text stringlengths 559 401k | source stringlengths 13 121 |
|---|---|
Entheogenic drugs have been used by various cultural groups for thousands of years, traditionally in a religious, shamanic, or spiritual context.
== Common era ==
A Finnish study assayed psilocybin concentrations in old herbarium specimens, and concluded that although psilocybin concentration decreased linearly over time, it was relatively stable. They were able to detect the chemical in specimens that were 115 years old.
== New World ==
The Maya, Olmecs, and Aztecs have well-documented entheogenic complexes. North American cultures also have a tradition of entheogens. In South America, especially in Peru, the archaeological study of cultures like Chavin, Cupisnique, Nazca and Moche, have demonstrated the use of entheogens through archaeobotanical, iconographic and paraphernalia.
=== Egypt ===
In Egypt, the use of opium was generally restricted to priests, magicians, and warriors, its invention is credited to Thoth, and it was said to have been given by Isis to Ra as treatment for a headache. A figure of the Minoan "goddess of the narcotics", wearing a crown of three opium poppies, BCE, was recovered from the Sanctuary of Gazi, Crete, together with a simple smoking apparatus.
=== Olmec ===
The Olmec (1200 BCE to 400 BCE) lived in Central America and are largely viewed by many as the mother culture of Aztecs and Maya. The Olmecs left no written works on their belief structures, so many interpretations on Olmec beliefs are largely based on interpretations of murals and artifacts. Archaeologists state three reasons for believing that the Olmecs used entheogens:
Burials of Bufo toads with priests
The use of entheogens in later Olmec-inspired cultures
Sculptures of shamans and other figures have strong Therianthropic imagery.
=== Maya ===
The Maya (250 BCE to 900 CE) flourished in Central America and were prevalent even until the arrival of the Spanish. The Maya religious tradition was complex and well-developed. Unlike the Olmec, the Maya possessed religious texts that have survived to this day. The Maya religion displayed characteristic Mesoamerican mythology, with a strong emphasis on an individual being a communicator between the physical world and the spiritual world. Mushroom stone effigies, dated to 1000 BCE, give evidence that mushrooms were at least revered in a religious way.
The late Maya archaeologist, Dr Stephan F. de Borhegyi, published the first of several articles in which he proposed the existence of a Mesoamerican mushroom cult in the Guatemalan highlands as early as 1000 BCE. This cult, which was associated from its beginnings with ritual human decapitation, a trophy head cult, warfare and the Mesoamerican ballgame, appears to have had its origins along the Pacific coastal piedmont. Borhegyi developed this proposition after finding a significant number of small, mushroom-shaped sculptures in the collections of the Guatemala National Museum and in numerous private collections in and around Guatemala City. While the majority of these small stone sculptures were of indeterminate provenance, a sufficient number had been found during the course of archaeological investigations as to permit him to determine approximate dates and to catalog them stylistically (Borhegyi de, S.F., 1957b, "Mushroom Stones of Middle America," in Mushrooms, Russia and History by Valentina P. Wasson and R. Gordon Wasson, eds. N.T.)
Archaeologist Stephan F. de Borhegyi wrote:
"My assignment for the so-called mushroom cult, earliest 1,000 B.C., is based on the excavations of Kidder and Shook at the Verbena cemetery at Kaminaljuyu. The mushroom stone found in this Pre-Classic grave, discovered in Mound E-III-3, has a circular groove on the cap. There are also a number of yet unpublished mushroom stone specimens in the Guatemalan Museum from Highland Guatemala where the pottery association would indicate that they are Pre-Classic. In each case the mushroom stone fragments has a circular groove on the top. Mushroom stones found during the Classic and Post-Classic periods do not have circular grooves. This was the basis on which I prepared the chart on mushroom stones which was then subsequently published by the Wassons. Based on Carbon 14 dates and stratigraphy, some of these Pre-Classic finds can be dated as early as 1,000 B.C. The reference is in the following".....(see Shook, E.M. & Kidder, A.V., 1952. Mound E-III-3, Kaminaljuyu, Guatemala; Contributions to American Anthropology & History No. 53 from Publ. 596, Carnegie Institution of Washington, D.C. (letter from de Borhegyi to Dr. Robert Ravicz, MPM archives December 1st 1960)
The most direct evidence of Maya entheogen use comes from modern descendants of the Maya who use entheogenic drugs today.
=== Aztec ===
The Aztec entheogenic complex is extremely well documented. Through historical evidence, there is proof that the Aztecs used several forms of psychoactive drugs. These drugs include Ololiuqui (the seed of Rivea corymbosa), Teonanácatl (translated as “mushroom of the gods", a psilocybe mushroom) and sinicuichi (a flower added to drinks). The Xochipilli statue, according to R.G. Wasson, gives the identity of several entheogenic plants. Other evidence for entheogenic use of the Aztecs comes from the Florentine Codex, a series of 12 books vividly describing the Aztec culture and society, including the use of entheogenic drugs.
=== Native Americans of the Southwestern United States ===
There are several contemporary indigenous groups who use entheogens, in both North and South America.
=== Native Americans of the Southeastern United States ===
Archeological evidence seems to indicate that some Indigenous peoples of the Southeastern Woodlands, specifically those of the Mississippian culture, used Datura stramonium as a hallucinogen.
== Old World ==
=== Paleolithic ===
During the Paleolithic, there is ample evidence of drug use as seen by preserved botanical remains and coprolites. Some scholars had suggested that the "Flower Burial" in Shanidar Cave, a Paleolithic site in Iraq, was evidence of a shamanic death ritual, but more recent evidence and analysis has contradicted that claim. The most direct evidence we have from the Paleolithic in terms of art comes from Tassili, Algeria cave paintings depicting Psilocybe mairei mushrooms dated 7000 to 9000 years before present. From this region, there are several therianthropic images portraying the painter and the animals around him as one (an often cited effect of many psychedelic drugs, Ego death or unity). One image, in particular, shows a man who has formed into one common form with a mushroom.
=== Mesolithic ===
A cave painting in Spain has been interpreted as depicting Psilocybe hispanica.
== See also ==
List of substances used in rituals
Ancient use of cannabis
Cannabis and religion
History of entheogenic drugs
Stela of the cactus bearer
== References ==
== Bibliography ==
Bierhorst, John (1990). The Mythology of Mexico and Central America. William Morrow & Company, New York. ISBN 9780688067212
Demarest, Arthur (2004). Ancient Maya: The Rise and Fall of the Rainforest Civilization. Cambridge: Cambridge University Press.
Dibble, Charles E., et al. (trans). "Florentine Codex: Book 11 - Earthly Things". The School of American Research. Santa Fe, New Mexico, 1963.
Furst, Peter T. (1972) Flesh of the Gods: The Ritual Use of Hallucinogens (with contributions from Wasson and others). Praeger Publishers, Westport. ASIN B000P5B2YI
Hofmann, Albert. "Teonanácatl and Ololiuqui, two ancient magic drugs of Mexico". In UNODC Bulletin on Narcotics, Issue 1, pp. 3–14, 1971.
McKenna, Terence. Food of the Gods. (New York, HarperCollins) p. 84.
Wasson, Robert Gordon, Stella Kramrisch, Jonathan Ott and Carl A. P. Ruck. (1986). Persephone's Quest: Entheogens and the Origins of Religion. ISBN 0-300-05266-9
Roberts, T. B. (editor) (2001). Psychoactive Sacramentals: Essays on Entheogens and Religion. San Francisco: Council on Spiritual Practices.
Roberts, T. B., and Hruby, P. J. (1995–2002). Religion and Psychoactive Sacraments An Entheogen Chrestomathy. Online archive. Council on Spiritual Practices
Roberts, T. B. "Chemical Input—Religious Output: Entheogens." Chapter 10 in Where God and Science Meet: Vol. 3: The Psychology of Religious Experience Robert McNamara (editor)(2006). Westport, Connecticut: Praeger/Greenwood.
Sharon, Douglas (2000). Shamanism & the Sacred Cactus: Ethnoarchaeological Evidence for San Pedro Use in Northern Peru. San Diego Museum of Man.
Torres, Constantino Manuel & David B. Repke (2006). Anadenanthera: Visionary Plant of Ancient South America. Haworth Press, New York. ISBN 978-0-7890-2641-5
== External links ==
Psychedelic Timeline by Tom Frame. Psychedelic Times. | Wikipedia/Entheogenic_drugs_and_the_archaeological_record |
Substance intoxication is a transient condition of altered consciousness and behavior associated with recent use of a substance. It is often maladaptive and impairing, but reversible. If the symptoms are severe, the term "substance intoxication delirium" may be used. Slang terms for the state include: getting high (generic), and being stoned, cooked, or fried (usually in reference to cannabis).
Substance intoxication may often accompany a substance use disorder (SUD); if persistent substance-related problems exist, SUD is the preferred diagnosis.
The term "intoxication" in common use most often refers to alcohol intoxication, or drug addiction usually opioids consisting of an overdose; resulting in death.
== Classification ==
The ICD-10 Mental and Behavioural Disorders due to psychoactive substance use shows:
F10. alcohol
F11. opioids
F12. cannabinoids
F13. sedatives and hypnotics
F14. cocaine
F15. caffeine
F16. hallucinogens
F17. tobacco
F18. volatile solvent
F19. multiple drug use and use of other psychoactive substances
=== Caffeine ===
The discussion over whether the coffee (caffeine) "buzz" counted as intoxication or not was hotly debated during the early to mid 16th century.
=== Contact high ===
Contact high is a phenomenon that occurs in otherwise sober people who experience a drug-like effect just by coming into contact with someone who is under the influence of a psychoactive drug. In a similar way to the placebo effect, a contact high may be caused by classical conditioning as well as by the physical and social
setting.
The term is often incorrectly used to describe the high obtained from passive inhalation of marijuana.
== Slang terms ==
Slang terms include: getting high (generic), being stoned, cooked, or blazed (usually in reference to cannabis), and many more specific slang terms for particular intoxicants. Alcohol intoxication is graded in intensity from buzzed, to tipsy then drunk all the way up to hammered, plastered, smashed, wasted, destroyed, shitfaced and a number of other terms. The term rolling is a common word used to describe being under the influence of MDMA and for LSD the phrases frying or tripping have been used. "Tripping" is a term that is considered applicable to virtually all hallucinogens which includes psychedelics, dissociatives, deliriants and possibly certain types of hypnotics.
== See also ==
"The spins", a state of dizziness and disorientation due to intoxication
Toxicity
Toxidrome
== References ==
== External links == | Wikipedia/Drug_intoxication |
3,4-Methylenedioxy-N-hydroxyamphetamine (MDOH, MDH, N-hydroxytenamphetamine) is an entactogen, psychedelic, and stimulant of the phenethylamine and amphetamine chemical classes. It is the N-hydroxy homologue of MDA, and the N-desmethyl homologue of MDHMA. MDOH was first synthesized and assayed by Alexander Shulgin. In his book PiHKAL (Phenethylamines i Have Known And Loved), Shulgin listed the dosage range as 100–160 mg, and the duration as approximately 3–6 hours. He describes MDOH as being very psychedelic and producing increased pleasure in beauty and nature. He also mentioned several negative side effects also seen with MDMA ("Ecstasy") such as difficulty urinating and internal dryness.
== References ==
== External links ==
MDOH entry in PiHKAL
MDOH entry in PiHKAL • info | Wikipedia/MDOH_(drug) |
2,5-Dimethoxy-4-ethylamphetamine (DOET) is a psychedelic drug of the phenethylamine, amphetamine, and DOx families. It is closely related to DOM and is a synthetic analogue of the naturally occurring phenethylamine psychedelic mescaline. The drug acts as a selective agonist of the serotonin 5-HT2 receptors, including of the serotonin 5-HT2A, 5-HT2B, and 5-HT2C receptors.
DOET was first discovered by Alexander Shulgin in the 1960s. It was clinically studied at low and sub-hallucinogenic doses for potential use as a pharmaceutical drug acting as a "psychic energizer" by Dow Chemical Company in the 1960s. However, its development was terminated after DOM emerged as a street drug and caused a public health crisis in San Francisco in 1967. Nonetheless, DOET's effects at low doses were extensively characterized in small clinical trials. The psychedelic effects of DOET at higher doses were subsequently described by Shulgin in his book PiHKAL in 1991.
DOET is taken by mouth. It has a slow onset of 1 to 3 hours, a delayed peak of 3 to 5 hours, and a dose-dependent and potentially very long duration of 5 to 20 hours. Effects at low doses include mild euphoria, enhanced self-awareness, and talkativeness, among others. Mild closed-eye visuals can also occur. At higher doses, DOET produces psychedelic effects including heightened emotions, sensory enhancement, rich closed-eye visuals, and open-eye visuals, among others. Physical effects include pupil dilation, increased heart rate, and increased blood pressure.
== Effects ==
In a 1968 clinical trial, DOET at an oral dose of 1.5 mg (as the hydrochloride salt) produced mild euphoria and enhanced self-awareness, but no hallucinogenic effects (in terms of perceptual distortions or hallucinations/open-eye visuals), marked behavioral changes, or intellectual impairment. Other reported effects included feeling high, feelings of insight, feelings of pleasantness, body image awareness, impatience, slight difficulty concentrating, talkativeness, racing thoughts, mild closed-eye visuals, time dilation in some, feeling alert, and feeling "washed out" after the drug. Some of the effects of DOET in the study resembled those of dextroamphetamine, including talkativeness, euphoria, and feeling alert. The subjective effects began 1 to 1.5 hours after dosing, peaked around 3 to 4 hours after administration, and the duration was about 5 to 6 hours. Pupil dilation was also observed, but there were no marked changes in heart rate or blood pressure. There were also changes on cognitive tests of association and serial learning. The effects of DOET were similar to those of low doses of DOM (2.7–3.3 mg) but DOET appeared to be more potent (with 2.0 mg DOM being indistinguishable from placebo).
In a subsequent 1971 clinical trial, DOET hydrochloride at oral doses of 0.75 to 4 mg again produced pupil dilation (dose-dependent), mild euphoria, feelings of enhanced self-awareness, and many of the other effects observed in the previous trial. Once again, there were no hallucinogenic effects, aside from closed-eye visuals in a minority of individuals, and there was no cognitive impairment. New assessed and reported effects included feeling relaxed, feelings of unpleasantness in some, lightheadedness, reduced depressive feelings, and feeling anxious or restless. The feelings of nervousness and restlessness occurred more at the higher doses. DOET appeared to show a greater apparent separation between threshold and hallucinogenic doses than had been documented for other psychedelics. Other psychedelics like LSD and DOM show a 2- to 3-fold separation, whereas DOET showed an at least 5-fold separation. The lesser influence of DOET on perceptual processes than equivalent doses of DOM was in spite of the greater potency of DOET than DOM in producing subjective effects in general.
A third and final 1974 clinical trial assessed oral doses of 1 to 4 mg (S)-(+)-DOET, 1 to 2 mg (R)-(–)-DOET, and 2 to 4 mg (RS)-(±)-DOET. It was found that 1 mg (R)-(–)-DOET was equivalent to 4 mg (S)-(+)-DOET in producing psychoactive effects and hence that (R)-(–)-DOET was about 4 times as potent as (S)-(+)-DOET. The onset was 1.5 to 3 hours, peak effects were at 4 to 5 hours, and the duration was 6 to 10 hours. The subjective effects were similar to the earlier trials, but new reported effects included enhanced perception of all senses, difficult-to-describe cognitive alteration, relaxed well-being, and heightened emotions with rapid mood changes. No hallucinogenic effects or visual distortions with eyes open occurred, but vivid imagery with eyes closed could be experienced at the higher doses.
Based on the preceding clinical trials, DOET does not produce clear hallucinogenic effects, aside from closed-eye visuals, at doses of up to 4 mg. However, Alexander Shulgin has stated that DOET is psychedelic at doses of 3 mg and above. In PiHKAL, Shulgin listed the dosage of DOET as 2 to 6 mg and its duration as 14 to 20 hours. In experience reports of 1 to 7 mg DOET in different individuals, 1 mg produced relaxation but no psychedelic effects; 2.5 mg produced both open- and closed-eye visuals; 4 mg produced mood-energizing effects but very little or no hallucinogenic effect; 6 mg produced sensory enhancement, rich closed-eye visuals, and no open-eye visual movement; and 7 mg produced strong feelings with themes of love, eroticism, and divinity, openness, not much visually, closed-eye visuals, and body load symptoms. There was considerable variation in subjective effects between individuals. Shulgin has described both DOET and DOM as being effective antidepressants at lower doses and DOET as being a cognitive enhancer at modest doses.
