen which contributes to their higher rates of osteoporosis. A 60-year-old woman has a 44% risk of fracture while a 60-year-old man has a 25% risk of fracture.


title: Osteoporosis

text: There are 8.9 million fractures worldwide per year due to osteoporosis. Globally, 1 in 3 women and 1 in 5 men over the age of 50 will have an osteoporotic fracture. Data from the United States shows a decrease in osteoporosis within the general population and in white women, from 18% in 1994 to 10% in 2006. White and Asian people are at greater risk. People of African descent are at a decreased risk of fractures due to osteoporosis, although they have the highest risk of death following an osteoporotic fracture.


title: Osteoporosis

text: It has been shown that latitude affects risk of osteoporotic fracture. Areas of higher latitude such as Northern Europe receive less Vitamin D through sunlight compared to regions closer to the equator, and consequently have higher fracture rates in comparison to lower latitudes. For example, Swedish men and women have a 13% and 28.5% risk of hip fracture by age 50, respectively, whereas this risk is only 1.9% and 2.4% in Chinese men and women. Diet may also be a factor that is responsible for this difference, as vitamin D, calcium, magnesium, and folate are all linked to bone mineral density.


title: Osteoporosis

text: There is also an association between Celiac Disease and increased risk of osteoporosis. In studies with premenopausal females and males, there was a correlation between Celiac Disease and osteoporosis and osteopenia. Celiac Disease can decrease absorption of nutrients in the small intestine such as calcium, and a gluten-free diet can help people with Celiac Disease to revert to normal absorption in the gut.


title: Osteoporosis

text: About 22 million women and 5.5 million men in the European Union had osteoporosis in 2010. In the United States in 2010 about 8 million women and one to 2 million men had osteoporosis. This places a large economic burden on the healthcare system due to costs of treatment, long-term disability, and loss of productivity in the working population. The EU spends 37 billion euros per year in healthcare costs related to osteoporosis, and the US spends an estimated US$19 billion annually for related healthcare costs.


title: Osteoporosis

text: The link between age-related reductions in bone density goes back to the early 1800s. French pathologist Jean Lobstein coined the term "osteoporosis". The American endocrinologist Fuller Albright linked osteoporosis with the postmenopausal state.


title: Osteoporosis

text: Anthropologists have studied skeletal remains that showed loss of bone density and associated structural changes that were linked to a chronic malnutrition in the agricultural area in which these individuals lived. "It follows that the skeletal deformation may be attributed to their heavy labor in agriculture as well as to their chronic malnutrition", causing the osteoporosis seen when radiographs of the remains were made.


Don't F**k with Cats: Hunting an Internet Killer is a 2019 true crime docuseries about an online manhunt. It is written & directed by Mark Lewis and was released on Netflix on December 18, 2019. The series chronicles events following a crowd-sourced amateur investigation into a series of animal cruelty acts committed by Canadian pornographic actor Luka Magnotta, culminating in his murder of Chinese international student Jun Lin. It was one of Netflix's Top 5 most-watched documentaries of 2019.


title: Don't F**k with Cats: Hunting an Internet Killer

text: The three-part docuseries follows a group of amateur internet sleuths who launched a manhunt for Luka Magnotta after he gained international notoriety in 2010 for sharing a graphic video online of himself killing two kittens in a plastic bag, and suffocating them with a vacuum cleaner. Magnotta was later convicted for murdering Chinese international student Jun Lin in grisly circumstances in 2012.


text: The series started with Deanna Thompson, a data analyst for a casino in Las Vegas, and John Green, from Los Angeles. In 2010, a viral video called "1 boy 2 kittens" was linked on Facebook and posted on YouTube. The video shows a man playing with two kittens before he puts them in a very tight vacuum seal bag and vacuums out the air, suffocating the kittens. Thompson and Green subsequently started a Facebook group to build evidence and find the perpetrator. The group worked together to examine the details of the video, including the objects in the room, to help solve the mystery.


text: Two weeks after its debut, the docuseries became one of Netflix's Top 5 most-watched documentaries of 2019. On the review aggregator website Rotten Tomatoes, the series has a 69% approval rating, based on 13 reviews, with an average rating of 8.3/10. The website's consensus reads, ""Don't F**k With Cats" offers an intriguing tale, but questionable intent and muddled storytelling make it a hard sell for anyone but true crime completists."


title: Speedball (drug)

text: Speedball (or powerball) is a polydrug mixture of a stimulant (most often cocaine or amphetamine) with an opioid (heroin, morphine, and/or fentanyl) that may be taken intravenously or by nasal insufflation. Original speedball combinations used cocaine hydrochloride mixed with morphine sulfate, while modern speedballs may also use pharmaceutical opioids, benzodiazepines, or barbiturates along with stimulants.


title: Speedball (drug)

text: Speedballs often give stronger effects than either drug when taken alone due to drug synergy, and are considered a particularly hazardous mixture that can easily cause heart attack, respiratory arrest and death. Evidence suggests that when compared to single drugs, speedballs are more likely to lead to addiction, and users are more likely to relapse and also to overdose.