In line with notions that DOET is a "psychic energizer", the related psychedelic DOPR has shown pro-motivational effects in rodents at sub-hallucinogenic doses and the related drug Ariadne (4C-DOM) has reportedly shown pro-motivational effects in monkeys despite being non-hallucinogenic. ASR-2001 (2CB-5PrO), a non-hallucinogenic analogue of the related psychedelic 2C-B, is under development for use as a stimulant-like medication for the treatment of psychiatric disorders.
== Interactions ==
== Pharmacology ==
=== Pharmacodynamics ===
DOET acts as a selective serotonin 5-HT2 receptor agonist, including of the serotonin 5-HT2A, 5-HT2B, and 5-HT2C receptors. In one study, its affinities (Ki) were 12 nM for the serotonin 5-HT2A receptor, 108 nM for the serotonin 5-HT2C receptor (9-fold lower than for 5-HT2A), and 9,727 nM for the serotonin 5-HT1A receptor (811-fold lower than for 5-HT2A). The drug's EC50Tooltip half-maximal effective concentration for activation of the serotonin 5-HT2A receptor was 1.7 to 8.1 nM depending on the intracellular signaling cascade, while its EmaxTooltip maximal efficacy was 99%. At the serotonin 5-HT2B receptor, its EC50 was 68 nM (8- to 40-fold lower than for 5-HT2A) and its Emax was 73%. DOET is a full agonist of the serotonin 5-HT2A receptor and a high-efficacy partial agonist of the serotonin 5-HT2B and 5-HT2C receptors. The drug is a very weak or inactive agonist of the human trace amine-associated receptor 1 (TAAR1) and is inactive at the rhesus monkey TAAR1. In contrast to many other amphetamines, but like other DOx drugs, DOET does not bind to the monoamine transporters.
DOET produces the head-twitch response (HTR), a behavioral proxy of psychedelic effects, in rodents. As with other psychedelics, DOET shows a biphasic or inverted U-shaped dose–response curve for production of the HTR. The drug induces the HTR to a similar maximal extent as other related psychedelics like DOM and DOI. DOET substitutes for the phenethylamine psychedelics mescaline and DOM, partially substitutes for the tryptamine psychedelic 5-MeO-DMT, and does not substitute for the psychostimulant dextroamphetamine in animal drug discrimination tests. DOET produces hyperlocomotion in mice. However, like other psychedelics, it shows a biphasic or inverted U-shaped dose–response curve, increasing locomotor activity at low to moderate doses and reducing it at high doses. DOET produces serotonin receptor-dependent pressor and hyperthermic effects in rodents.
=== Pharmacokinetics ===
In terms of effects in humans, the onset of lower doses of DOET and its individual enantiomers (0.75–4 mg) is 1 to 3 hours, peak effects occur after 3 to 5 hours, and the duration is 5 to 10 hours. At higher doses of DOET (2 to 6 mg), the duration was reported to be 14 to 20 hours. DOET, like other DOx drugs, has an unusually slow onset and long duration. In rodents, DOET is metabolized by oxidation of the ethyl group at the 4 position. It appears to be metabolized more quickly than DOM. In humans, DOET is excreted 10 to 40% in urine unchanged within 24 hours. The greatest excretion rate occurred between 3 and 6 hours.
== Chemistry ==
DOET, also known as 2,5-dimethoxy-4-ethylamphetamine or as 2,5-dimethoxy-4-ethyl-α-methylphenethylamine, is a substituted phenethylamine and amphetamine and is a member of the DOx group of drugs. It is structurally related to the naturally occurring phenethylamine psychedelic mescaline (3,4,5-trimethoxyphenethylamine). Analogues of DOET include other DOx drugs such as DOM, DOPR, DOBU, DOAM, DOB, and DOI. The α-desmethyl or phenethylamine analogue of DOET is 2C-E. Ariadne is the α-ethyl or phenylisobutylamine analogue of DOM.
== History ==
DOET was discovered by Alexander Shulgin in the 1960s. He assessed DOET after synthesizing DOM in 1963 and discovering DOM's psychedelic effects in 1964. Shulgin found that DOET was a remarkable "psychic energizer" at low doses without producing psychedelic effects at these doses. The effects that he experienced included positive mood, talkativeness, and disinhibition that lasted the whole day. In contrast to Shulgin however, a friend and colleague of Shulgin's that he had try DOET a month later only experienced intense lethargy followed by profound depression after taking the drug. Nonetheless, Shulgin's enthusiasm was not dissuaded, and he felt that the drug should be exploited. Shulgin was working at Dow Chemical Company at the time, and he pitched DOET to the company. They selected DOET as a promising compound and decided to move forward with clinical trials for potential use as a pharmaceutical drug. Shulgin and the company filed a patent for DOET in 1966, which was published in 1970. Dow Chemical Company tasked neuroscientist Solomon H. Snyder at Johns Hopkins University with clinically studying DOET.
In 1967, DOM emerged as a street drug and LSD replacement with the name "STP" in San Francisco and caused a public health crisis. This occurred after LSD distributor Owsley Stanley learned of DOM from Shulgin and began distributing very-high-dose DOM tablets for free. LSD had become illegal in California in 1966 and an alternative had been sought by Stanley. The DOET tablets he distributed could have very long durations (up to 3–4 days) and resulted in intense experiences, worrying physical side effects, and hospitalizations. DOM was first described in the media and scientific literature in 1967 as a result of the crisis. The drug became illegal in the United States in 1968. It is unclear why Shulgin told Stanley about DOM and risked his professional career as well as the DOET clinical development. However, it might have been because Shulgin felt that DOM was a promising compound but was not being further pursued by Dow Chemical Company and would otherwise be forgotten.
Dow Chemical Company terminated its clinical research program on DOET due to the DOM public health crisis. DOET was subsequently first described in the scientific literature by Snyder and colleagues in 1968. Snyder continued to be interested in DOET as a potential medicine, but it was never further developed. Snyder conducted and published a series of three clinical trials of low-dose DOET between 1968 and 1974. In these trials, he compared DOET with DOM, dextroamphetamine, and placebo. As with Shulgin, he found DOET to produce amphetamine-like mild euphoria and talkativeness, among other effects, without producing significant hallucinogenic effects at the assessed doses. Snyder also studied the individual enantiomers of DOET. Shulgin first discussed DOET in publications in 1969 and 1970. DOET became a Schedule I controlled substance in the United States in February 1973.
Ariadne (4C-D, 4C-DOM, BL-3912, Dimoxamine), the α-ethyl or phenylisobutylamine analogue of DOM, was developed by Shulgin in the 1970s. He found it to be psychoactive and to produce "the alert of a psychedelic, with none of the rest of the package". This threshold psychoactivity without psychedelic effects was reminiscent of low doses of DOET. However, in contrast to DOET and other DOx drugs like DOM, Ariadne remained completely non-hallucinogenic even at very high doses, showing a hard ceiling to its psychoactive effects and a lack of recreational potential. Ariadne was patented and developed by Shulgin and Bristol Laboratories for potential use as an antidepressant and for a variety of other clinical indications in the 1970s. (R)-Ariadne (BL-3912A) completed phase 2 clinical trials and showed promising initial clinical benefits. However, further clinical development was halted for strategic economic reasons. In 2023, Ariadne was found to exhibit reduced-efficacy partial agonism of the serotonin 5-HT2A receptor compared to DOM, and this was considered to account for its dramatically reduced hallucinogenic potential.
Shulgin first synthesized 2C-E, the α-desmethyl or phenethylamine analogue of DOET, in 1977. Shulgin first published reports describing the psychedelic effects of higher doses of DOET in PiHKAL in 1991. Prior to this, no reports had clearly been published of hallucinogenic effects of DOET, although Snyder had observed some closed-eye visuals with low-dose DOET in his clinical trials. Shulgin also described 2C-E as producing robust psychedelic effects in PiHKAL, though with much higher doses required than DOET.
== Society and culture ==
=== Names ===
DOET was originally named DOE by Alexander Shulgin. However, he subsequently recalled that this was also an acronym for desoxyephedrine (methamphetamine). As a result, he changed his name for the drug from DOE to DOET or DOEt. Other names that Shulgin has given DOET have included HECATE or Hecate (after the Greek goddess) and DMEA (short for dimethoxyethylamphetamine).
=== Legal status ===
Internationally, DOET is a Schedule I controlled drug; under the Convention on Psychotropic Substances, it is legal only for medical uses or scientific research.
==== United States ====
DOET is classified as a Schedule I substance in the United States and is similarly controlled in other parts of the world.
==== Australia ====
DOET is considered a Schedule 9 prohibited substance in Australia under the Poisons Standard (October 2015). A Schedule 9 substance is a substance which may be abused or misused, the manufacture, possession, sale or use of which should be prohibited by law except when required for medical or scientific research, or for analytical, teaching or training purposes with approval of Commonwealth and/or State or Territory Health Authorities.
== References ==
== External links ==
DOET - Isomer Design
DOET Experience Reports - Erowid
DOET - PiHKAL - Erowid
DOET - PiHKAL - Isomer Design
DOET: Exploring This Rare DOX Psychedelic - Tripsitter | Wikipedia/DOET_(drug) |
F-2, also known as 6-(2-aminopropyl)-5-methoxy-2-methyl-2,3-dihydrobenzofuran or as benzofuran-2-methyl-5-methoxy-6-(2-aminopropane), is a lesser-known psychedelic drug. F-2 was first synthesized by Alexander Shulgin. In his book PiHKAL, the minimum dosage is listed as 15 mg, and its duration is unknown. F-2 produces few to no effects at this dose in humans. Animal studies showed it to substitute for the psychedelic drug DOM, but with less than one tenth the potency. F-2 is the derivative of 6-APDB with a methyl group at the carbon atom of the 3,4-methylenedioxy ring and a methoxy group at the 6 position.
== Legality ==
=== United Kingdom ===
This substance is a Class A drug in the Drugs controlled by the UK Misuse of Drugs Act.
== See also ==
F-22 (drug)
Substituted benzofuran
== References == | Wikipedia/F-2_(drug) |
MALT (N-methyl-N-allyltryptamine or N,N-methylallyltryptamine) is a lesser-known drug from the tryptamine family. It is a novel compound with very little history of human use. It is closely related to methylpropyltryptamine (MPT), as well as N-methyltryptamine. It has been sold online as a designer drug. Very little information on the pharmacology or toxicity of MALT is available.
== Legality ==
MALT is not explicitly scheduled in any countries; however, it could be considered a psychoactive substance under the UK Psychoactive Substances Act, which requires the prosecutor to prove that the substance is psychoactive in order for a person to be charged with an offense.
It could also be considered a structural analog of a scheduled substance under the US Federal Analogue Act due to its similarity to scheduled tryptamines.
== See also ==
5-Methoxy-N,N-Methylallyltryptamine (5-MeO-MALT)
N,N-Diallyltryptamine (DALT)
Methylpropyltryptamine (MPT)
== References ==
== Further reading == | Wikipedia/MALT_(drug) |
Utopioids (U-type opioids) are a class of synthetic opioid analgesic drugs first developed in the 1970s by the pharmaceutical company Upjohn. However, they were never marketed for medical use. Some compounds from this class have been used for scientific research as model kappa opioid receptor agonists. In the mid-2010s, one mu opioid receptor selective compound from this class, U-47700, re-emerged as a designer drug and became widely sold around the world for several years before being banned in various jurisdictions from 2016 onwards. Following the prohibition of U-47700, a number of related compounds have continued to appear on illicit drug markets. They are often marketed online or included as components in mixtures sold under the guise of "street heroin." U-47700 itself is the most potent mu opioid agonist from this class, with around 7 to 10 times the potency of morphine. Some other compounds such as 3,4-MDO-U-47700 and N-Ethyl-U-47700 retain similar mu selectivity but with lower potency similar to that of morphine, while others have a mixture of mu- and kappa-mediated effects, such as U-48800. Most utopioid derivatives are, however, selective kappa agonists, which may have limited abuse potential as dissociative hallucinogens, but do not alleviate withdrawal distress in opioid dependent individuals or maintain addiction in a typical sense. Nevertheless, this has not stopped them from being sold as designer drugs, and a number of these compounds are now banned in many jurisdictions alongside U-47700 itself.
== Table of Utopioids ==
== See also ==
List of benzimidazole opioids
List of fentanyl analogues
== References == | Wikipedia/Utopioid_(drug_class) |
Paisley or paisley pattern is an ornamental textile design using the boteh (Persian: بته) or buta, a teardrop-shaped motif with a curved upper end. Of Persian origin, paisley designs became popular in the West in the 18th and 19th centuries, following imports of post-Mughal Empire versions of the design from India, especially in the form of Kashmir shawls, and were then replicated locally.
The English name for the patterns comes from the town of Paisley, in the west of Scotland, a centre for textiles where paisley designs were reproduced using jacquard looms.
The pattern is still commonly seen in Britain and other English-speaking countries on neckties, waistcoats, and scarves, and remains popular in other items of clothing and textiles in Iran and South and Central Asian countries.
== Origins ==
Some design scholars believe the buta is the convergence of a stylized floral spray and a cypress tree: a Zoroastrian symbol of life and eternity. The "bent" cedar is also a sign of strength and resistance but modesty. The floral motif originated in the Sassanid dynasty, was used later in the Safavid dynasty of Persia (1501–1736), and was a major textile pattern in Iran during the Qajar and Pahlavi dynasties. In these periods, the pattern was used to decorate royal regalia, crowns, and court garments, as well as textiles used by the general population. Persian and Central Asian designs usually range the motifs in orderly rows, with a plain background.
=== Ancient Indo-Iranian origins ===
There is significant speculation as to the origins and symbolism of boteh jegheh, or "ancient motif", known in English as paisley. With experts contesting different time periods for its emergence, to understand the proliferation in the popularity of boteh jegheh design and eventually Paisley, it is important to understand South Asian history. The early Indo-Iranian people flourished in South Asia, where they eventually exchanged linguistic, cultural, and even religious similarities. The ancient Indo-Iranian people shared a religion called Zoroastrianism. Zoroastrianism, some experts argue, served as one of the earliest influences for boteh jegheh's design with the shape representing the cypress tree, an ancient Zoroastrian religious symbol. Others contest that the earliest representation of the pattern's shape comes from the later Sassanid dynasty. The design was representative of a tear drop. Some will argue that boteh jegheh's origins stem from old religious beliefs and its meaning could symbolize the sun, a phoenix, or even an ancient Iranian religious sign for an eagle. Around the same time, a pattern called Boteh was gaining popularity in Iran; the pattern was a floral design, and was used to represent elite status, mostly serving to decorate royal objects. The pattern was traditionally woven onto silk clothing using silver and gold material.
== Spread of the pattern in South Asia ==
One of the earliest evidence of the pattern as it relates to Islamic culture has been found at Noh Gumba mosque, in the city of Balkh in Afghanistan, where it is believed that the pattern was included in the design as early as the 800s when the mosque was built. In early Iranian culture, the design was woven onto Termeh, one of the most valuable materials in early Iran where the design served to make clothing for the nobility. At this time, the Iranian nobility wore distinct uniforms called khalat; historically, the design was commonly found on the khalat uniforms. It is stated that at some point in the 1400s, Boteh was transported from Persia to Kashmir.
In the same century, in the 1400s, some of the earliest recorded Kashmir shawls were produced in India, records from the 1500s, during Emperor Akbar's reign over the Mughal people in this area indicate that shawl making was already fashionable in India prior to Mughal conquest which took place in the early 1400s. It has been stated that during Emperor Akbars reign over the Mughal empire, boteh jegheh shawls were extremely popular and fashionable. While one shawl was traditionally worn previously, it was during the rule of Emperor Akbar that the emperor decided to wear two shawls at a time to serve as a status symbol. Along with wearing the shawls frequently, Emperor Akbar also used the shawls as gifts to other rulers and high officials. It is believed that by the 1700s, Kashmir shawls were produced in the image that someone today would associate with modern paisley.
== Introduction of boteh jegheh to Western culture ==
In the 18th and 19th centuries, the British East India Company introduced Kashmir shawls from India to England and Scotland, where they were extremely fashionable and soon duplicated. The first place in the Western world to imitate the design was the town of Paisley in Scotland, Europe's top producer of textiles at this time. Before being produced in Paisley, thus gaining its name in Western culture, the paisley motif was originally referred to by Westerners simply as "pine and cone." European technological innovation in textile manufacturing made Western imitations of Kashmir shawls competitive with Indian-made shawls from Kashmir.
The shawls from India could be quite expensive at the time, but, with the industrial revolution taking place in Europe, paisley shawls were manufactured on a large scale, so lowering their price that they became commonplace among the middle class and boosting the design's popularity even more. While the Western world appropriated much of Eastern culture and design, the Boteh design was by far the most popular. Records indicate that William Moorcroft, an English businessman and explorer, visited the Himalayan mountains in the mid-1800s; upon his arrival, he was enthralled by Boteh-adorned Kashmir shawls and tried to arrange for entire families of Indian textile workers to move to the United Kingdom. The earliest paisley shawls made in the United Kingdom, in Paisley, Scotland, were of fleece, a material with a soft, fluffy texture on one side.
In Asia, the paisley shawls were primarily worn by males, often in formal or ceremonial contexts, but in Europe they were primarily worn instead by women. While still closely resembling its original form, the paisley design would change once it began to be produced in Western culture, with different towns in the United Kingdom applying their own spin to the design.
In the 1800s, European production of paisley increased, particularly in the Scottish town from which the pattern takes its modern name. Soldiers returning from the colonies brought home cashmere wool shawls from India, and the East India Company imported more. The design was copied from the costly silk and wool Kashmir shawls and adapted first for use on handlooms, and, after 1820, on Jacquard looms. The paisley pattern also appeared on European-made bandanas from the early 1800s, the patterns imitating Kashmir shawls.
From roughly 1800 to 1850, the weavers of the town of Paisley in Renfrewshire, Scotland, became the foremost producers of Paisley shawls. Unique additions to their hand-looms and Jacquard looms allowed them to work in five colours when most weavers were producing paisley using only two. The design became known as the Paisley pattern. By 1860, Paisley could produce shawls with 15 colours, which was still only a quarter of the number used in the multicolour paisleys then still being imported from Kashmir. In addition to the loom-woven fabric, the town of Paisley became a major site for the manufacture of printed cotton and wool in the 1800s, according to the Paisley Museum and Art Galleries. In this process, the paisley pattern was printed, rather than woven, onto other textiles, including cotton squares which were the precursors of the modern bandanna. Printed paisley was cheaper than the costly woven paisley, and this added to its popularity. The key places of printing paisley were Britain and the Alsace region of France. The peak period of paisley as a fashionable design ended in the 1870s, perhaps as so many cheap printed versions were on the market.
== Modern use ==
The 1960s proved to be a time of great revival for the paisley design in Western culture. Popular culture in the United States developed a sort of fixation on eastern cultures, including many traditionally Indian styles. Paisley was one of them, being worn by the likes of the Beatles; even the guitar company Fender used the design to decorate one of their most famous electric guitars, the Fender Telecaster. Today, Brad Paisley plays a Telecaster decorated in that pattern, and the design remains common, appearing on jewellery, suit ties, pocket books, cake decorations, tattoos, mouse pads for computers, scarves, and dresses. Paisley bandanas, long a fixture of cowboys, came in the latter twentieth century to be worn by many blue-collar and labor workers as protection from dust and were sported by entertainers popular with such workers, such as the country musician Willie Nelson. The motif also influences furniture design internationally, with many countries applying paisley decoration to wallpaper, pillows, curtains, bed spreads, and like furnishings.
=== Music ===
In the mid- to late 1960s, paisley became identified with psychedelic style and enjoyed mainstream popularity, partly due to the Beatles. The style was particularly popular during the Summer of Love in 1967. The company Fender made a pink paisley version of their Telecaster guitar by sticking paisley wallpaper onto the guitar bodies.
Prince paid tribute to the rock and roll history of paisley when he created the Paisley Park Records recording label and established Paisley Park Studios, both named after his 1985 song "Paisley Park". The Paisley Underground was a music scene active around the same time.
=== Architecture ===
Paisley was a favorite design element of British-Indian architect Laurie Baker. He has made numerous drawings and collages of what he called "mango designs". He used to include the shape in the buildings he designed also.
=== Sports ===
At the 2010 Winter Olympics, Azerbaijan's team sported colorful paisley trousers.
It was the emblem of the 2012 FIFA U-17 Women's World Cup, held in Azerbaijan.
It was part of the emblem for the 2020 FIFA U-17 Women's World Cup, held in India.
== Other languages ==
In Persian, Boteh can be translated to shrub or bush, while in Kashmir it carried the same meaning but was referred to as Buta, or Bu.
The modern French words for paisley are boteh (meaning bush, cluster of leaves or a flower bud) in Persian as well as cachemire (Cachemire (tissu)) and palme ("palm", which – along with the pine and the cypress – is one of the traditional botanical motifs thought to have influenced the shape of the paisley element as it is now known).
In various languages of Bangladesh, India and Pakistan, the design's name is related to the word for mango:
In Bengali: kalka
In Kannada: Maavinakai, unripe mango
In Telugu: mamidi pinde, young mango pattern
In Tamil: mankolam, mango pattern
In Marathi: koyari, mango seed
In Sindhi: aami or ambri, small mango.
In Hindi/Urdu: carrey or kerii, means unripe mango
In Punjabi: ambi, from amb, mango.
In Chinese, paisley is known as the "ham hock pattern" (Chinese: 火腿纹; pinyin: huǒtuǐwén) in mainland China, or "amoeba pattern" in Taiwan (Chinese: 變形蟲; pinyin: biànxíngchóng). In Russia, this ornament is known as "cucumbers" (огурцы).
== References ==
=== Sources ===
Dusenbury, Mary M.; Bier, Carol, Flowers, Dragons & Pine Trees: Asian Textiles in the Spencer Museum of Art, 2004, Hudson Hills, ISBN 1555952380, 9781555952389, p. 48
Petri, F. Origin of the Book of the Dead Angient Egipt. 1926. June part 2 с 41–45
Ashurbeyli, S. [Ашурбейли, С.] "New research on the history of Baku and the Maiden Tower" [«Новые изыскания по истории Баку и Девичьей башни»]. Almanac of Arts [Альманах искусств]. 1972. In Russian.
Ashurbeyli, S. [Ашурбейли, С.] "On the dating and purpose of Giz Galasy in the fortress" [«О датировке и назначении Гыз галасы в крепости»]. Elm [Элм]. 1974. In Russian.
== Further reading ==
Irwin, John (1973). The Kashmir Shawl. Victoria and Albert Museum. ISBN 978-0-11-290164-8..
Levi-Strauss, Monique (1987). The French Shawls. Dryad. ISBN 978-0-85219-759-2..
Reilly, Valerie (1987). The Paisley Pattern: The Official Illustrated History. Glasgow: Richard Drew. ISBN 978-0-87905-317-8..
== External links == | Wikipedia/Paisley_(design) |
Clinical trials are prospective biomedical or behavioral research studies on human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel vaccines, drugs, dietary choices, dietary supplements, and medical devices) and known interventions that warrant further study and comparison. Clinical trials generate data on dosage, safety and efficacy. They are conducted only after they have received health authority/ethics committee approval in the country where approval of the therapy is sought. These authorities are responsible for vetting the risk/benefit ratio of the trial—their approval does not mean the therapy is 'safe' or effective, only that the trial may be conducted.
Depending on product type and development stage, investigators initially enroll volunteers or patients into small pilot studies, and subsequently conduct progressively larger scale comparative studies. Clinical trials can vary in size and cost, and they can involve a single research center or multiple centers, in one country or in multiple countries. Clinical study design aims to ensure the scientific validity and reproducibility of the results.
Costs for clinical trials can range into the billions of dollars per approved drug, and the complete trial process to approval may require 7–15 years. The sponsor may be a governmental organization or a pharmaceutical, biotechnology or medical-device company. Certain functions necessary to the trial, such as monitoring and lab work, may be managed by an outsourced partner, such as a contract research organization or a central laboratory. Only 10 percent of all drugs started in human clinical trials become approved drugs.
== Overview ==
=== Trials of drugs ===
Some clinical trials involve healthy subjects with no pre-existing medical conditions. Other clinical trials pertain to people with specific health conditions who are willing to try an experimental treatment. Pilot experiments are conducted to gain insights for design of the clinical trial to follow.
There are two goals to testing medical treatments: to learn whether they work well enough, called "efficacy", or "effectiveness"; and to learn whether they are safe enough, called "safety". Neither is an absolute criterion; both safety and efficacy are evaluated relative to how the treatment is intended to be used, what other treatments are available, and the severity of the disease or condition. The benefits must outweigh the risks.: 8 For example, many drugs to treat cancer have severe side effects that would not be acceptable for an over-the-counter pain medication, yet the cancer drugs have been approved since they are used under a physician's care and are used for a life-threatening condition.
In the US the elderly constitute 14% of the population, while they consume over one-third of drugs. People over 55 (or a similar cutoff age) are often excluded from trials because their greater health issues and drug use complicate data interpretation, and because they have different physiological capacity than younger people. Children and people with unrelated medical conditions are also frequently excluded. Pregnant women are often excluded due to potential risks to the fetus.
The sponsor designs the trial in coordination with a panel of expert clinical investigators, including what alternative or existing treatments to compare to the new drug and what type(s) of patients might benefit. If the sponsor cannot obtain enough test subjects at one location investigators at other locations are recruited to join the study.
During the trial, investigators recruit subjects with the predetermined characteristics, administer the treatment(s) and collect data on the subjects' health for a defined time period. Data include measurements such as vital signs, concentration of the study drug in the blood or tissues, changes to symptoms, and whether improvement or worsening of the condition targeted by the study drug occurs. The researchers send the data to the trial sponsor, who then analyzes the pooled data using statistical tests.
Examples of clinical trial goals include assessing the safety and relative effectiveness of a medication or device:
On a specific kind of patient
At varying dosages
For a new indication
Evaluation for improved efficacy in treating a condition as compared to the standard therapy for that condition
Evaluation of the study drug or device relative to two or more already approved/common interventions for that condition
While most clinical trials test one alternative to the novel intervention, some expand to three or four and may include a placebo.
Except for small, single-location trials, the design and objectives are specified in a document called a clinical trial protocol. The protocol is the trial's "operating manual" and ensures all researchers perform the trial in the same way on similar subjects and that the data is comparable across all subjects.
As a trial is designed to test hypotheses and rigorously monitor and assess outcomes, it can be seen as an application of the scientific method, specifically the experimental step.
The most common clinical trials evaluate new pharmaceutical products, medical devices, biologics, diagnostic assays, psychological therapies, or other interventions. Clinical trials may be required before a national regulatory authority approves marketing of the innovation.
=== Trials of devices ===
Similarly to drugs, manufacturers of medical devices in the United States are required to conduct clinical trials for premarket approval. Device trials may compare a new device to an established therapy, or may compare similar devices to each other. An example of the former in the field of vascular surgery is the Open versus Endovascular Repair (OVER trial) for the treatment of abdominal aortic aneurysm, which compared the older open aortic repair technique to the newer endovascular aneurysm repair device. An example of the latter are clinical trials on mechanical devices used in the management of adult female urinary incontinence.
=== Trials of procedures ===
Similarly to drugs, medical or surgical procedures may be subjected to clinical trials, such as comparing different surgical approaches in treatment of fibroids for subfertility. However, when clinical trials are unethical or logistically impossible in the surgical setting, case-controlled studies will be replaced.
=== Patient and public involvement ===
Besides being participants in a clinical trial, members of the public can be actively collaborate with researchers in designing and conducting clinical research. This is known as patient and public involvement (PPI). Public involvement involves a working partnership between patients, caregivers, people with lived experience, and researchers to shape and influence what is researcher and how. PPI can improve the quality of research and make it more relevant and accessible. People with current or past experience of illness can provide a different perspective than professionals and compliment their knowledge. Through their personal knowledge they can identify research topics that are relevant and important to those living with an illness or using a service. They can also help to make the research more grounded in the needs of the specific communities they are part of. Public contributors can also ensure that the research is presented in plain language that is clear to the wider society and the specific groups it is most relevant for.
== History ==
=== Development ===
Although early medical experimentation was performed often, the use of a control group to provide an accurate comparison for the demonstration of the intervention's efficacy was generally lacking. For instance, Lady Mary Wortley Montagu, who campaigned for the introduction of inoculation (then called variolation) to prevent smallpox, arranged for seven prisoners who had been sentenced to death to undergo variolation in exchange for their life. Although they survived and did not contract smallpox, there was no control group to assess whether this result was due to the inoculation or some other factor. Similar experiments performed by Edward Jenner over his smallpox vaccine were equally conceptually flawed.
The first proper clinical trial was conducted by the Scottish physician James Lind. The disease scurvy, now known to be caused by a Vitamin C deficiency, would often have terrible effects on the welfare of the crew of long-distance ocean voyages. In 1740, the catastrophic result of Anson's circumnavigation attracted much attention in Europe; out of 1900 men, 1400 had died, most of them allegedly from having contracted scurvy. John Woodall, an English military surgeon of the British East India Company, had recommended the consumption of citrus fruit from the 17th century, but their use did not become widespread.
Lind conducted the first systematic clinical trial in 1747. He included a dietary supplement of an acidic quality in the experiment after two months at sea, when the ship was already afflicted with scurvy. He divided twelve scorbutic sailors into six groups of two. They all received the same diet but, in addition, group one was given a quart of cider daily, group two twenty-five drops of elixir of vitriol (sulfuric acid), group three six spoonfuls of vinegar, group four half a pint of seawater, group five received two oranges and one lemon, and the last group a spicy paste plus a drink of barley water. The treatment of group five stopped after six days when they ran out of fruit, but by then one sailor was fit for duty while the other had almost recovered. Apart from that, only group one also showed some effect of its treatment. Each year, May 20 is celebrated as Clinical Trials Day in honor of Lind's research.
After 1750 the discipline began to take its modern shape. The English doctor John Haygarth demonstrated the importance of a control group for the correct identification of the placebo effect in his celebrated study of the ineffective remedy called Perkin's tractors. Further work in that direction was carried out by the eminent physician Sir William Gull, 1st Baronet in the 1860s.
Frederick Akbar Mahomed (d. 1884), who worked at Guy's Hospital in London, made substantial contributions to the process of clinical trials, where "he separated chronic nephritis with secondary hypertension from what we now term essential hypertension. He also founded the Collective Investigation Record for the British Medical Association; this organization collected data from physicians practicing outside the hospital setting and was the precursor of modern collaborative clinical trials."
=== Modern trials ===
Ideas of Sir Ronald A. Fisher still play a role in clinical trials. While working for the Rothamsted experimental station in the field of agriculture, Fisher developed his Principles of experimental design in the 1920s as an accurate methodology for the proper design of experiments. Among his major ideas include the importance of randomization—the random assignment of individual elements (eg crops or patients) to different groups for the experiment; replication—to reduce uncertainty, measurements should be repeated and experiments replicated to identify sources of variation; blocking—to arrange experimental units into groups of units that are similar to each other, and thus reducing irrelevant sources of variation; use of factorial experiments—efficient at evaluating the effects and possible interactions of several independent factors. Of these, blocking and factorial design are seldom applied in clinical trials, because the experimental units are human subjects and there is typically only one independent intervention: the treatment.
The British Medical Research Council officially recognized the importance of clinical trials from the 1930s. The council established the Therapeutic Trials Committee to advise and assist in the arrangement of properly controlled clinical trials on new products that seem likely on experimental grounds to have value in the treatment of disease.
The first randomised curative trial was carried out at the MRC Tuberculosis Research Unit by Sir Geoffrey Marshall (1887–1982). The trial, carried out between 1946 and 1947, aimed to test the efficacy of the chemical streptomycin for curing pulmonary tuberculosis. The trial was both double-blind and placebo-controlled.
The methodology of clinical trials was further developed by Sir Austin Bradford Hill, who had been involved in the streptomycin trials. From the 1920s, Hill applied statistics to medicine, attending the lectures of renowned mathematician Karl Pearson, among others. He became famous for a landmark study carried out in collaboration with Richard Doll on the correlation between smoking and lung cancer. They carried out a case-control study in 1950, which compared lung cancer patients with matched control and also began a sustained long-term prospective study into the broader issue of smoking and health, which involved studying the smoking habits and health of more than 30,000 doctors over a period of several years. His certificate for election to the Royal Society called him "... the leader in the development in medicine of the precise experimental methods now used nationally and internationally in the evaluation of new therapeutic and prophylactic agents."