title: Speedball (drug)

text: Cocaine acts as a stimulant, whereas heroin/morphine acts as a depressant. Co-administration is meant to provide an intense rush of euphoria with a high that is supposed to combine the effects of both drugs, while hoping to reduce the negative effects, such as the anxiety, hypertension and palpitations associated with stimulants, and sedation/drowsiness from the depressant. While this can be somewhat effective, there is an imperfect overlap in the effects of stimulants and depressants. Some users report a higher rush and better comedown, and others report displeasure at the drugs effectively cancelling each other out.


title: Speedball (drug)

text: By suppressing the typical negative side effects of the two drugs, the user may falsely believe they have a higher tolerance, or that they are less intoxicated than they actually are. This can cause users to misjudge the intake of one or both of the drugs, resulting in a fatal overdose. Cocaine's stimulating effects also cause the body to use more oxygen, while the depressant effects of heroin slow breathing rates. This combination significantly increases the chance of experiencing respiratory depression or respiratory failure, which may become fatal.


title: Speedball (drug)

text: The United States Drug Enforcement Administration warned in 2019 that the rapid rise of fentanyl supply in the country has led to combinations of both fentanyl and heroin with cocaine ("super speedballs"). In addition, the cross-contamination of powdered fentanyl into cocaine supplies has led to reports of cocaine users unknowingly consuming a speedball-like combination.


title: Speedball (drug)

text: In 1996, Steven Adler had a stroke after taking a speedball, leaving him with a permanent speech impediment. That same year, Dave Gahan suffered a heart attack following a speedball overdose, but survived. According to his autobiography, Slash experienced cardiac arrest for eight minutes after taking a speedball, but was revived.


title: Lock, Stock and Two Smoking Barrels

text: Lock, Stock and Two Smoking Barrels is a 1998 British black comedy crime film written and directed by Guy Ritchie, produced by Matthew Vaughn and starring an ensemble cast featuring Jason Flemyng, Dexter Fletcher, Nick Moran, Steven Mackintosh, Sting with Vinnie Jones and Jason Statham in their feature film debuts.


title: Lock, Stock and Two Smoking Barrels

text: The story is a heist involving a self-confident young card sharp who loses £500,000 to a powerful crime lord in a rigged game of three-card brag. To pay off his debts, he and his friends decide to rob a small-time gang who happen to be operating out of the flat next door.


title: Lock, Stock and Two Smoking Barrels

text: The film brought Ritchie international acclaim and introduced actors Jones, a former Wales international footballer, and Statham, a former diver, to worldwide audiences. Based on a $1.35 million budget, the film had a box office gross of over $28 million, making it a commercial success.


title: Lock, Stock and Two Smoking Barrels

text: A British television series, "Lock, Stock...", followed in 2000, running for seven episodes including the pilot.


title: Lock, Stock and Two Smoking Barrels

text: In London, long-time friends and small-time criminals Eddie, Tom, Soap, and Bacon put together £100,000 so that Eddie, a genius card sharp, can buy into one of "Hatchet" Harry Lonsdale's high-stakes three-card brag games. The game is rigged and the friends end up owing Harry £500,000. Harry then sends his debt collector Big Chris to ensure that the quartet pay the debt within a week.


title: Lock, Stock and Two Smoking Barrels

text: Also interested in a pair of expensive antique Holland & Holland shotguns up for auction, Harry gets his enforcer Barry "the Baptist" to hire two thieves, Gary and Dean, to steal them from a bankrupt lord. The two turn out to be highly incompetent and unwittingly sell the shotguns to Nick "the Greek", a local fence. Barry threatens the two into getting the guns back. Eddie returns home one day and overhears his neighbours—a gang of robbers led by a brutal man called "Dog"—planning a heist on some cannabis growers loaded with cash and drugs. Eddie relays this information to the group, intending for them to rob the neighbours as they return from their heist. Preparing for the robbery, Tom visits Nick the Greek to buy weapons and ends up buying the two antique shotguns.


title: Lock, Stock and Two Smoking Barrels

text: The neighbours' heist gets underway and despite a gang member being killed by his own Bren gun and an incriminating encounter with a traffic warden, they succeed, returning home with a duffel bag full of money and a van loaded with bags of cannabis. Eddie and his friends ambush them as planned and drive away in the neighbours' van containing the cannabis and the traffic warden. They transfer the loot to their own van and return home, knocking out the traffic warden and dumping him by the road, then have Nick fence the drugs to violent gangster Rory Breaker. Rory agrees to buy the cannabis at half price but two of Rory's men visit the house of the cannabis-growers, discover they've been robbed and the cannabis he just bought had been stolen from his own growers. Rory threatens Nick into giving him Eddie's address and tasks one of the growers, Winston, to identify the robbers.


title: Lock, Stock and Two Smoking Barrels

text: Eddie and his friends celebrate at his father JD's bar. Dog's crew accidentally learns that their neighbours robbed them and set up an ambush in Eddie's flat. Rory and his gang arrive instead and in an ensuing shoot-out, all except Dog and Winston are killed. Winston leaves with the drugs, while Dog leaves with the two shotguns and the money but Big Chris incapacitates him and takes everything. Gary and Dean, having learned who bought the shotguns, follow Chris to Harry's place, unaware of the latter pair's relationship.