International clinical trials day is celebrated on 20 May.
The acronyms used in the titling of clinical trials are often contrived, and have been the subject of derision.
== Types ==
Clinical trials are classified by the research objective created by the investigators.
In an observational study, the investigators observe the subjects and measure their outcomes. The researchers do not actively manage the study.
In an interventional study, the investigators give the research subjects an experimental drug, surgical procedure, use of a medical device, diagnostic or other intervention to compare the treated subjects with those receiving no treatment or the standard treatment. Then the researchers assess how the subjects' health changes.
Trials are classified by their purpose. After approval for human research is granted to the trial sponsor, the U.S. Food and Drug Administration (FDA) organizes and monitors the results of trials according to type:
Prevention trials look for ways to prevent disease in people who have never had the disease or to prevent a disease from returning. These approaches may include drugs, vitamins or other micronutrients, vaccines, or lifestyle changes.
Screening trials test for ways to identify certain diseases or health conditions.
Diagnostic trials are conducted to find better tests or procedures for diagnosing a particular disease or condition.
Treatment trials test experimental drugs, new combinations of drugs, or new approaches to surgery or radiation therapy.
Quality of life trials (supportive care trials) evaluate how to improve comfort and quality of care for people with a chronic illness.
Genetic trials are conducted to assess the prediction accuracy of genetic disorders making a person more or less likely to develop a disease.
Epidemiological trials have the goal of identifying the general causes, patterns or control of diseases in large numbers of people.
Compassionate use trials or expanded access trials provide partially tested, unapproved therapeutics to a small number of patients who have no other realistic options. Usually, this involves a disease for which no effective therapy has been approved, or a patient who has already failed all standard treatments and whose health is too compromised to qualify for participation in randomized clinical trials. Usually, case-by-case approval must be granted by both the FDA and the pharmaceutical company for such exceptions.
Fixed trials consider existing data only during the trial's design, do not modify the trial after it begins, and do not assess the results until the study is completed.
Adaptive clinical trials use existing data to design the trial, and then use interim results to modify the trial as it proceeds. Modifications include dosage, sample size, drug undergoing trial, patient selection criteria and "cocktail" mix. Adaptive trials often employ a Bayesian experimental design to assess the trial's progress. In some cases, trials have become an ongoing process that regularly adds and drops therapies and patient groups as more information is gained. The aim is to more quickly identify drugs that have a therapeutic effect and to zero in on patient populations for whom the drug is appropriate.
Clinical trials are conducted typically in four phases, with each phase using different numbers of subjects and having a different purpose to construct focus on identifying a specific effect.
=== Phases ===
Clinical trials involving new drugs are commonly classified into five phases. Each phase of the drug approval process is treated as a separate clinical trial. The drug development process will normally proceed through phases I–IV over many years, frequently involving a decade or longer. If the drug successfully passes through phases I, II, and III, it will usually be approved by the national regulatory authority for use in the general population. Phase IV trials are performed after the newly approved drug, diagnostic or device is marketed, providing assessment about risks, benefits, or best uses.
== Trial design ==
A fundamental distinction in evidence-based practice is between observational studies and randomized controlled trials. Types of observational studies in epidemiology, such as the cohort study and the case-control study, provide less compelling evidence than the randomized controlled trial. In observational studies, the investigators retrospectively assess associations between the treatments given to participants and their health status, with potential for considerable errors in design and interpretation.
A randomized controlled trial can provide compelling evidence that the study treatment causes an effect on human health.
Some Phase II and most Phase III drug trials are designed as randomized, double-blind, and placebo-controlled.
Randomized: Each study subject is randomly assigned to receive either the study treatment or a placebo.
Blind: The subjects involved in the study do not know which study treatment they receive. If the study is double-blind, the researchers also do not know which treatment a subject receives. This intent is to prevent researchers from treating the two groups differently. A form of double-blind study called a "double-dummy" design allows additional insurance against bias. In this kind of study, all patients are given both placebo and active doses in alternating periods.
Placebo-controlled: The use of a placebo (fake treatment) allows the researchers to isolate the effect of the study treatment from the placebo effect.
Clinical studies having small numbers of subjects may be "sponsored" by single researchers or a small group of researchers, and are designed to test simple questions or feasibility to expand the research for a more comprehensive randomized controlled trial.
Clinical studies can be "sponsored" (financed and organized) by academic institutions, pharmaceutical companies, government entities and even private groups. Trials are conducted for new drugs, biotechnology, diagnostic assays or medical devices to determine their safety and efficacy prior to being submitted for regulatory review that would determine market approval.
=== Active control studies ===
In cases where giving a placebo to a person suffering from a disease may be unethical, "active comparator" (also known as "active control") trials may be conducted instead. In trials with an active control group, subjects are given either the experimental treatment or a previously approved treatment with known effectiveness. In other cases, sponsors may conduct an active comparator trial to establish an efficacy claim relative to the active comparator instead of the placebo in labeling.
=== Master protocol ===
A master protocol includes multiple substudies, which may have different objectives and involve coordinated efforts to evaluate one or more medical products in one or more diseases or conditions within the overall study structure. Trials that could develop a master protocol include the umbrella trial (multiple medical products for a single disease), platform trial (multiple products for a single disease entering and leaving the platform), and basket trial (one medical product for multiple diseases or disease subtypes).
Genetic testing enables researchers to group patients according to their genetic profile, deliver drugs based on that profile to that group and compare the results. Multiple companies can participate, each bringing a different drug. The first such approach targets squamous cell cancer, which includes varying genetic disruptions from patient to patient. Amgen, AstraZeneca and Pfizer are involved, the first time they have worked together in a late-stage trial. Patients whose genomic profiles do not match any of the trial drugs receive a drug designed to stimulate the immune system to attack cancer.
=== Clinical trial protocol ===
A clinical trial protocol is a document used to define and manage the trial. It is prepared by a panel of experts. All study investigators are expected to strictly observe the protocol.
The protocol describes the scientific rationale, objective(s), design, methodology, statistical considerations and organization of the planned trial. Details of the trial are provided in documents referenced in the protocol, such as an investigator's brochure.
The protocol contains a precise study plan to assure safety and health of the trial subjects and to provide an exact template for trial conduct by investigators. This allows data to be combined across all investigators/sites. The protocol also informs the study administrators (often a contract research organization).
The format and content of clinical trial protocols sponsored by pharmaceutical, biotechnology or medical device companies in the United States, European Union, or Japan have been standardized to follow Good Clinical Practice guidance issued by the International Conference on Harmonisation (ICH). Regulatory authorities in Canada, China, South Korea, and the UK also follow ICH guidelines. Journals such as Trials, encourage investigators to publish their protocols.
=== Design features ===
==== Informed consent ====
Clinical trials recruit study subjects to sign a document representing their "informed consent". The document includes details such as its purpose, duration, required procedures, risks, potential benefits, key contacts and institutional requirements. The participant then decides whether to sign the document. The document is not a contract, as the participant can withdraw at any time without penalty.
Informed consent is a legal process in which a recruit is instructed about key facts before deciding whether to participate. Researchers explain the details of the study in terms the subject can understand. The information is presented in the subject's native language. Generally, children cannot autonomously provide informed consent, but depending on their age and other factors, may be required to provide informed assent.
==== Statistical power ====
In any clinical trial, the number of subjects, also called the sample size, has a large impact on the ability to reliably detect and measure the effects of the intervention. This ability is described as its "power", which must be calculated before initiating a study to figure out if the study is worth its costs. In general, a larger sample size increases the statistical power, also the cost.
The statistical power estimates the ability of a trial to detect a difference of a particular size (or larger) between the treatment and control groups. For example, a trial of a lipid-lowering drug versus placebo with 100 patients in each group might have a power of 0.90 to detect a difference between placebo and trial groups receiving dosage of 10 mg/dL or more, but only 0.70 to detect a difference of 6 mg/dL.
=== Placebo groups ===
Merely giving a treatment can have nonspecific effects. These are controlled for by the inclusion of patients who receive only a placebo. Subjects are assigned randomly without informing them to which group they belonged. Many trials are doubled-blinded so that researchers do not know to which group a subject is assigned.
Assigning a subject to a placebo group can pose an ethical problem if it violates his or her right to receive the best available treatment. The Declaration of Helsinki provides guidelines on this issue.
=== Duration ===
Clinical trials are only a small part of the research that goes into developing a new treatment. Potential drugs, for example, first have to be discovered, purified, characterized, and tested in labs (in cell and animal studies) before ever undergoing clinical trials. In all, about 1,000 potential drugs are tested before just one reaches the point of being tested in a clinical trial. For example, a new cancer drug has, on average, six years of research behind it before it even makes it to clinical trials. But the major holdup in making new cancer drugs available is the time it takes to complete clinical trials themselves. On average, about eight years pass from the time a cancer drug enters clinical trials until it receives approval from regulatory agencies for sale to the public. Drugs for other diseases have similar timelines.
Some reasons a clinical trial might last several years:
For chronic conditions such as cancer, it takes months, if not years, to see if a cancer treatment has an effect on a patient.
For drugs that are not expected to have a strong effect (meaning a large number of patients must be recruited to observe 'any' effect), recruiting enough patients to test the drug's effectiveness (i.e., getting statistical power) can take several years.
Only certain people who have the target disease condition are eligible to take part in each clinical trial. Researchers who treat these particular patients must participate in the trial. Then they must identify the desirable patients and obtain consent from them or their families to take part in the trial.
A clinical trial might also include an extended post-study follow-up period from months to years for people who have participated in the trial, a so-called "extension phase", which aims to identify long-term impact of the treatment.
The biggest barrier to completing studies is the shortage of people who take part. All drug and many device trials target a subset of the population, meaning not everyone can participate. Some drug trials require patients to have unusual combinations of disease characteristics. It is a challenge to find the appropriate patients and obtain their consent, especially when they may receive no direct benefit (because they are not paid, the study drug is not yet proven to work, or the patient may receive a placebo). In the case of cancer patients, fewer than 5% of adults with cancer will participate in drug trials. According to the Pharmaceutical Research and Manufacturers of America (PhRMA), about 400 cancer medicines were being tested in clinical trials in 2005. Not all of these will prove to be useful, but those that are may be delayed in getting approved because the number of participants is so low.
For clinical trials involving potential for seasonal influences (such as airborne allergies, seasonal affective disorder, influenza, and skin diseases), the study may be done during a limited part of the year (such as spring for pollen allergies), when the drug can be tested.
Clinical trials that do not involve a new drug usually have a much shorter duration. (Exceptions are epidemiological studies, such as the Nurses' Health Study).
== Administration ==
Clinical trials designed by a local investigator, and (in the US) federally funded clinical trials, are almost always administered by the researcher who designed the study and applied for the grant. Small-scale device studies may be administered by the sponsoring company. Clinical trials of new drugs are usually administered by a contract research organization (CRO) hired by the sponsoring company. The sponsor provides the drug and medical oversight. A CRO is contracted to perform all the administrative work on a clinical trial. For Phases II–IV the CRO recruits participating researchers, trains them, provides them with supplies, coordinates study administration and data collection, sets up meetings, monitors the sites for compliance with the clinical protocol, and ensures the sponsor receives data from every site. Specialist site management organizations can also be hired to coordinate with the CRO to ensure rapid IRB/IEC approval and faster site initiation and patient recruitment. Phase I clinical trials of new medicines are often conducted in a specialist clinical trial clinic, with dedicated pharmacologists, where the subjects can be observed by full-time staff. These clinics are often run by a CRO which specialises in these studies.
At a participating site, one or more research assistants (often nurses) do most of the work in conducting the clinical trial. The research assistant's job can include some or all of the following: providing the local institutional review board (IRB) with the documentation necessary to obtain its permission to conduct the study, assisting with study start-up, identifying eligible patients, obtaining consent from them or their families, administering study treatment(s), collecting and statistically analyzing data, maintaining and updating data files during followup, and communicating with the IRB, as well as the sponsor and CRO.
=== Quality ===
In the context of a clinical trial, quality typically refers to the absence of errors which can impact decision making, both during the conduct of the trial and in use of the trial results.
=== Marketing ===
An Interactional Justice Model may be used to test the effects of willingness to talk with a doctor about clinical trial enrollment. Results found that potential clinical trial candidates were less likely to enroll in clinical trials if the patient is more willing to talk with their doctor. The reasoning behind this discovery may be patients are happy with their current care. Another reason for the negative relationship between perceived fairness and clinical trial enrollment is the lack of independence from the care provider. Results found that there is a positive relationship between a lack of willingness to talk with their doctor and clinical trial enrollment. Lack of willingness to talk about clinical trials with current care providers may be due to patients' independence from the doctor. Patients who are less likely to talk about clinical trials are more willing to use other sources of information to gain a better insight of alternative treatments. Clinical trial enrollment should be motivated to utilize websites and television advertising to inform the public about clinical trial enrollment.
=== Information technology ===
The last decade has seen a proliferation of information technology use in the planning and conduct of clinical trials. Clinical trial management systems are often used by research sponsors or CROs to help plan and manage the operational aspects of a clinical trial, particularly with respect to investigational sites. Advanced analytics for identifying researchers and research sites with expertise in a given area utilize public and private information about ongoing research. Web-based electronic data capture (EDC) and clinical data management systems are used in a majority of clinical trials to collect case report data from sites, manage its quality and prepare it for analysis. Interactive voice response systems are used by sites to register the enrollment of patients using a phone and to allocate patients to a particular treatment arm (although phones are being increasingly replaced with web-based (IWRS) tools which are sometimes part of the EDC system). While patient-reported outcome were often paper based in the past, measurements are increasingly being collected using web portals or hand-held ePRO (or eDiary) devices, sometimes wireless. Statistical software is used to analyze the collected data and prepare them for regulatory submission. Access to many of these applications are increasingly aggregated in web-based clinical trial portals. In 2011, the FDA approved a Phase I trial that used telemonitoring, also known as remote patient monitoring, to collect biometric data in patients' homes and transmit it electronically to the trial database. This technology provides many more data points and is far more convenient for patients, because they have fewer visits to trial sites. As noted below, decentralized clinical trials are those that do not require patients' physical presence at a site, and instead rely largely on digital health data collection, digital informed consent processes, and so on.
== Analysis ==
A clinical trial produces data that could reveal quantitative differences between two or more interventions; statistical analyses are used to determine whether such differences are true, result from chance, or are the same as no treatment (placebo). Data from a clinical trial accumulate gradually over the trial duration, extending from months to years. Accordingly, results for participants recruited early in the study become available for analysis while subjects are still being assigned to treatment groups in the trial. Early analysis may allow the emerging evidence to assist decisions about whether to stop the study, or to reassign participants to the more successful segment of the trial. Investigators may also want to stop a trial when data analysis shows no treatment effect.
== Ethical aspects ==
Clinical trials are closely supervised by appropriate regulatory authorities. All studies involving a medical or therapeutic intervention on patients must be approved by a supervising ethics committee before permission is granted to run the trial. The local ethics committee has discretion on how it will supervise noninterventional studies (observational studies or those using already collected data). In the US, this body is called the Institutional Review Board (IRB); in the EU, they are called Ethics committees. Most IRBs are located at the local investigator's hospital or institution, but some sponsors allow the use of a central (independent/for profit) IRB for investigators who work at smaller institutions.
To be ethical, researchers must obtain the full and informed consent of participating human subjects. (One of the IRB's main functions is to ensure potential patients are adequately informed about the clinical trial.) If the patient is unable to consent for him/herself, researchers can seek consent from the patient's legally authorized representative. In addition, the clinical trial participants must be made aware that they can withdraw from the clinical trial at any time without any adverse action taken against them. In California, the state has prioritized the individuals who can serve as the legally authorized representative.
In some US locations, the local IRB must certify researchers and their staff before they can conduct clinical trials. They must understand the federal patient privacy (HIPAA) law and good clinical practice. The International Conference of Harmonisation Guidelines for Good Clinical Practice is a set of standards used internationally for the conduct of clinical trials. The guidelines aim to ensure the "rights, safety and well being of trial subjects are protected".
The notion of informed consent of participating human subjects exists in many countries but its precise definition may still vary.
Informed consent is clearly a 'necessary' condition for ethical conduct but does not 'ensure' ethical conduct. In compassionate use trials the latter becomes a particularly difficult problem. The final objective is to serve the community of patients or future patients in a best-possible and most responsible way. See also Expanded access. However, it may be hard to turn this objective into a well-defined, quantified, objective function. In some cases this can be done, however, for instance, for questions of when to stop sequential treatments (see Odds algorithm), and then quantified methods may play an important role.
Additional ethical concerns are present when conducting clinical trials on children (pediatrics), and in emergency or epidemic situations.
Ethically balancing the rights of multiple stakeholders may be difficult. For example, when drug trials fail, the sponsors may have a duty to tell current and potential investors immediately, which means both the research staff and the enrolled participants may first hear about the end of a trial through public business news.
=== Conflicts of interest and unfavorable studies ===
In response to specific cases in which unfavorable data from pharmaceutical company-sponsored research were not published, the Pharmaceutical Research and Manufacturers of America published new guidelines urging companies to report all findings and limit the financial involvement in drug companies by researchers. The US Congress signed into law a bill which requires Phase II and Phase III clinical trials to be registered by the sponsor on the clinicaltrials.gov website compiled by the National Institutes of Health.
Drug researchers not directly employed by pharmaceutical companies often seek grants from manufacturers, and manufacturers often look to academic researchers to conduct studies within networks of universities and their hospitals, e.g., for translational cancer research. Similarly, competition for tenured academic positions, government grants and prestige create conflicts of interest among academic scientists. According to one study, approximately 75% of articles retracted for misconduct-related reasons have no declared industry financial support. Seeding trials are particularly controversial.
In the United States, all clinical trials submitted to the FDA as part of a drug approval process are independently assessed by clinical experts within the Food and Drug Administration, including inspections of primary data collection at selected clinical trial sites.
In 2001, the editors of 12 major journals issued a joint editorial, published in each journal, on the control over clinical trials exerted by sponsors, particularly targeting the use of contracts which allow sponsors to review the studies prior to publication and withhold publication. They strengthened editorial restrictions to counter the effect. The editorial noted that contract research organizations had, by 2000, received 60% of the grants from pharmaceutical companies in the US. Researchers may be restricted from contributing to the trial design, accessing the raw data, and interpreting the results.
Despite explicit recommendations by stakeholders of measures to improve the standards of industry-sponsored medical research, in 2013, Tohen warned of the persistence of a gap in the credibility of conclusions arising from industry-funded clinical trials, and called for ensuring strict adherence to ethical standards in industrial collaborations with academia, in order to avoid further erosion of the public's trust. Issues referred for attention in this respect include potential observation bias, duration of the observation time for maintenance studies, the selection of the patient populations, factors that affect placebo response, and funding sources.
=== During public health crisis ===
Conducting clinical trials of vaccines during epidemics and pandemics is subject to ethical concerns. For diseases with high mortality rates like Ebola, assigning individuals to a placebo or control group can be viewed as a death sentence. In response to ethical concerns regarding clinical research during epidemics, the National Academy of Medicine authored a report identifying seven ethical and scientific considerations. These considerations are:
=== Pregnant women and children ===
Pregnant women and children are typically excluded from clinical trials as vulnerable populations, though the data to support excluding them is not robust. By excluding them from clinical trials, information about the safety and effectiveness of therapies for these populations is often lacking. During the early history of the HIV/AIDS epidemic, a scientist noted that by excluding these groups from potentially life-saving treatment, they were being "protected to death". Projects such as Research Ethics for Vaccines, Epidemics, and New Technologies (PREVENT) have advocated for the ethical inclusion of pregnant women in vaccine trials. Inclusion of children in clinical trials has additional moral considerations, as children lack decision-making autonomy. Trials in the past had been criticized for using hospitalized children or orphans; these ethical concerns effectively stopped future research. In efforts to maintain effective pediatric care, several European countries and the US have policies to entice or compel pharmaceutical companies to conduct pediatric trials. International guidance recommends ethical pediatric trials by limiting harm, considering varied risks, and taking into account the complexities of pediatric care.
== Safety ==
Responsibility for the safety of the subjects in a clinical trial is shared between the sponsor, the local site investigators (if different from the sponsor), the various IRBs that supervise the study, and (in some cases, if the study involves a marketable drug or device), the regulatory agency for the country where the drug or device will be sold.
A systematic concurrent safety review is frequently employed to assure research participant safety. The conduct and on-going review is designed to be proportional to the risk of the trial. Typically this role is filled by a Data and Safety Committee, an externally appointed Medical Safety Monitor, an Independent Safety Officer, or for small or low-risk studies the principal investigator.
For safety reasons, many clinical trials of drugs are designed to exclude women of childbearing age, pregnant women, or women who become pregnant during the study. In some cases, the male partners of these women are also excluded or required to take birth control measures.
=== Sponsor ===
Throughout the clinical trial, the sponsor is responsible for accurately informing the local site investigators of the true historical safety record of the drug, device or other medical treatments to be tested, and of any potential interactions of the study treatment(s) with already approved treatments. This allows the local investigators to make an informed judgment on whether to participate in the study or not. The sponsor is also responsible for monitoring the results of the study as they come in from the various sites as the trial proceeds. In larger clinical trials, a sponsor will use the services of a data monitoring committee (DMC, known in the US as a data safety monitoring board). This independent group of clinicians and statisticians meets periodically to review the unblinded data the sponsor has received so far. The DMC has the power to recommend termination of the study based on their review, for example if the study treatment is causing more deaths than the standard treatment, or seems to be causing unexpected and study-related serious adverse events. The sponsor is responsible for collecting adverse event reports from all site investigators in the study, and for informing all the investigators of the sponsor's judgment as to whether these adverse events were related or not related to the study treatment.
The sponsor and the local site investigators are jointly responsible for writing a site-specific informed consent that accurately informs the potential subjects of the true risks and potential benefits of participating in the study, while at the same time presenting the material as briefly as possible and in ordinary language. FDA regulations state that participating in clinical trials is voluntary, with the subject having the right not to participate or to end participation at any time.
=== Local site investigators ===
The ethical principle of primum non-nocere ("first, do no harm") guides the trial, and if an investigator believes the study treatment may be harming subjects in the study, the investigator can stop participating at any time. On the other hand, investigators often have a financial interest in recruiting subjects, and could act unethically to obtain and maintain their participation.
The local investigators are responsible for conducting the study according to the study protocol, and supervising the study staff throughout the duration of the study. The local investigator or his/her study staff are also responsible for ensuring the potential subjects in the study understand the risks and potential benefits of participating in the study. In other words, they (or their legally authorized representatives) must give truly informed consent.
Local investigators are responsible for reviewing all adverse event reports sent by the sponsor. These adverse event reports contain the opinions of both the investigator (at the site where the adverse event occurred) and the sponsor, regarding the relationship of the adverse event to the study treatments. Local investigators also are responsible for making an independent judgment of these reports, and promptly informing the local IRB of all serious and study treatment-related adverse events.
When a local investigator is the sponsor, there may not be formal adverse event reports, but study staff at all locations are responsible for informing the coordinating investigator of anything unexpected. The local investigator is responsible for being truthful to the local IRB in all communications relating to the study.
=== Institutional review boards (IRBs) ===
Approval by an Institutional Review Board (IRB), or Independent Ethics Committee (IEC), is necessary before all but the most informal research can begin. In commercial clinical trials, the study protocol is not approved by an IRB before the sponsor recruits sites to conduct the trial. However, the study protocol and procedures have been tailored to fit generic IRB submission requirements. In this case, and where there is no independent sponsor, each local site investigator submits the study protocol, the consent(s), the data collection forms, and supporting documentation to the local IRB. Universities and most hospitals have in-house IRBs. Other researchers (such as in walk-in clinics) use independent IRBs.
The IRB scrutinizes the study both for medical safety and for protection of the patients involved in the study, before it allows the researcher to begin the study. It may require changes in study procedures or in the explanations given to the patient. A required yearly "continuing review" report from the investigator updates the IRB on the progress of the study and any new safety information related to the study.
=== Regulatory agencies ===
In the US, the FDA can audit the files of local site investigators after they have finished participating in a study, to see if they were correctly following study procedures. This audit may be random, or for cause (because the investigator is suspected of fraudulent data). Avoiding an audit is an incentive for investigators to follow study procedures. A 'covered clinical study' refers to a trial submitted to the FDA as part of a marketing application (for example, as part of an NDA or 510(k)), about which the FDA may require disclosure of financial interest of the clinical investigator in the outcome of the study. For example, the applicant must disclose whether an investigator owns equity in the sponsor, or owns proprietary interest in the product under investigation. The FDA defines a covered study as "... any study of a drug, biological product or device in humans submitted in a marketing application or reclassification petition that the applicant or FDA relies on to establish that the product is effective (including studies that show equivalence to an effective product) or any study in which a single investigator makes a significant contribution to the demonstration of safety."
Alternatively, many American pharmaceutical companies have moved some clinical trials overseas. Benefits of conducting trials abroad include lower costs (in some countries) and the ability to run larger trials in shorter timeframes, whereas a potential disadvantage exists in lower-quality trial management. Different countries have different regulatory requirements and enforcement abilities. An estimated 40% of all clinical trials now take place in Asia, Eastern Europe, and Central and South America. "There is no compulsory registration system for clinical trials in these countries and many do not follow European directives in their operations", says Jacob Sijtsma of the Netherlands-based WEMOS, an advocacy health organisation tracking clinical trials in developing countries.
Beginning in the 1980s, harmonization of clinical trial protocols was shown as feasible across countries of the European Union. At the same time, coordination between Europe, Japan and the United States led to a joint regulatory-industry initiative on international harmonization named after 1990 as the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH)
Currently, most clinical trial programs follow ICH guidelines, aimed at "ensuring that good quality, safe and effective medicines are developed and registered in the most efficient and cost-effective manner. These activities are pursued in the interest of the consumer and public health, to prevent unnecessary duplication of clinical trials in humans and to minimize the use of animal testing without compromising the regulatory obligations of safety and effectiveness."
=== Aggregation of safety data during clinical development ===
Aggregating safety data across clinical trials during drug development is important because trials are generally designed to focus on determining how well the drug works. The safety data collected and aggregated across multiple trials as the drug is developed allows the sponsor, investigators and regulatory agencies to monitor the aggregate safety profile of experimental medicines as they are developed. The value of assessing aggregate safety data is: a) decisions based on aggregate safety assessment during development of the medicine can be made throughout the medicine's development and b) it sets up the sponsor and regulators well for assessing the medicine's safety after the drug is approved.
== Economics ==
Clinical trial costs vary depending on trial phase, type of trial, and disease studied. A study of clinical trials conducted in the United States from 2004 to 2012 found the average cost of Phase I trials to be between $1.4 million and $6.6 million, depending on the type of disease. Phase II trials ranged from $7 million to $20 million, and Phase III trials from $11 million to $53 million.
=== Sponsor ===
The cost of a study depends on many factors, especially the number of sites conducting the study, the number of patients involved, and whether the study treatment is already approved for medical use.
The expenses incurred by a pharmaceutical company in administering a Phase III or IV clinical trial may include, among others:
production of the drug(s) or device(s) being evaluated
staff salaries for the designers and administrators of the trial
payments to the contract research organization, the site management organization (if used) and any outside consultants
payments to local researchers and their staff for their time and effort in recruiting test subjects and collecting data for the sponsor
the cost of study materials and the charges incurred to ship them
communication with the local researchers, including on-site monitoring by the CRO before and (in some cases) multiple times during the study
one or more investigator training meetings
expense incurred by the local researchers, such as pharmacy fees, IRB fees and postage
any payments to subjects enrolled in the trial
the expense of treating a test subject who develops a medical condition caused by the study drug
These expenses are incurred over several years.
In the US, sponsors may receive a 50 percent tax credit for clinical trials conducted on drugs being developed for the treatment of orphan diseases. National health agencies, such as the US National Institutes of Health, offer grants to investigators who design clinical trials that attempt to answer research questions of interest to the agency. In these cases, the investigator who writes the grant and administers the study acts as the sponsor, and coordinates data collection from any other sites. These other sites may or may not be paid for participating in the study, depending on the amount of the grant and the amount of effort expected from them. Using internet resources can, in some cases, reduce the economic burden.
=== Investigators ===
Investigators are often compensated for their work in clinical trials. These amounts can be small, just covering a partial salary for research assistants and the cost of any supplies (usually the case with national health agency studies), or be substantial and include "overhead" that allows the investigator to pay the research staff during times between clinical trials.
=== Subjects ===
Participants in Phase I drug trials do not gain any direct health benefit from taking part. They are generally paid a fee for their time, with payments regulated and not related to any risk involved. Motivations of healthy volunteers is not limited to financial reward and may include other motivations such as contributing to science and others. In later phase trials, subjects may not be paid to ensure their motivation for participating with potential for a health benefit or contributing to medical knowledge. Small payments may be made for study-related expenses such as travel or as compensation for their time in providing follow-up information about their health after the trial treatment ends.
== Participant recruitment and participation ==
Phase 0 and Phase I drug trials seek healthy volunteers. Most other clinical trials seek patients who have a specific disease or medical condition. The diversity observed in society should be reflected in clinical trials through the appropriate inclusion of ethnic minority populations. Patient recruitment or participant recruitment plays a significant role in the activities and responsibilities of sites conducting clinical trials.
All volunteers being considered for a trial are required to undertake a medical screening. Requirements differ according to the trial needs, but typically volunteers would be screened in a medical laboratory for:
Measurement of the electrical activity of the heart (ECG)
Measurement of blood pressure, heart rate, and body temperature
Blood sampling
Urine sampling
Weight and height measurement
Drug abuse testing
Pregnancy testing
It has been observed that participants in clinical trials are disproportionately white. Often, minorities are not informed about clinical trials. One recent systematic review of the literature found that race/ethnicity as well as sex were not well-represented nor at times even tracked as participants in a large number of clinical trials of hearing loss management in adults. This may reduce the validity of findings in respect of non-white patients by not adequately representing the larger populations.
=== Locating trials ===
Depending on the kind of participants required, sponsors of clinical trials, or contract research organizations working on their behalf, try to find sites with qualified personnel as well as access to patients who could participate in the trial. Working with those sites, they may use various recruitment strategies, including patient databases, newspaper and radio advertisements, flyers, posters in places the patients might go (such as doctor's offices), and personal recruitment of patients by investigators.
Volunteers with specific conditions or diseases have additional online resources to help them locate clinical trials. For example, the Fox Trial Finder connects Parkinson's disease trials around the world to volunteers who have a specific set of criteria such as location, age, and symptoms. Other disease-specific services exist for volunteers to find trials related to their condition. Volunteers may search directly on ClinicalTrials.gov to locate trials using a registry run by the U.S. National Institutes of Health and National Library of Medicine. There also is software that allows clinicians to find trial options for an individual patient based on data such as genomic data.
=== Research ===
The risk information seeking and processing (RISP) model analyzes social implications that affect attitudes and decision making pertaining to clinical trials. People who hold a higher stake or interest in the treatment provided in a clinical trial showed a greater likelihood of seeking information about clinical trials. Cancer patients reported more optimistic attitudes towards clinical trials than the general population. Having a more optimistic outlook on clinical trials also leads to greater likelihood of enrolling.
=== Matching ===
Matching involves a systematic comparison of a patient's clinical and demographic information against the eligibility criteria of various trials. Methods include:
Manual: Healthcare providers or clinical trial coordinators manually review patient records and available trial criteria to identify potential matches. This might also include manually searching in clinical trial databases.
Electronic health records (EHR). Some systems integrate with EHRs to automatically flag patients that may be eligible for trials based on their medical data. These systems may leverage machine learning, artificial intelligence or precision medicine methods to more effectively match patients to trials. These methods are faced with the challenge of overcoming the limitations of EHR records such as omissions and logging errors.
Direct-to-patient services: Resources are specialized to support patients in finding clinical trials through online platforms, hotlines, and personalized support.
== Decentralized trials ==
Although trials are commonly conducted at major medical centers, some participants are excluded due to the distance and expenses required for travel, leading to hardship, disadvantage, and inequity for participants, especially those in rural and underserved communities. Therefore, the concept of a "decentralized clinical trial" that minimizes or eliminates the need for patients to travel to sites, is now more widespread, a capability improved by telehealth and wearable technologies.