title: Lock, Stock and Two Smoking Barrels

text: Chris delivers the money and guns to Harry but upon returning to his car he finds Dog holding his son Little Chris at knifepoint, demanding the money be returned to him. Chris complies and starts the car. Gary and Dean burst into Harry's office, and the ensuing confrontation results in their deaths along with Harry's and Barry's. Returning to see the carnage at their flat and their loot missing, Eddie and his friends head to Harry's but upon discovering Harry's corpse, they decide to take the money for themselves. Before they are able to leave, Chris crashes into their car to disable Dog and then bludgeons him to death with his car door. He then takes the debt money back from the unconscious friends but allows Tom to leave with the antique shotguns after a brief stand-off in Harry's office.


title: Lock, Stock and Two Smoking Barrels

text: The friends are arrested but soon acquitted after the traffic warden identifies Dog and his crew as the culprits. Back at the bar, they dispatch Tom to dispose of the antique shotguns—the only remaining evidence linking them to the case. Chris then arrives to give back the duffel bag, from which he has taken all the money for himself and his son and which now contains a catalogue of antique weapons. Leafing through the catalogue, the friends learn that the shotguns are actually quite valuable (worth £250,000 to £300,000) and quickly call Tom to stop him from disposing of the guns. The film ends with Tom leaning over a bridge, with his mobile phone in his mouth and ringing, as he prepares to drop the shotguns into the River Thames.


title: Lock, Stock and Two Smoking Barrels

text: The soundtrack to the film was released in 1998 in the United Kingdom by Island Records. Madonna's Maverick Records label released the soundtrack in the United States in 1999 but omitted nine tracks from the UK release.


title: Lock, Stock and Two Smoking Barrels

text: The production of the film followed Guy Ritchie's single short film which preceded "Lock, Stock". As stated in filmscouts.com:Although it was Ritchie's first feature, his previous short film "The Hard Case" was sufficiently impressive to secure interest not only from financial backers but also persuaded Sting to take the role of JD. "I'd seen Guy's short film and was excited by the pace and energy in it. The way in which he handles violence and action appealed to me. I don't like gratuitous violence. I think it's much more chilling when it's suggested rather than graphic." For Ritchie, getting exactly the right actor for each role was essential. "The casting took forever and we auditioned hundreds of people, but I was determined to hold out until we got the real McCoy." This led to employing several genuine ex-cons, who certainly invest the film with its menacing undertones. Ritchie also looked to the celebrity arena to secure the right cast such as Vinnie Jones. "I didn't hesitate in casting Vinnie as I have the most incredible respect for his acting capabilities."


title: Lock, Stock and Two Smoking Barrels

text: A one-hour documentary of the production of the film was released featuring much of the cast along with Ritchie.


title: Lock, Stock and Two Smoking Barrels

text: The film poster depicting the lead characters as very graphic black and white portraits against a stark white background was created by the advertising photographer John Mac, who is known for his advertising campaigns for luxury brands. He would use a similar technique some years later in 2019 when creating the front cover for the psychological thriller "The Chair Man" by Alex Pearl, which features a man in a wheelchair as a black silhouette against a stark white background.


title: Lock, Stock and Two Smoking Barrels

text: The film was released on 28 August 1998 in the United Kingdom and was the second-highest grossing local production for the year behind "Sliding Doors" with a gross of $18.9 million. It was released on 5 March 1999 in the United States, where its total gross was .


title: Lock, Stock and Two Smoking Barrels

text: On Rotten Tomatoes, the film has an approval rating of 75% based on 67 reviews, with an average rating of 6.70/10. The site's critical consensus reads ""Lock, Stock, and Two Smoking Barrels" is a grimy, twisted, and funny twist on the Tarantino hip gangster formula". On Metacritic, the film has a weighted average score of 66 out of 100 based on 30 reviews, indicating "generally favorable reviews".


title: Lock, Stock and Two Smoking Barrels

text: John Ferguson, writing for the "Radio Times", called the film "the best British crime movie since "The Long Good Friday"". Roger Ebert, in his review for Chicago Sun-Times, wrote: "Lock, Stock, etc.<nowiki>"</nowiki> seems more like an exercise in style than anything else. And so it is. We don't care much about the characters (I felt more actual affection for the phlegmatic bouncer, Barry the Baptist, than for any of the heroes). We realize that the film's style stands outside the material and is lathered on top (there are freeze frames, jokey subtitles, speed-up and slo-mo). And that the characters are controlled by the demands of the clockwork plot. But "Lock, Stock<nowiki>"</nowiki> is fun, in a slapdash way; it has an exuberance, and in a time when movies follow formulas like zombies, it's alive".


title: Lock, Stock and Two Smoking Barrels

text: The film was nominated for a British Academy Film Award in 1998 for the outstanding British Film of the Year. In 2000, Ritchie won an Edgar Award from the Mystery Writers of America for Best Motion Picture Screenplay. In 2004, "Total Film" named it the 38th greatest British film of all time. In 2016, "Empire" magazine ranked "Lock, Stock" 75th on their list of the 100 best British films, with their entry stating, “to call the plot "complex" is to do it a disservice – it's all so slickly done, delivered with such balls-out confidence and written with such an amazing turn of phrase that somehow the convoluted to-ing-and-froing works like clockwork. So well, in fact, that over 18 years later, it remains Ritchie's finest film, a fantastic achievement from a first-time director who took a group of meticulously-cast but relatively unknown actors and spun them into solid fackin' gold.”


title: Lock, Stock and Two Smoking Barrels

text: Focus Features released the "Locked n' Loaded Director's Cut" in 2006. This version of the film contains more of each of the characters' backstories, and runs at a total time of 120 minutes.