== See also ==
Outcome measure
Odds algorithm
Preregistration (science)
Marketing authorisation
== References ==
== External links ==
The International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use, a guideline for regulation of clinical trials
ClinicalTrials.gov, a worldwide database of registered clinical trials; US National Library of Medicine
Cochrane Central Register of Controlled Trials (CENTRAL); a concentrated source for bibliographic reports of randomized controlled trials
ClinicalTrials.eu, European Clinical Trials Information Network; Clinical Trials easily understood.
The Hidden World of Clinical Trials: A Journey into Medical Innovation - A blog providing insights into medical innovation in clinical trials. | Wikipedia/Clinical_study |
Gq protein alpha subunit is a family of heterotrimeric G protein alpha subunits. This family is also commonly called the Gq/11 (Gq/G11) family or Gq/11/14/15 family to include closely related family members. G alpha subunits may be referred to as Gq alpha, Gαq, or Gqα.
Gq proteins couple to G protein-coupled receptors to activate beta-type phospholipase C (PLC-β) enzymes. PLC-β in turn hydrolyzes phosphatidylinositol 4,5-bisphosphate (PIP2) to diacyl glycerol (DAG) and inositol trisphosphate (IP3). IP3 acts as a second messenger to release stored calcium into the cytoplasm, while DAG acts as a second messenger that activates protein kinase C (PKC).
== Family members ==
In humans, there are four distinct proteins in the Gq alpha subunit family:
Gαq is encoded by the gene GNAQ.
Gα11 is encoded by the gene GNA11.
Gα14 is encoded by the gene GNA14.
Gα15 is encoded by the gene GNA15.
== Function ==
The general function of Gq is to activate intracellular signaling pathways in response to activation of cell surface G protein-coupled receptors (GPCRs). GPCRs function as part of a three-component system of receptor-transducer-effector. The transducer in this system is a heterotrimeric G protein, composed of three subunits: a Gα protein such as Gαq, and a complex of two tightly linked proteins called Gβ and Gγ in a Gβγ complex. When not stimulated by a receptor, Gα is bound to guanosine diphosphate (GDP) and to Gβγ to form the inactive G protein trimer. When the receptor binds an activating ligand outside the cell (such as a hormone or neurotransmitter), the activated receptor acts as a guanine nucleotide exchange factor to promote GDP release from and guanosine triphosphate (GTP) binding to Gα, which drives dissociation of GTP-bound Gα from Gβγ. Recent evidence suggests that Gβγ and Gαq-GTP could maintain partial interaction via the N-α-helix region of Gαq. GTP-bound Gα and Gβγ are then freed to activate their respective downstream signaling enzymes.
Gq/11/14/15 proteins all activate beta-type phospholipase C (PLC-β) to signal through calcium and PKC signaling pathways. PLC-β then cleaves a specific plasma membrane phospholipid, phosphatidylinositol 4,5-bisphosphate (PIP2) into diacyl glycerol (DAG) and inositol 1,4,5-trisphosphate (IP3). DAG remains bound to the membrane, and IP3 is released as a soluble molecule into the cytoplasm. IP3 diffuses to bind to IP3 receptors, a specialized calcium channel in the endoplasmic reticulum (ER). These channels are specific to calcium and only allow the passage of calcium from the ER into the cytoplasm. Since cells actively sequester calcium in the ER to keep cytoplasmic levels low, this release causes the cytosolic concentration of calcium to increase, causing a cascade of intracellular changes and activity through calcium binding proteins and calcium-sensitive processes.
Further reading: Calcium function in vertebrates
DAG works together with released calcium to activate specific isoforms of PKC, which are activated to phosphorylate other molecules, leading to further altered cellular activity.
Further reading: function of protein kinase C
The Gαq / Gα11 (Q209L) mutation is associated with the development of uveal melanoma and its pharmacological inhibition (cyclic depsipeptide FR900359 inhibitor), decreases tumor growth in preclinical trials.
== Receptors ==
The following G protein-coupled receptors couple to Gq subunits:
5-HT2 serotonergic receptors
Alpha-1 adrenergic receptor
Vasopressin type 1 receptors: 1A and 1B
Angiotensin II receptor type 1
Calcitonin receptor
Glutamate mGluR1 and mGluR5 receptors
Gonadotropin-releasing hormone receptor
Histamine H1 receptor
M1, M3, and M5 muscarinic receptors
Thyrotropin-releasing hormone receptor
Trace amine-associated receptor 1
At least some Gq-coupled receptors (e.g., the muscarinic acetylcholine M3 receptor) can be found preassembled (pre-coupled) with Gq. The common polybasic domain in the C-tail of Gq-coupled receptors appears necessary for this receptor¬G protein preassembly.
== Inhibitors ==
The cyclic depsipeptides FR900359 and YM-254890 are strong, highly specific inhibitors of Gq and G11.
== See also ==
Second messenger system
G protein-coupled receptor
Heterotrimeric G protein
Phospholipase C
Calcium signaling
Protein kinase C
Gs alpha subunit
Gi alpha subunit
G12/G13 alpha subunits
== References ==
== External links ==
Gq+protein at the U.S. National Library of Medicine Medical Subject Headings (MeSH) | Wikipedia/Gq_protein |
Drugs or medicines may be withdrawn from commercial markets because of risks to patients, but also because of commercial reasons (e.g. lack of demand and relatively high production costs) or because it turns out that they are less effective in clinical practice than premarketing efficacy trials suggested. When risks or harms are the cause, withdrawals will usually have been prompted by unexpected adverse effects that were not detected during the early, premaketing, clinical trials, i.e. they became apparent only from postmarketing surveillance data collected from the wider community during routine use over longer periods of time.
This list is not limited to drugs that were ever approved by specific jurisdictions. Some of them (lumiracoxib, rimonabant, tolrestat, ximelagatran, and zimeldine, for example) received marketing approval in Europe but had not yet been approved for marketing in the USA when adverse effects became clear and they were withdrawn from the market. Some drugs in this list (e.g. LSD) were never approved for marketing in the USA or Europe.
== Significant withdrawals ==
== See also ==
Adverse drug reaction
Adverse events
European Medicines Agency
Food and Drug Administration
== References ==
== External links ==
CDER Report to the Nation: 2005 Has a list of US withdrawals through 2005. | Wikipedia/Withdrawn_drug |
Cannabis (), commonly known as marijuana (), weed, pot, and ganja, among other names, is a non-chemically uniform psychoactive drug from the Cannabis plant. Native to Central or South Asia, cannabis has been used as a drug for both recreational and entheogenic purposes and in various traditional medicines for centuries. Tetrahydrocannabinol (THC) is the main psychoactive component of cannabis, which is one of the 483 known compounds in the plant, including at least 65 other cannabinoids, such as cannabidiol (CBD). Cannabis can be used by smoking, vaporizing, within food, or as an extract.
Cannabis has various mental and physical effects, which include euphoria, altered states of mind and sense of time, difficulty concentrating, impaired short-term memory, impaired body movement (balance and fine psychomotor control), relaxation, and an increase in appetite. Onset of effects is felt within minutes when smoked, but may take up to 90 minutes when eaten (as orally consumed drugs must be digested and absorbed). The effects last for two to six hours, depending on the amount used. At high doses, mental effects can include anxiety, delusions (including ideas of reference), hallucinations, panic, paranoia, and psychosis. There is a strong relation between cannabis use and the risk of psychosis, though the direction of causality is debated. Physical effects include increased heart rate, difficulty breathing, nausea, and behavioral problems in children whose mothers used cannabis during pregnancy; short-term side effects may also include dry mouth and red eyes. Long-term adverse effects may include addiction, decreased mental ability in those who started regular use as adolescents, chronic coughing, susceptibility to respiratory infections, and cannabinoid hyperemesis syndrome.
Cannabis is mostly used recreationally or as a medicinal drug, although it may also be used for spiritual purposes. In 2013, between 128 and 232 million people used cannabis (2.7% to 4.9% of the global population between the ages of 15 and 65). It is the most commonly used largely-illegal drug in the world, with the highest use among adults in Zambia, the United States, Canada, and Nigeria. Since the 1970s, the potency of illicit cannabis has increased, with THC levels rising and CBD levels dropping.
Cannabis plants have been grown since at least the 3rd millennium BCE and there is evidence of it being smoked for its psychoactive effects around 500 BCE in the Pamir Mountains, Central Asia. Since the 14th century, cannabis has been subject to legal restrictions. The possession, use, and cultivation of cannabis has been illegal in most countries since the 20th century. In 2013, Uruguay became the first country to legalize recreational use of cannabis. Other countries to do so are Canada, Georgia, Germany, Luxembourg, Malta, South Africa, and Thailand. In the U.S., the recreational use of cannabis is legalized in 24 states, 3 territories, and the District of Columbia, though the drug remains federally illegal. In Australia, it is legalized only in the Australian Capital Territory.
== Etymology ==
Cannabis is a Scythian word. The ancient Greeks learned of the use of cannabis by observing Scythian funerals, during which cannabis was consumed. In Akkadian, cannabis was known as qunubu (𐎯𐎫𐎠𐎭𐏂). The word was adopted in to the Hebrew as qaneh bosem (קָנֶה בֹּשׂם).
== Uses ==
=== Medical ===
Medical cannabis, or medical marijuana, refers to the use of cannabis to treat disease or improve symptoms; however, there is no single agreed-upon definition (e.g., cannabinoids derived from cannabis and synthetic cannabinoids are also used). The rigorous scientific study of cannabis as a medicine has been hampered by production restrictions and by the fact that it is classified as an illegal drug by many governments. There is some evidence suggesting cannabis can be used to reduce nausea and vomiting during chemotherapy, to improve appetite in people with HIV/AIDS, or to treat chronic pain and muscle spasms. Evidence for its use for other medical applications is insufficient for drawing conclusions about safety or efficacy. There is evidence supporting the use of cannabis or its derivatives in the treatment of chemotherapy-induced nausea and vomiting, neuropathic pain, and multiple sclerosis. Lower levels of evidence support its use for AIDS wasting syndrome, epilepsy, rheumatoid arthritis, and glaucoma.
The medical use of cannabis is legal only in a limited number of territories, including Canada, Belgium, Australia, the Netherlands, New Zealand, Spain, and many U.S. states. This usage generally requires a prescription, and distribution is usually done within a framework defined by local laws.
=== Recreational ===
Being under the effects of cannabis is usually referred to as being "high". Cannabis consumption has both psychoactive and physiological effects. The "high" experience can vary widely, based (among other things) on the user's prior experience with cannabis, and the type of cannabis consumed.: p647 When smoking cannabis, a euphoriant effect can occur within minutes of smoking.: p104 Aside from a subjective change in perception and mood, the most common short-term physical and neurological effects include increased heart rate, increased appetite, impairment of short-term and working memory, and impairment of psychomotor coordination.
Additional desired effects from consuming cannabis include relaxation, a general alteration of conscious perception, increased awareness of sensation, increased libido and distortions in the perception of time and space. In some cases, cannabis can lead to dissociative states such as depersonalization and derealization.
=== Spiritual ===
Cannabis has held sacred status in several religions and has served as an entheogen – a chemical substance used in religious, shamanic, or spiritual contexts – in the Indian subcontinent since the Vedic period. The earliest known reports regarding the sacred status of cannabis in the Indian subcontinent come from the Atharva Veda, estimated to have been composed sometime around 1400 BCE.
The Hindu god Shiva is described as a cannabis user, known as the "Lord of bhang".: p19
In modern culture, the spiritual use of cannabis has been spread by the disciples of the Rastafari movement who use cannabis as a sacrament and as an aid to meditation.
== Consumption ==
=== Modes of consumption ===
Many different ways to consume cannabis involve heat to decarboxylate THCA into THC; common modes include:
Smoking, involves burning and inhaling cannabinoids ("smoke") from small pipes, bongs (portable versions of hookahs with a water chamber), paper-wrapped joints, tobacco-leaf-wrapped blunts, or the like.
Vaporizing, heating various forms of cannabis to 165–190 °C (329–374 °F), causing the active ingredients to form vapor without combustion of the plant material (the boiling point of THC is 157 °C (315 °F) at atmospheric pressure).
Edibles, adding cannabis as an ingredient to a wide variety of foods, including butter and baked goods. In India it is commonly consumed as the beverage bhang.
Cannabis tea, prepared with attention to the lipophilic quality of THC, which is only slightly water-soluble (2.8 mg per liter), often involving cannabis in a saturated fat.
Tincture of cannabis, sometimes known as green dragon, is an alcoholic cannabis concentrate.
Capsules, typically containing cannabis oil, and other dietary supplement products, for which some 220 were approved in Canada in 2018.
=== Consumption by country ===
In 2013, between 128 and 232 million people used cannabis (2.7% to 4.9% of the global population between the ages of 15 and 65). Cannabis is by far the most widely used illicit substance, with the highest use among adults (as of 2018) in Zambia, the United States, Canada, and Nigeria.
==== United States ====
Between 1973 and 1978, eleven states decriminalized marijuana. In 2001, Nevada reduced marijuana possession to a misdemeanor and since 2012, several other states have decriminalized and even legalized marijuana.
In 2018, surveys indicated that almost half of the people in the United States had tried marijuana, 16% had used it in the past year, and 11% had used it in the past month. In 2014, surveys said daily marijuana use amongst US college students had reached its highest level since records began in 1980, rising from 3.5% in 2007 to 5.9% in 2014 and had surpassed daily cigarette use.
In the US, men are over twice as likely to use marijuana as women, and 18–29-year-olds are six times more likely to use as over-65-year-olds. In 2015, a record 44% of the US population has tried marijuana in their lifetime, an increase from 38% in 2013 and 33% in 1985.
Marijuana use in the United States is three times above the global average, but in line with other Western democracies. Forty-four percent of American 12th graders have tried the drug at least once, and the typical age of first-use is 16, similar to the typical age of first-use for alcohol but lower than the first-use age for other illicit drugs.
A 2022 Gallup poll concluded Americans are smoking more marijuana than cigarettes for the first time.
== Adverse effects ==
=== Short-term ===
Acute negative effects may include anxiety and panic, impaired attention and memory, an increased risk of psychotic symptoms, the inability to think clearly, and an increased risk of accidents. Cannabis impairs a person's driving ability, and THC was the illicit drug most frequently found in the blood of drivers who have been involved in vehicle crashes. Those with THC in their system are from three to seven times more likely to be the cause of the accident than those who had not used either cannabis or alcohol, although its role is not necessarily causal because THC stays in the bloodstream for days to weeks after intoxication.
Some immediate undesired side effects include a decrease in short-term memory, dry mouth, impaired motor skills, reddening of the eyes, dizziness, feeling tired and vomiting. Some users may experience an episode of acute psychosis, which usually abates after six hours, but in rare instances, heavy users may find the symptoms continuing for many days.
Legalization has increased the rates at which children are exposed to cannabis, particularly from edibles. While the toxicity and lethality of THC in children is not known, they are at risk for encephalopathy, hypotension, respiratory depression severe enough to require ventilation, somnolence and coma.
=== Fatality ===
There is no clear evidence for a link between cannabis use and deaths from cardiovascular disease, but a 2019 review noted that it may be an under-reported, contributory factor or direct cause in cases of sudden death, due to the strain it can place on the cardiovascular system. Some deaths have also been attributed to cannabinoid hyperemesis syndrome. There is an association between cannabis use and suicide, particularly in younger users.
A 16-month survey of Oregon and Alaska emergency departments found a report of the death of an adult who had been admitted for acute cannabis toxicity.
A recent study in 2025 suggests that individuals diagnosed with cannabis use disorder—characterized by an inability to stop using cannabis despite its negative effects—face a nearly threefold increase in mortality rates compared to those without the condition over a five-year period. The research indicates that people with this disorder are ten times more likely to die by suicide than the general population. Additionally, they have a higher risk of death from trauma, drug poisoning, and lung cancer. In a separate study researchers found an increase in schizophrenia and psychosis cases in Canada linked to cannabis use disorder following the drug’s legalization.
=== Long-term ===
==== Psychological effects ====
A 2015 meta-analysis found that, although a longer period of abstinence was associated with smaller magnitudes of impairment, both retrospective and prospective memory were impaired in cannabis users. The authors concluded that some, but not all, of the deficits associated with cannabis use were reversible. A 2012 meta-analysis found that deficits in most domains of cognition persisted beyond the acute period of intoxication, but was not evident in studies where subjects were abstinent for more than 25 days. Few high quality studies have been performed on the long-term effects of cannabis on cognition, and the results were generally inconsistent. Furthermore, effect sizes of significant findings were generally small. One review concluded that, although most cognitive faculties were unimpaired by cannabis use, residual deficits occurred in executive functions. Impairments in executive functioning are most consistently found in older populations, which may reflect heavier cannabis exposure, or developmental effects associated with adolescent cannabis use. One review found three prospective cohort studies that examined the relationship between self-reported cannabis use and intelligence quotient (IQ). The study following the largest number of heavy cannabis users reported that IQ declined between ages 7–13 and age 38. Poorer school performance and increased incidence of leaving school early were both associated with cannabis use, although a causal relationship was not established. Cannabis users demonstrated increased activity in task-related brain regions, consistent with reduced processing efficiency.
A reduced quality of life is associated with heavy cannabis use, although the relationship is inconsistent and weaker than for tobacco and other substances. The direction of cause and effect, however, is unclear.
The long-term effects of cannabis are not clear. There are concerns surrounding memory and cognition problems, risk of addiction, and the risk of schizophrenia in young people.
==== Neuroimaging ====
Although global abnormalities in white matter and grey matter are not consistently associated with cannabis use, reduced hippocampal volume is consistently found. Amygdala abnormalities are sometimes reported, although findings are inconsistent.
Cannabis use is associated with increased recruitment of task-related areas, such as the dorsolateral prefrontal cortex, which is thought to reflect compensatory activity due to reduced processing efficiency. Cannabis use is also associated with downregulation of CB1 receptors. The magnitude of down regulation is associated with cumulative cannabis exposure, and is reversed after one month of abstinence. There is limited evidence that chronic cannabis use can reduce levels of glutamate metabolites in the human brain.
=== Cannabis dependence ===
About 9% of those who experiment with marijuana eventually become dependent according to DSM-IV (1994) criteria. A 2013 review estimates daily use is associated with a 10–20% rate of dependence. The highest risk of cannabis dependence is found in those with a history of poor academic achievement, deviant behavior in childhood and adolescence, rebelliousness, poor parental relationships, or a parental history of drug and alcohol problems. Of daily users, about 50% experience withdrawal upon cessation of use (i.e. are dependent), characterized by sleep problems, irritability, dysphoria, and craving. Cannabis withdrawal is less severe than withdrawal from alcohol.
According to DSM-5 criteria, 9% of those who are exposed to cannabis develop cannabis use disorder, compared to 20% for cocaine, 23% for alcohol and 68% for nicotine. Cannabis use disorder in the DSM-5 involves a combination of DSM-IV criteria for cannabis abuse and dependence, plus the addition of craving, without the criterion related to legal troubles.
==== Psychiatric ====
From a clinical perspective, two significant school of thought exists for psychiatric conditions associated with cannabis (or cannabinoids) use: transient, non-persistent psychotic reactions, and longer-lasting, persistent disorders that resemble schizophrenia. The former is formally known as acute cannabis-associated psychotic symptoms (CAPS).
At an epidemiological level, a dose–response relationship exists between cannabis use and increased risk of psychosis and earlier onset of psychosis. Although the epidemiological association is robust, evidence to prove a causal relationship is lacking.
Cannabis may also increase the risk of depression, but insufficient research has been performed to draw a conclusion. Cannabis use is associated with increased risk of anxiety disorders, although causality has not been established.
A review in 2019 found that research was insufficient to determine the safety and efficacy of using cannabis to treat schizophrenia, psychosis, or other mental disorders. Another found that cannabis during adolescence was associated with an increased risk of developing depression and suicidal behavior later in life, while finding no effect on anxiety.
==== Physical ====
Heavy, long-term exposure to marijuana may have physical, mental, behavioral and social health consequences. It may be "associated with diseases of the liver (particularly with co-existing hepatitis C), lungs, heart, and vasculature". A 2014 review found that while cannabis use may be less harmful than alcohol use, the recommendation to substitute it for problematic drinking was premature without further study. Various surveys conducted between 2015 and 2019 found that many users of cannabis substitute it for prescription drugs (including opioids), alcohol, and tobacco; most of those who used it in place of alcohol or tobacco either reduced or stopped their intake of the latter substances.
Cannabinoid hyperemesis syndrome (CHS) is a severe condition seen in some chronic cannabis users where they have repeated bouts of uncontrollable vomiting for 24–48 hours.
Four cases of death have been reported as a result of CHS.
A limited number of studies have examined the effects of cannabis smoking on the respiratory system. Chronic heavy marijuana smoking is associated with respiratory infections, coughing, production of sputum, wheezing, and other symptoms of chronic bronchitis. The available evidence does not support a causal relationship between cannabis use and chronic obstructive pulmonary disease. Short-term use of cannabis is associated with bronchodilation. Other side effects of cannabis use include cannabinoid hyperemesis syndrome (CHS), a condition which involves recurrent nausea, cramping abdominal pain, and vomiting.
Cannabis smoke contains thousands of organic and inorganic chemical compounds. This tar is chemically similar to that found in tobacco smoke, and over fifty known carcinogens have been identified in cannabis smoke, including; nitrosamines, reactive aldehydes, and polycyclic aromatic hydrocarbons, including benz[a]pyrene. Cannabis smoke is also inhaled more deeply than tobacco smoke. As of 2015, there is no consensus regarding whether cannabis smoking is associated with an increased risk of cancer. Light and moderate use of cannabis is not believed to increase risk of lung or upper airway cancer. Evidence for causing these cancers is mixed concerning heavy, long-term use. In general there are far lower risks of pulmonary complications for regular cannabis smokers when compared with those of tobacco. A 2015 review found an association between cannabis use and the development of testicular germ cell tumors (TGCTs), particularly non-seminoma TGCTs. Another 2015 meta-analysis found no association between lifetime cannabis use and risk of head or neck cancer. Combustion products are not present when using a vaporizer, consuming THC in pill form, or consuming cannabis foods.
There is concern that cannabis may contribute to cardiovascular disease, but as of 2018, evidence of this relationship was unclear. Research in these events is complicated because cannabis is often used in conjunction with tobacco, and drugs such as alcohol and cocaine that are known to have cardiovascular risk factors. Smoking cannabis has also been shown to increase the risk of myocardial infarction by 4.8 times for the 60 minutes after consumption.
There is preliminary evidence that cannabis interferes with the anticoagulant properties of prescription drugs used for treating blood clots. As of 2019, the mechanisms for the anti-inflammatory and possible pain relieving effects of cannabis were not defined, and there were no governmental regulatory approvals or clinical practices for use of cannabis as a drug.
===== Emergency department visits =====
Emergency room (ER) admissions associated with cannabis use rose significantly from 2012 to 2016; adolescents from age 12–17 had the highest risk. At one Colorado medical center following legalization, approximately two percent of ER admissions were classified as cannabis users. The symptoms of one quarter of these users were partially attributed to cannabis (a total of 2567 out of 449,031 patients); other drugs were sometimes involved. Of these cannabis admissions, one quarter were for acute psychiatric effects, primarily suicidal ideation, depression, and anxiety. An additional third of the cases were for gastrointestinal issues including cannabinoid hyperemesis syndrome.
According to the United States Department of Health and Human Services, there were 455,000 emergency room visits associated with cannabis use in 2011. These statistics include visits in which the patient was treated for a condition induced by or related to recent cannabis use. The drug use must be "implicated" in the emergency department visit, but does not need to be the direct cause of the visit. Most of the illicit drug emergency room visits involved multiple drugs. In 129,000 cases, cannabis was the only implicated drug.
==== Reproductive health ====
=== Secondhand cannabis smoke ===
A 2022 study found that smoking cannabis using a bong can greatly increase background levels of fine particulate matter, a carcinogen, in an enclosed space such as a living room. After 15 minutes, mean levels of particulate matter were more than twice the Environmental Protection Agency hazardous air quality threshold, and after 140 minutes, the concentrations were four times greater than those generated by smoking tobacco using a cigarette or hookah. This suggests secondhand cannabis smoke from bongs may present a health risk to non-smokers.
== Pharmacology ==
=== Mechanism of action ===
THC is a weak partial agonist at CB1 receptors, while CBD is a CB1 receptor antagonist.
The CB1 receptor is found primarily in the brain as well as in some peripheral tissues, and the CB2 receptor is found primarily in peripheral tissues, but is also expressed in neuroglial cells. THC appears to alter mood and cognition through its agonist actions on the CB1 receptors, which inhibit a secondary messenger system (adenylate cyclase) in a dose-dependent manner.
Via CB1 receptor activation, THC indirectly increases dopamine release and produces psychotropic effects. CBD also acts as an allosteric modulator of the μ- and δ-opioid receptors. THC also potentiates the effects of the glycine receptors. It is unknown if or how these actions contribute to the effects of cannabis.
=== Pharmacokinetics ===
The high lipid-solubility of cannabinoids results in their persisting in the body for long periods of time. Even after a single administration of THC, detectable levels of THC can be found in the body for weeks or longer (depending on the amount administered and the sensitivity of the assessment method). Investigators have suggested that this is an important factor in marijuana's effects, perhaps because cannabinoids may accumulate in the body, particularly in the lipid membranes of neurons.
== Chemistry ==
=== Chemical composition ===
The main psychoactive component of cannabis is tetrahydrocannabinol (THC), which is formed via decarboxylation of tetrahydrocannabinolic acid (THCA) from the application of heat. Raw leaf is not psychoactive because the cannabinoids are in the form of carboxylic acids. THC is one of the 483 known compounds in the plant, including at least 65 other cannabinoids, such as cannabidiol (CBD).
=== Detection in body fluids ===
THC and its major (inactive) metabolite, THC-COOH, can be measured in blood, urine, hair, oral fluid or sweat using chromatographic techniques as part of a drug use testing program or a forensic investigation of a traffic or other criminal offense. The concentrations obtained from such analyses can often be helpful in distinguishing active use from passive exposure, elapsed time since use, and extent or duration of use. These tests cannot, however, distinguish authorized cannabis smoking for medical purposes from unauthorized recreational smoking. Commercial cannabinoid immunoassays, often employed as the initial screening method when testing physiological specimens for marijuana presence, have different degrees of cross-reactivity with THC and its metabolites. Urine contains predominantly THC-COOH, while hair, oral fluid and sweat contain primarily THC. Blood may contain both substances, with the relative amounts dependent on the recency and extent of usage.
The Duquenois–Levine test is commonly used as a screening test in the field, but it cannot definitively confirm the presence of cannabis, as a large range of substances have been shown to give false positives. Researchers at John Jay College of Criminal Justice reported that dietary zinc supplements can mask the presence of THC and other drugs in urine. However, a 2013 study conducted by researchers at the University of Utah School of Medicine refute the possibility of self-administered zinc producing false-negative urine drug tests.
== Varieties and strains ==
CBD is a 5-HT1A receptor agonist, which is under laboratory research to determine if it has an anxiolytic effect. It is often claimed that sativa strains provide a more stimulating psychoactive high while indica strains are more sedating with a body high. However, this is disputed by researchers.
A 2015 review found that the use of high CBD-to-THC strains of cannabis showed significantly fewer positive symptoms, such as delusions and hallucinations, better cognitive function and both lower risk for developing psychosis, as well as a later age of onset of the illness, compared to cannabis with low CBD-to-THC ratios.
=== Psychoactive ingredients ===
According to the United Nations Office on Drugs and Crime (UNODC), "the amount of THC present in a cannabis sample is generally used as a measure of cannabis potency." The three main forms of cannabis products are the flower/fruit, resin (hashish), and oil (hash oil). The UNODC states that cannabis often contains 5% THC content, resin "can contain up to 20% THC content", and that "Cannabis oil may contain more than 60% THC content."
Studies have found that the potency of illicit cannabis has greatly increased since the 1970s, with THC levels rising and CBD levels dropping. It is unclear, however, whether the increase in THC content has caused people to consume more THC or if users adjust based on the potency of the cannabis. It is likely that the higher THC content allows people to ingest less tar. At the same time, CBD levels in seized samples have lowered, in part because of the desire to produce higher THC levels and because more illegal growers cultivate indoors using artificial lights. This helps avoid detection but reduces the CBD production of the plant.
Australia's National Cannabis Prevention and Information Centre (NCPIC) states that the buds (infructescences) of the female Cannabis plant contain the highest concentration of THC, followed by the leaves. The stalks and seeds have "much lower THC levels". The UN states that the leaves can contain ten times less THC than the buds, and the stalks 100 times less THC.
After revisions to cannabis scheduling in the UK, the government moved cannabis back from a class C to a class B drug. A purported reason was the appearance of high potency cannabis. They believe skunk accounts for between 70% and 80% of samples seized by police (despite the fact that skunk can sometimes be incorrectly mistaken for all types of herbal cannabis). Extracts such as hashish and hash oil typically contain more THC than high potency cannabis infructescences.
==== Laced cannabis and synthetic cannabinoids ====
Hemp buds (or low-potency cannabis buds) laced with synthetic cannabinoids started to be sold as cannabis street drug in 2020.
The short-term effects of cannabis can be altered if it has been laced with opioid drugs such as heroin or fentanyl. The added drugs are meant to enhance the psychoactive properties, add to its weight, and increase profitability, despite the increased danger of overdose.
== Preparations ==
=== Marijuana ===
Marijuana or marihuana (herbal cannabis) consists of the dried flowers and fruits and subtending leaves and stems of the female cannabis plant. This is the most widely consumed form, containing 3% to 20% THC, with reports of up to 33% THC. This is the stock material from which all other preparations are derived. Although herbal cannabis and industrial hemp derive from the same species and contain the psychoactive component (THC), they are distinct strains with unique biochemical compositions and uses. Hemp has lower concentrations of THC and higher concentrations of CBD, which gives lesser psychoactive effects.
=== Kief ===
Kief is a powder, rich in trichomes, which can be sifted from the leaves, flowers and fruits of cannabis plants and either consumed in powder form or compressed to produce cakes of hashish. The word "kif" derives from colloquial Arabic كيف kēf/kīf, meaning pleasure.
=== Hashish ===
Hashish (also spelled hasheesh, hashisha, or simply hash) is a concentrated resin cake or ball produced from pressed kief, the detached trichomes and fine material that falls off cannabis fruits, flowers and leaves, or from scraping the resin from the surface of the plants and rolling it into balls. It varies in color from black to golden brown depending upon purity and variety of cultivar it was obtained from. It can be consumed orally or smoked, and is also vaporized, or 'vaped'. The term "rosin hash" refers to a high quality solventless product obtained through heat and pressure.
=== Tincture ===
Cannabinoids can be extracted from cannabis plant matter using high-proof spirits (often grain alcohol) to create a tincture, often referred to as "green dragon".: p17 Nabiximols is a branded product name from a tincture manufacturing pharmaceutical company.
=== Hash oil ===
Hash oil is a resinous matrix of cannabinoids obtained from the cannabis plant by solvent extraction, formed into a hardened or viscous mass. Hash oil can be the most potent of the main cannabis products because of its high level of psychoactive compound per its volume, which can vary depending on the plant's mix of essential oils and psychoactive compounds. Butane and supercritical carbon dioxide hash oil have become popular in recent years.
=== Infusions ===
There are many varieties of cannabis infusions owing to the variety of non-volatile solvents used. The plant material is mixed with the solvent and then pressed and filtered to express the oils of the plant into the solvent. Examples of solvents used in this process are cocoa butter, dairy butter, cooking oil, glycerine, and skin moisturizers. Depending on the solvent, these may be used in cannabis foods or applied topically.
=== Marihuana prensada ===
Marihuana prensada ('pressed marijuana') is a cannabis-derived product widespread among the lower classes of South America, especially from the 90s. Locally it is known as "paraguayo" or "paragua", since its main producer is Paraguay. Marijuana is dried and mixed with binding agents that make it toxic and highly harmful to health. It is cut into the shape of bricks (ladrillos) and sold for a low price in Argentina, Brazil, Chile, Peru, Venezuela, and even the United States.