title: Haemophilia

text: Haemophilia, or hemophilia (), is a mostly inherited genetic disorder that impairs the body's ability to make blood clots, a process needed to stop bleeding. This results in people bleeding for a longer time after an injury, easy bruising, and an increased risk of bleeding inside joints or the brain. Those with a mild case of the disease may have symptoms only after an accident or during surgery. Bleeding into a joint can result in permanent damage while bleeding in the brain can result in long term headaches, seizures, or a decreased level of consciousness.


title: Haemophilia

text: There are two main types of haemophilia: haemophilia A, which occurs due to low amounts of clotting factor VIII, and haemophilia B, which occurs due to low levels of clotting factor IX. They are typically inherited from one's parents through an X chromosome carrying a nonfunctional gene. Rarely a new mutation may occur during early development or haemophilia may develop later in life due to antibodies forming against a clotting factor. Other types include haemophilia C, which occurs due to low levels of factor XI, Von Willebrand disease, which occur due to low level of a substance called von Willebrand factor in their blood, and parahaemophilia, which occurs due to low levels of factor V. Haemophilia A, B, and C prevent the intrinsic pathway from functioning properly; this clotting pathway is necessary when there is damage to the endothelium of a blood vessel. Acquired haemophilia is associated with cancers, autoimmune disorders, and pregnancy. Diagnosis is by testing the blood for its ability to clot and its levels of clotting factors.


title: Haemophilia

text: Prevention may occur by removing an egg, fertilizing it, and testing the embryo before transferring it to the uterus. Human embryos in research can be regarded as the technical object/process. Missing blood clotting factors are replaced to treat haemophilia. This may be done on a regular basis or during bleeding episodes. Replacement may take place at home or in hospital. The clotting factors are made either from human blood or by recombinant methods. Up to 20% of people develop antibodies to the clotting factors which makes treatment more difficult. The medication desmopressin may be used in those with mild haemophilia A. Studies of gene therapy are in early human trials.


title: Haemophilia

text: Haemophilia A affects about 1 in 5,000–10,000, while haemophilia B affects about 1 in 40,000, males at birth. As haemophilia A and B are both X-linked recessive disorders, females are rarely severely affected. Some females with a nonfunctional gene on one of the X chromosomes may be mildly symptomatic. Haemophilia C occurs equally in both sexes and is mostly found in Ashkenazi Jews. In the 1800s haemophilia B was common within the royal families of Europe. The difference between haemophilia A and B was determined in 1952.


title: Haemophilia

text: Characteristic symptoms vary with severity. In general symptoms are internal or external bleeding episodes, which are called "bleeds". People with more severe haemophilia experience more severe and more frequent bleeds, while people with mild haemophilia usually experience more minor symptoms except after surgery or serious trauma. In cases of moderate haemophilia symptoms are variable which manifest along a spectrum between severe and mild forms.


title: Haemophilia

text: In both haemophilia A and B, there is spontaneous bleeding but a normal bleeding time, normal prothrombin time, normal thrombin time, but prolonged partial thromboplastin time. Internal bleeding is common in people with severe haemophilia and some individuals with moderate haemophilia. The most characteristic type of internal bleed is a joint bleed where blood enters into the joint spaces. This is most common with severe haemophiliacs and can occur spontaneously (without evident trauma). If not treated promptly, joint bleeds can lead to permanent joint damage and disfigurement. Bleeding into soft tissues such as muscles and subcutaneous tissues is less severe but can lead to damage and requires treatment.


title: Haemophilia

text: Children with mild to moderate haemophilia may not have any signs or symptoms at birth, especially if they do not undergo circumcision. Their first symptoms are often frequent and large bruises and haematomas from frequent bumps and falls as they learn to walk. Swelling and bruising from bleeding in the joints, soft tissue, and muscles may also occur. Children with mild haemophilia may not have noticeable symptoms for many years. Often, the first sign in very mild haemophiliacs is heavy bleeding from a dental procedure, an accident, or surgery. Females who are carriers usually have enough clotting factors from their one normal gene to prevent serious bleeding problems, though some may present as mild haemophiliacs.


title: Haemophilia

text: Severe complications are much more common in cases of severe and moderate haemophilia. Complications may arise from the disease itself or from its treatment:


title: Haemophilia

text: Haemophilic arthropathy is characterized by chronic proliferative synovitis and cartilage destruction. If an intra-articular bleed is not drained early, it may cause apoptosis of chondrocytes and affect the synthesis of proteoglycans. The hypertrophied and fragile synovial lining while attempting to eliminate excessive blood may be more likely to easily rebleed, leading to a vicious cycle of hemarthrosis-synovitis-hemarthrosis. In addition, iron deposition in the synovium may induce an inflammatory response activating the immune system and stimulating angiogenesis, resulting in cartilage and bone destruction.


title: Haemophilia

text: Typically, females possess two X-chromosomes, and males have one X and one Y-chromosome. Since the mutations causing the disease are X-linked recessive, a female carrying the defect on one of her X-chromosomes may not be affected by it, as the equivalent dominant allele on her other chromosome should express itself to produce the necessary clotting factors, due to X inactivation. Therefore, heterozygous females are just carriers of this genetic disposition. However, the Y-chromosome in the male has no gene for factors VIII or IX. If the genes responsible for production of factor VIII or factor IX present on a male's X-chromosome are deficient there is no equivalent on the Y-chromosome to cancel it out, so the deficient gene is not masked and the disorder will develop.


title: Haemophilia

text: Since a male receives his single X-chromosome from his mother, the son of a healthy female silently carrying the deficient gene will have a 50% chance of inheriting that gene from her and with it the disease; and if his mother is affected with haemophilia, he will have a 100% chance of being a haemophiliac. In contrast, for a female to inherit the disease, she must receive two deficient X-chromosomes, one from her mother and the other from her father (who must therefore be a haemophiliac himself). Hence, haemophilia is expressed far more commonly among males than females, while females, who must have two deficient X-chromosomes in order to have haemophilia, are far more likely to be silent carriers, survive childhood and to submit each of her genetic children to an at least 50% risk of receiving the deficient gene. However, it is possible for female carriers to become mild haemophiliacs due to lyonisation (inactivation) of the X-chromosomes. Haemophiliac daughters are more common than they once were, as improved treatments for the disease have allowed more haemophiliac males to survive to adulthood and become parents. Adult females may experience menorrhagia (heavy periods) due to the bleeding tendency. The pattern of inheritance is criss-cross type. This type of pattern is also seen in colour blindness.


title: Haemophilia

text: A mother who is a carrier has a 50% chance of passing the faulty X-chromosome to her daughter, while an affected father will always pass on the affected gene to his daughters. A son cannot inherit the defective gene from his father. Genetic testing and genetic counselling is recommended for families with haemophilia. Prenatal testing, such as amniocentesis, is available to pregnant women who may be carriers of the condition.


title: Haemophilia

text: As with all genetic disorders, it is also possible for a human to acquire it spontaneously through mutation, rather than inheriting it, because of a new mutation in one of their parents' gametes. Spontaneous mutations account for about 33% of all cases of haemophilia A. About 30% of cases of haemophilia B are the result of a spontaneous gene mutation.


title: Haemophilia

text: If a female gives birth to a haemophiliac son, either the female is a carrier for the blood disorder or the haemophilia was the result of a spontaneous mutation. Until modern direct DNA testing, however, it was impossible to determine if a female with only healthy children was a carrier or not.


title: Haemophilia

text: If a male has the disease and has children with a female who is not a carrier, his daughters will be carriers of haemophilia. His sons, however, will not be affected with the disease. The disease is X-linked and the father cannot pass haemophilia through the Y-chromosome. Males with the disorder are then no more likely to pass on the gene to their children than carrier females, though all daughters they sire will be carriers and all sons they father will not have haemophilia (unless the mother is a carrier) </ref> .


title: Haemophilia

text: There are numerous different mutations which cause each type of haemophilia. Due to differences in changes to the genes involved, people with haemophilia often have some level of active clotting factor. Individuals with less than 1% active factor are classified as having severe haemophilia, those with 1–5% active factor have moderate haemophilia, and those with mild haemophilia have between 5% and 40% of normal levels of active clotting factor.


title: Haemophilia

text: Haemophilia can be diagnosed before, during or after birth if there is a family history of the condition. Several options are available to parents. If there is no family history of haemophilia, it is usually only diagnosed when a child begins to walk or crawl. They may experience joint bleeds or easy bruising.


title: Haemophilia

text: Mild haemophilia may only be discovered later, usually after an injury or a dental or surgical procedure.


title: Haemophilia

text: Genetic testing and counselling are available to help determine the risk of passing the condition onto a child. This may involve testing a sample of tissue or blood to look for signs of the genetic mutation that causes haemophilia.


title: Haemophilia

text: A pregnant woman with a history of haemophilia in her family can test for the haemophilia gene. Such tests include:


title: Haemophilia

text: There is a small risk of these procedures causing problems such as miscarriage or premature labour, so the woman may discuss this with the doctor in charge of her care.


title: Haemophilia

text: If haemophilia is suspected after a child has been born, a blood test can usually confirm the diagnosis. Blood from the umbilical cord can be tested at birth if there's a family history of haemophilia. A blood test will also be able to identify whether a child has haemophilia A or B, and how severe it is.


title: Haemophilia

text: There are several types of haemophilia: haemophilia A, haemophilia B, haemophilia C, "parahaemophilia", "acquired haemophilia A", and "acquired haemophilia B".


title: Haemophilia

text: Haemophilia A is a recessive X-linked genetic disorder resulting in a deficiency of functional clotting Factor VIII. Haemophilia B is also a recessive X-linked genetic disorder involving a lack of functional clotting Factor IX. Haemophilia C is an autosomal genetic disorder involving a lack of functional clotting Factor XI. Haemophilia C is not completely recessive, as heterozygous individuals also show increased bleeding.


title: Haemophilia

text: The type of haemophilia known as "parahaemophilia" is a mild and rare form and is due to a deficiency in factor V. This type can be inherited or acquired.


title: Haemophilia

text: A non-genetic form of haemophilia is caused by autoantibodies against factor VIII and so is known as "acquired haemophilia A". It is a rare but potentially life-threatening bleeding disorder caused by the development of autoantibodies (inhibitors) directed against plasma coagulation factors. Acquired haemophilia can be associated with cancers, autoimmune disorders and following childbirth.


title: Haemophilia

text: There is no long-term cure. Treatment and prevention of bleeding episodes is done primarily by replacing the missing blood clotting factors.


title: Haemophilia

text: Clotting factors are usually not needed in mild haemophilia. In moderate haemophilia clotting factors are typically only needed when bleeding occurs or to prevent bleeding with certain events. In severe haemophilia preventive use is often recommended two or three times a week and may continue for life. Rapid treatment of bleeding episodes decreases damage to the body.


title: Haemophilia

text: Factor VIII is used in haemophilia A and factor IX in haemophilia B. Factor replacement can be either isolated from human blood serum, recombinant, or a combination of the two. Some people develop antibodies (inhibitors) against the replacement factors given to them, so the amount of the factor has to be increased or non-human replacement products must be given, such as porcine factor VIII.


title: Haemophilia

text: If a person becomes refractory to replacement coagulation factor as a result of high levels of circulating inhibitors, this may be partially overcome with recombinant human factor VIII.


title: Haemophilia

text: In early 2008, the US Food and Drug Administration (FDA) approved an anti-haemophilic drug completely free of albumin, which made it the first anti-haemophilic drug in the US to use an entirely synthetic purification process. Since 1993 recombinant factor products (which are typically cultured in Chinese hamster ovary (CHO) tissue culture cells and involve little, if any human plasma products) have been available and have been widely used in wealthier western countries. While recombinant clotting factor products offer higher purity and safety, they are, like concentrate, extremely expensive, and not generally available in the developing world. In many cases, factor products of any sort are difficult to obtain in developing countries.


title: Haemophilia

text: Clotting factors are either given preventively or on-demand. Preventive use involves the infusion of clotting factor on a regular schedule in order to keep clotting levels sufficiently high to prevent spontaneous bleeding episodes. On-demand (or episodic) treatment involves treating bleeding episodes once they arise. In 2007, a trial comparing on-demand treatment of boys (< 30 months) with haemophilia A with prophylactic treatment (infusions of 25 IU/kg body weight of Factor VIII every other day) in respect to its effect on the prevention of joint-diseases. When the boys reached 6 years of age, 93% of those in the prophylaxis group and 55% of those in the episodic-therapy group had a normal index joint-structure on MRI. Preventative treatment, however, resulted in average costs of $300,000 per year. The author of an editorial published in the same issue of the "NEJM" supports the idea that prophylactic treatment not only is more effective than on demand treatment but also suggests that starting after the first serious joint-related haemorrhage may be more cost effective than waiting until the fixed age to begin. Most haemophiliacs in third world countries have limited or no access to commercial blood clotting factor products.


title: Haemophilia

text: Desmopressin (DDAVP) may be used in those with mild haemophilia A. Tranexamic acid or epsilon aminocaproic acid may be given along with clotting factors to prevent breakdown of clots.


title: Haemophilia

text: Pain medicines, steroids, and physical therapy may be used to reduce pain and swelling in an affected joint. In those with severe hemophilia A already receiving FVIII, emicizumab may provide some benefit. Different treatments are used to help those with an acquired form of hemophilia in addition to the normal clotting factors. Often the most effective treatment is corticosteroids which remove the auto-antibodies in half of people. As a secondary route of treatment, cyclophosphamide and cyclosporine are used and are proven effective for those who did not respond to the steroid treatments. In rare cases a third route or treatment is used, high doses of intravenous immunoglobulin or immunosorbent that works to help control bleeding instead of battling the auto-antibodies.


title: Haemophilia

text: Anticoagulants such as heparin and warfarin are contraindicated for people with haemophilia as these can aggravate clotting difficulties. Also contraindicated are those drugs which have "blood thinning" side effects. For instance, medicines which contain aspirin, ibuprofen, or naproxen sodium should not be taken because they are well known to have the side effect of prolonged bleeding.


title: Haemophilia

text: Also contraindicated are activities with a high likelihood of trauma, such as motorcycling and skateboarding. Popular sports with very high rates of physical contact and injuries such as American football, hockey, boxing, wrestling, and rugby should be avoided by people with haemophilia. Other active sports like soccer, baseball, and basketball also have a high rate of injuries, but have overall less contact and should be undertaken cautiously and only in consultation with a doctor.


title: Haemophilia

text: Like most aspects of the disorder, life expectancy varies with severity and adequate treatment. People with severe haemophilia who do not receive adequate, modern treatment have greatly shortened lifespans and often do not reach maturity. Prior to the 1960s when effective treatment became available, average life expectancy was only 11 years. By the 1980s the life span of the average haemophiliac receiving appropriate treatment was 50–60 years. Today with appropriate treatment, males with haemophilia typically have a near normal quality of life with an average lifespan approximately 10 years shorter than an unaffected male.


title: Haemophilia

text: Since the 1980s the primary leading cause of death of people with severe haemophilia has shifted from haemorrhage to HIV/AIDS acquired through treatment with contaminated blood products. The second leading cause of death related to severe haemophilia complications is intracranial haemorrhage which today accounts for one third of all deaths of people with haemophilia. Two other major causes of death include hepatitis infections causing cirrhosis and obstruction of air or blood flow due to soft tissue haemorrhage.


title: Haemophilia

text: Haemophilia frequency is about 1 instance in every 10,000 births (or 1 in 5,000 male births) for haemophilia A and 1 in 50,000 births for haemophilia B. About 18,000 people in the United States have haemophilia. Each year in the US, about 400 babies are born with the disorder. Haemophilia usually occurs in males and less often in females. It is estimated that about 2,500 Canadians have haemophilia A, and about 500 Canadians have haemophilia B.


title: Haemophilia

text: The excessive bleeding was known to ancient people. The Talmud instructs that a boy must not be circumcised if he had two brothers who died due to complications arising from their circumcisions, and Maimonides says that this excluded paternal half-brothers. This may have been due to a concern about hemophilia. The first medical professional to describe the disease was Arab surgeon Al-Zahrawi, also known as Abulcasis. In the tenth century he described families whose males died of bleeding after only minor traumas. While many other such descriptive and practical references to the disease appear throughout historical writings, scientific analysis did not begin until the start of the nineteenth century.


title: Haemophilia

text: In 1803, John Conrad Otto, a Philadelphian physician, wrote an account about "a hemorrhagic disposition existing in certain families" in which he called the affected males "bleeders". He recognised that the disorder was hereditary and that it affected mostly males and was passed down by healthy females. His paper was the second paper to describe important characteristics of an X-linked genetic disorder (the first paper being a description of colour blindness by John Dalton who studied his own family). Otto was able to trace the disease back to a woman who settled near Plymouth, New Hampshire, in 1720. The idea that affected males could pass the trait onto their unaffected daughters was not described until 1813 when John F. Hay, published an account in "The New England Journal of Medicine".


title: Haemophilia

text: In 1924, a Finnish doctor discovered a hereditary bleeding disorder similar to haemophilia localised in Åland, southwest of Finland. This bleeding disorder is called "Von Willebrand Disease".


title: Haemophilia

text: The term "haemophilia" is derived from the term "haemorrhaphilia" which was used in a description of the condition written by Friedrich Hopff in 1828, while he was a student at the University of Zurich. In 1937, Patek and Taylor, two doctors from Harvard, discovered anti-haemophilic globulin. In 1947, Pavlosky, a doctor from Buenos Aires, found haemophilia A and haemophilia B to be separate diseases by doing a lab test. This test was done by transferring the blood of one haemophiliac to another haemophiliac. The fact that this corrected the clotting problem showed that there was more than one form of haemophilia.


title: Haemophilia

text: Haemophilia has featured prominently in European royalty and thus is sometimes known as 'the royal disease'. Queen Victoria passed the mutation for haemophilia B to her son Leopold and, through two of her daughters, Alice and Beatrice, to various royals across the continent, including the royal families of Spain, Germany, and Russia. In Russia, Tsarevich Alexei, the son and heir of Tsar Nicholas II, famously had haemophilia, which he had inherited from his mother, Empress Alexandra, one of Queen Victoria's granddaughters. The haemophilia of Alexei would result in the rise to prominence of the Russian mystic Grigori Rasputin, at the imperial court.


title: Haemophilia

text: It was claimed that Rasputin was successful at treating Tsarevich Alexei's haemophilia. At the time, a common treatment administered by professional doctors was to use aspirin, which worsened rather than lessened the problem. It is believed that, by simply advising against the medical treatment, Rasputin could bring visible and significant improvement to the condition of Tsarevich Alexei.


title: Haemophilia

text: In Spain, Queen Victoria's youngest daughter, Princess Beatrice, had a daughter Victoria Eugenie of Battenberg, who later became Queen of Spain. Two of her sons were haemophiliacs and both died from minor car accidents. Her eldest son, Prince Alfonso of Spain, Prince of Asturias, died at the age of 31 from internal bleeding after his car hit a telephone booth. Her youngest son, Infante Gonzalo, died at age 19 from abdominal bleeding following a minor car accident in which he and his sister hit a wall while avoiding a cyclist. Neither appeared injured or sought immediate medical care and Gonzalo died two days later from internal bleeding.


title: Haemophilia

text: The method for the production of an antihaemophilic factor was discovered by Judith Graham Pool from Stanford University in 1964, and approved for commercial use in 1971 in the United States under the name "Cryoprecipitated AHF". Together with the development of a system for transportation and storage of human plasma in 1965, this was the first time an efficient treatment for haemophilia became available.


title: Haemophilia

text: Up until late 1985 many people with haemophilia received clotting factor products that posed a risk of HIV and hepatitis C infection. The plasma used to create the products was not screened or tested, nor had most of the products been subject to any form of viral inactivation.


title: Haemophilia

text: Tens of thousands worldwide were infected as a result of contaminated factor products including more than 10,000 people in the United States, 3,500 British, 1,400 Japanese, 700 Canadians, 250 Irish, and 115 Iraqis.


title: Haemophilia

text: Infection via the tainted factor products had mostly stopped by 1986 by which time viral inactivation methods had largely been put into place, although some products were shown to still be dangerous in 1987.


title: Haemophilia

text: In those with severe haemophilia, gene therapy may reduce symptoms to those that a person with mild or moderate haemophilia might have. The best results have been found in haemophilia B. In 2016 early stage human research was ongoing with a few sites recruiting participants. In 2017 a gene therapy trial on nine people with haemophilia A reported that high doses did better than low doses. It is not currently an accepted treatment for haemophilia.


title: Haemophilia

text: In July 2022 results of a gene therapy candidate for haemophilia B called FLT180 were announced, it works using an adeno-associated virus (AAV) to restore the clotting factor IX (FIX) protein, normal levels of the protein were observed with low doses of the therapy but immunosuppression was necessitated to decrease the risk of vector-related immune responses.


title: Alfre Woodard

text: Alfre Woodard (; born November 8, 1952) is an American actress. She has received various accolades, including four Primetime Emmy Awards (tying the record for the most acting Emmys won by an African-American performer, along with Regina King), a Golden Globe Award, and three Screen Actors Guild Awards, in addition to nominations for an Academy Award and two Grammy Awards. In 2020, "The New York Times" ranked Woodard seventeenth on its list of "The 25 Greatest Actors of the 21st Century". She is also known for her work as a political activist and producer. Woodard is a founder of Artists for a New South Africa, an organization devoted to advancing democracy and equality in that country. She is a board member of Academy of Motion Picture Arts and Sciences.


title: Alfre Woodard

text: Woodard began her acting career in theater. After her breakthrough role in the Off-Broadway play "For Colored Girls Who Have Considered Suicide / When the Rainbow Is Enuf" (1977), she made her film debut in "Remember My Name" (1978). In 1983, she won major critical praise and was nominated for an Academy Award for Best Supporting Actress for her role in "Cross Creek". In the same year, Woodard won her first Primetime Emmy Award for her performance in the NBC drama series "Hill Street Blues". Later in the 1980s, Woodard had leading Emmy Award–nominated performances in a number of made for television films, and another Emmy-winning role as a woman dying of leukemia in the pilot episode of "L.A. Law". She also starred as Dr. Roxanne Turner in the NBC medical drama "St. Elsewhere", for which she was nominated for a Primetime Emmy Award for Outstanding Lead Actress in a Drama Series in 1986, and for Guest Actress in 1988.


title: Alfre Woodard

text: In the 1990s, Woodard starred in films such as "Grand Canyon" (1991), "Heart and Souls" (1993), "Crooklyn" (1994), "How to Make an American Quilt" (1995), "Primal Fear" (1996) and "" (1996). She also drew critical praise for her performances in the independent dramas "Passion Fish" (1992), for which she won an Independent Spirit Award and was nominated for a Golden Globe Award for Best Supporting Actress, as well as "Down in the Delta" (1998). For her lead role in the HBO film "Miss Evers' Boys" (1997), Woodard won Golden Globe, Emmy, Screen Actors Guild, and several other awards. In later years, she has appeared in several blockbusters, like "K-PAX" (2001), "The Core" (2003), and "The Forgotten" (2004), starred in independent films, and won her fourth Emmy Award for "The Practice" in 2003. From 2005 to 2006, Woodard starred as Betty Applewhite in the ABC comedy-drama series "Desperate Housewives", and later starred in several short-lived series. She appeared in the critically acclaimed films "12 Years a Slave" (2013), "Juanita" (2019), "Clemency" (2019, for which she was nominated for a BAFTA Award for Best Actress in a Leading Role) as well as the box office hits "Annabelle" (2014) and the remake of "The Lion King" (2019). In the Marvel Cinematic Universe (MCU) multimedia franchise, Woodard portrays grieving mother Miriam Sharpe and crime boss "Black" Mariah Dillard Stokes respectively in the feature film "" (2016) and the streaming television series "Luke Cage" (2016–2018).


title: Alfre Woodard

text: Woodard was born in Tulsa, Oklahoma to Constance, a homemaker, and Marion H. Woodard, an entrepreneur and interior designer. She is the youngest of three children. Woodard attended Bishop Kelley High School, a private Catholic school in Tulsa, graduating from there in 1970. She studied drama at Boston University, from which she graduated.


title: Alfre Woodard

text: Woodard made her professional theater debut in 1974 on Washington, D.C.'s Arena Stage. In 1976, she moved to Los Angeles, California. She later said, "When I came to L.A., people told me there were no film roles for black actors. I'm not a fool. I know that. But I was always confident that I knew my craft." Her breakthrough role was in the Off-Broadway play "For Colored Girls Who Have Considered Suicide When the Rainbow Is Enuf" in 1977. The next year, Woodard made her film debut in "Remember My Name", a thriller written and directed by Alan Rudolph. In the same year, she had a leading role in "The Trial of the Moke", a "Great Performances" television film co-starring Samuel L. Jackson.


title: Alfre Woodard

text: In 1980, Woodard had a role in the ensemble comedy film "Health" directed by Robert Altman. She later appeared in the NBC miniseries "The Sophisticated Gents", and had a regular role alongside Catherine Hicks and Tim Matheson in the short-lived comedy-drama "Tucker's Witch" (1982–83). Later in 1983, Woodard starred opposite Mary Steenburgen in the biography drama film "Cross Creek" directed by Martin Ritt. For her performance in the film, she was nominated for the Academy Award for Best Supporting Actress. Later in 1983, Woodard won her first Primetime Emmy Award in the Outstanding Supporting Actress in a Drama Series category for her three-episode arc as Doris Robson in the NBC critically acclaimed serial drama "Hill Street Blues". Her next television role was on the short-lived NBC sitcom "Sara" starring Geena Davis. In the next few years, Woodard received critical acclaim for her lead performances in a number of made-for-television films. She was nominated for Primetime Emmy Awards for her roles in the films "Words by Heart" (1985), "Unnatural Causes" (1986), and "A Mother's Courage: The Mary Thomas Story" (1989).