== History ==
=== Ancient history ===
Cannabis is indigenous to Central or South Asia and its uses for fabric and rope dates back to the Neolithic age in China and Japan. It is unclear when cannabis first became known for its psychoactive properties. The oldest archeological evidence for the burning of cannabis was found in Romanian kurgans dated 3,500 BC, and scholars suggest that the drug was first used in ritual ceremonies by Proto-Indo-European tribes living in the Pontic-Caspian steppe during the Chalcolithic period, a custom they eventually spread throughout Western Eurasia during the Indo-European migrations. Some research suggests that the ancient Indo-Iranian drug soma, mentioned in the Vedas, sometimes contained cannabis. This is based on the discovery of a basin containing cannabis in a shrine of the second millennium BC in Turkmenistan.
Cannabis was known to the ancient Assyrians, who discovered its psychoactive properties through the Iranians. Using it in some religious ceremonies, they called it qunubu (meaning "way to produce smoke"), a probable origin of the modern word cannabis. The Iranians also introduced cannabis to the Scythians, Thracians and Dacians, whose shamans (the kapnobatai – "those who walk on smoke/clouds") burned cannabis infructescences to induce trance. The plant was used in China before 2800 BC, and found therapeutic use in India by 1000 BC, where it was used in food and drink, including bhang.
Cannabis has an ancient history of ritual use and has been used by religions around the world. It has been used as a drug for both recreational and entheogenic purposes and in various traditional medicines for centuries. The earliest evidence of cannabis smoking has been found in the 2,500-year-old tombs of Jirzankal Cemetery in the Pamir Mountains in Western China, where cannabis residue were found in burners with charred pebbles possibly used during funeral rituals. Hemp seeds discovered by archaeologists at Pazyryk suggest early ceremonial practices like eating by the Scythians occurred during the 5th to 2nd century BC, confirming previous historical reports by Herodotus. It was used by Muslims in various Sufi orders as early as the Mamluk period, for example by the Qalandars. Smoking pipes uncovered in Ethiopia and carbon-dated to around c. AD 1320 were found to have traces of cannabis.
=== Modern history ===
Cannabis was introduced to the New World by the Spaniards in 1530–1545. Following an 1836–1840 travel in North Africa and the Middle East, French physician Jacques-Joseph Moreau wrote on the psychological effects of cannabis use; he founded the Paris' Club des Hashischins in 1844. In 1842, Irish physician William Brooke O'Shaughnessy, who had studied the drug while working as a medical officer in Bengal with the East India Company, brought a quantity of cannabis with him on his return to Britain, provoking renewed interest in the West. Examples of classic literature of the period featuring cannabis include Les paradis artificiels (1860) by Charles Baudelaire and The Hasheesh Eater (1857) by Fitz Hugh Ludlow.
Cannabis was criminalized in some countries beginning in the 14th century and was illegal in most countries by the middle of the 20th century. The colonial government of Mauritius banned cannabis in 1840 over concerns on its effect on Indian indentured workers; the same occurred in Singapore in 1870. In the United States, the first restrictions on sale of cannabis came in 1906 (in the District of Columbia). Canada criminalized cannabis in The Opium and Narcotic Drug Act, 1923, before any reports of the use of the drug in Canada, but eventually legalized its consumption for recreational and medicinal purposes in 2018.
In 1925, a compromise was made at an international conference in The Hague about the International Opium Convention that banned exportation of "Indian hemp" to countries that had prohibited its use, and requiring importing countries to issue certificates approving the importation and stating that the shipment was required "exclusively for medical or scientific purposes". It also required parties to "exercise an effective control of such a nature as to prevent the illicit international traffic in Indian hemp and especially in the resin". In the United States in 1937, the Marihuana Tax Act was passed, and prohibited the production of hemp in addition to cannabis.
In 1972, the Dutch government divided drugs into more- and less-dangerous categories, with cannabis being in the lesser category. Accordingly, possession of 30 grams (1.1 oz) or less was made a misdemeanor. Cannabis has been available for recreational use in coffee shops since 1976. Cannabis products are only sold openly in certain local "coffeeshops" and possession of up to 5 grams (0.18 oz) for personal use is decriminalized, however: the police may still confiscate it, which often happens in car checks near the border. Other types of sales and transportation are not permitted, although the general approach toward cannabis was lenient even before official decriminalization.
In Uruguay, President Jose Mujica signed legislation to legalize recreational cannabis in December 2013, making Uruguay the first country in the modern era to legalize cannabis. In August 2014, Uruguay legalized growing up to six plants at home, as well as the formation of growing clubs (Cannabis social club), and a state-controlled marijuana dispensary regime.
As of 17 October 2018, when recreational use of cannabis was legalized in Canada, dietary supplements for human use and veterinary health products containing not more than 10 parts per million of THC extract were approved for marketing; Nabiximols (as Sativex) is used as a prescription drug in Canada.
The United Nations' World Drug Report stated that cannabis "was the world's most widely produced, trafficked, and consumed drug in the world in 2010", and estimated between 128 million and 238 million users globally in 2015.
== Culture, legality and economics ==
=== Culture ===
Cannabis has been one of the most used psychoactive drugs in the world since the late 20th century, following only tobacco and alcohol in popularity. According to Vera Rubin, the use of cannabis has been encompassed by two major cultural complexes over time: a continuous, traditional folk stream, and a more circumscribed, contemporary configuration. The former involves both sacred and secular use, and is usually based on small-scale cultivation: the use of the plant for cordage, clothing, medicine, food, and a "general use as an euphoriant and symbol of fellowship." The second stream of expansion of cannabis use encompasses "the use of hemp for commercial manufacturers utilizing large-scale cultivation primarily as a fiber for mercantile purposes"; but it is also linked to the search for psychedelic experiences (which can be traced back to the formation of the Parisian Club des Hashischins).
=== Legality ===
Since the beginning of the 20th century, most countries have enacted laws against the cultivation, possession or transfer of cannabis. These laws have had an adverse effect on cannabis cultivation for non-recreational purposes, but there are many regions where handling of cannabis is legal or licensed. Many jurisdictions have lessened the penalties for possession of small quantities of cannabis so that it is punished by confiscation and sometimes a fine, rather than imprisonment, focusing more on those who traffic the drug on the black market.
In some areas where cannabis use had been historically tolerated, new restrictions were instituted, such as the closing of cannabis coffee shops near the borders of the Netherlands, and closing of coffee shops near secondary schools in the Netherlands. In Copenhagen, Denmark in 2014, mayor Frank Jensen discussed possibilities for the city to legalize cannabis production and commerce.
Some jurisdictions use free voluntary or mandatory treatment programs for frequent known users. Simple possession can carry long prison terms in some countries, particularly in East Asia, where the sale of cannabis may lead to a sentence of life in prison or even execution. Political parties, non-profit organizations, and causes based on the legalization of medical cannabis or legalizing the plant entirely (with some restrictions) have emerged in such countries as China and Thailand.
In December 2012, the U.S. state of Washington became the first state to officially legalize cannabis in a state law (Washington Initiative 502) (but still illegal by federal law), with the state of Colorado following close behind (Colorado Amendment 64). On 1 January 2013, the first cannabis "club" for private marijuana smoking (no buying or selling, however) was allowed for the first time in Colorado. The California Supreme Court decided in May 2013 that local governments can ban medical cannabis dispensaries despite a state law in California that permits the use of cannabis for medical purposes. At least 180 cities across California have enacted bans in recent years.
On 30 April 2024, the United States Department of Justice announced it would move to reclassify cannabis from a Schedule I to a Schedule III controlled substance.
In December 2013, Uruguay became the first country to legalize growing, sale and use of cannabis. After a long delay in implementing the retail component of the law, in 2017 sixteen pharmacies were authorized to sell cannabis commercially. On 19 June 2018, the Canadian Senate passed a bill and the Prime Minister announced the effective legalization date as 17 October 2018. Canada is the second country to legalize the drug.
In November 2015, Uttarakhand became the first state of India to legalize the cultivation of hemp for industrial purposes. Usage within the Hindu and Buddhist cultures of the Indian subcontinent is common, with many street vendors in India openly selling products infused with cannabis, and traditional medical practitioners in Sri Lanka selling products infused with cannabis for recreational purposes and well as for religious celebrations. Indian laws criminalizing cannabis date back to the colonial period. India and Sri Lanka have allowed cannabis to be taken in the context of traditional culture for recreational/celebratory purposes and also for medicinal purposes.
On 17 October 2015, Australian health minister Sussan Ley presented a new law that will allow the cultivation of cannabis for scientific research and medical trials on patients.
On 17 October 2018, Canada legalized cannabis for recreational adult use making it the second country in the world to do so after Uruguay and the first G7 nation. This legalization comes with regulation similar to that of alcohol in Canada, age restrictions, limiting home production, distribution, consumption areas and sale times. Laws around use vary from province to province including age limits, retail structure, and growing at home. The Canadian Licensed Producer system aims to become the Gold Standard in the world for safe and secure cannabis production, including provisions for a robust craft cannabis industry where many expect opportunities for experimenting with different strains.
As the drug has increasingly been seen as a health issue instead of criminal behavior, cannabis has also been legalized or decriminalized in: Czech Republic, Colombia, Ecuador, Portugal, South Africa and Canada. Medical marijuana was legalized in Mexico in mid-2017 and legalized for recreational use in June 2021.
Germany legalized cannabis for recreational use in April 2024.
==== Legal status by country ====
As of 2022, Uruguay and Canada are the only countries that have fully legalized the cultivation, consumption and bartering of recreational cannabis nationwide. In the United States, 24 states, 3 territories, and the District of Columbia have legalized the recreational use of cannabis – though the drug remains illegal at the federal level. Laws vary from state to state when it comes to the commercial sale. Court rulings in Georgia and South Africa have led to the legalization of cannabis consumption, but not legal sales. A policy of limited enforcement has also been adopted in many countries, in particular Spain and the Netherlands where the sale of cannabis is tolerated at licensed establishments. Contrary to popular belief, cannabis is not legal in the Netherlands, but it has been decriminalized since the 1970s. In 2021, Malta was the first European Union member to legalize the use of cannabis for recreational purposes. In Estonia, it is only legal to sell cannabis products with a THC content of less than 0.2%, although products may contain more cannabidiol. Lebanon has recently become the first Arab country to legalize the plantation of cannabis for medical use.
Penalties for illegal recreational use ranges from confiscation or small fines to jail time and even death. In some countries citizens can be punished if they have used the drug in another country, including Singapore and South Korea.
=== Economics ===
==== Production ====
Sinsemilla (Spanish for "without seed") is the dried, seedless (i.e. parthenocarpic) infructescences of female cannabis plants. Because THC production drops off once pollination occurs, the male plants (which produce little THC themselves) are eliminated before they shed pollen to prevent pollination, thus inducing the development of parthenocarpic fruits gathered in dense infructescences. Advanced cultivation techniques such as hydroponics, cloning, high-intensity artificial lighting, and the sea of green method are frequently employed as a response (in part) to prohibition enforcement efforts that make outdoor cultivation more risky.
"Skunk" refers to several named strains of potent cannabis, grown through selective breeding and sometimes hydroponics. It is a cross-breed of Cannabis sativa and C. indica (although other strains of this mix exist in abundance). Skunk cannabis potency ranges usually from 6% to 15% and rarely as high as 20%. The average THC level in coffee shops in the Netherlands is about 18–19%.
The average levels of THC in cannabis sold in the United States rose dramatically between the 1970s and 2000. This is disputed for various reasons, and there is little consensus as to whether this is a fact or an artifact of poor testing methodologies. According to Daniel Forbes writing for slate.com, the relative strength of modern strains are likely skewed because undue weight is given to much more expensive and potent, but less prevalent, samples. Some suggest that results are skewed by older testing methods that included low-THC-content plant material such as leaves in the samples, which are excluded in contemporary tests. Others believe that modern strains actually are significantly more potent than older ones.
The main producing countries of cannabis are Afghanistan, Canada, China, Colombia, India, Jamaica, Lebanon, Mexico, Morocco, the Netherlands, Pakistan, Paraguay, Spain, Thailand, Turkey, the United Kingdom, and the United States.
==== Price ====
The price or street value of cannabis varies widely depending on geographic area and potency. Prices and overall markets have also varied considerably over time.
In 1997, cannabis was estimated to be overall the number four value crop in the US, and number one or two in many states, including California, New York, and Florida. This estimate is based on a value to growers of ~60% of retail value, or $3,000 per pound ($6,600/kg).
In 2006, cannabis was estimated to have been a $36 billion market. This estimate has been challenged as exaggerated. The UN World Drug Report (2008) estimated that 2006 street prices in the US and Canada ranged from about US$8.8 to $25 per gram (approximately $250 to $700 per ounce), depending on quality. Typical U.S. retail prices were $10–15 per gram (approximately $280–420 per ounce).
In 2017, the U.S. was estimated to constitute 90% of the worldwide $9.5 billion legal trade in cannabis.
After some U.S. states legalized cannabis, street prices began to drop. In Colorado, the price of smokable buds (infructescences) dropped 40 percent between 2014 and 2019, from $200 per ounce to $120 per ounce ($7 per gram to $4.19 per gram).
The European Monitoring Centre for Drugs and Drug Addiction reports that typical retail prices in Europe for cannabis varied from €2 to €20 per gram in 2008, with a majority of European countries reporting prices in the range €4–10.
== Cannabis as a gateway drug ==
The gateway hypothesis states that cannabis use increases the probability of trying "harder" drugs. The hypothesis has been hotly debated as it is regarded by some as the primary rationale for the United States prohibition on cannabis use. A Pew Research Center poll found that political opposition to marijuana use was significantly associated with concerns about the health effects and whether legalization would increase cannabis use by children.
Some studies state that while there is no proof for the gateway hypothesis, young cannabis users should still be considered as a risk group for intervention programs. Other findings indicate that hard drug users are likely to be poly-drug users, and that interventions must address the use of multiple drugs instead of a single hard drug. Almost two-thirds of the poly drug users in the 2009–2010 Scottish Crime and Justice Survey used cannabis.
The gateway effect may appear due to social factors involved in using any illegal drug. Because of the illegal status of cannabis, its consumers are likely to find themselves in situations allowing them to acquaint with individuals using or selling other illegal drugs. Studies have shown that alcohol and tobacco may additionally be regarded as gateway drugs; however, a more parsimonious explanation could be that cannabis is simply more readily available (and at an earlier age) than illegal hard drugs. In turn, alcohol and tobacco are typically easier to obtain at an earlier age than is cannabis (though the reverse may be true in some areas), thus leading to the "gateway sequence" in those individuals, since they are most likely to experiment with any drug offered.
A related alternative to the gateway hypothesis is the common liability to addiction (CLA) theory. It states that some individuals are, for various reasons, willing to try multiple recreational substances. The "gateway" drugs are merely those that are (usually) available at an earlier age than the harder drugs. Researchers have noted in an extensive review that it is dangerous to present the sequence of events described in gateway "theory" in causative terms as this hinders both research and intervention.
In 2020, the National Institute on Drug Abuse released a study backing allegations that marijuana is a gateway to harder drugs, though not for the majority of marijuana users. The National Institute on Drug Abuse determined that marijuana use is "likely to precede use of other licit and illicit substances" and that "adults who reported marijuana use during the first wave of the survey were more likely than adults who did not use marijuana to develop an alcohol use disorder within 3 years; people who used marijuana and already had an alcohol use disorder at the outset were at greater risk of their alcohol use disorder worsening. Marijuana use is also linked to other substance use disorders including nicotine addiction." It also reported that "These findings are consistent with the idea of marijuana as a "gateway drug". However, the majority of people who use marijuana do not go on to use other, "harder" substances. Also, cross-sensitization is not unique to marijuana. Alcohol and nicotine also prime the brain for a heightened response to other drugs and are, like marijuana, also typically used before a person progresses to other, more harmful substances."
== Research ==
Research on cannabis is challenging since the plant is illegal in most countries. Research-grade samples of the drug are difficult to obtain for research purposes, unless granted under authority of national regulatory agencies, such as the US Food and Drug Administration.
There are also other difficulties in researching the effects of cannabis. Many people who smoke cannabis also smoke tobacco. This causes confounding factors, where questions arise as to whether the tobacco, the cannabis, or both that have caused a cancer. Another difficulty researchers have is in recruiting people who smoke cannabis into studies. Because cannabis is an illegal drug in many countries, people may be reluctant to take part in research, and if they do agree to take part, they may not say how much cannabis they actually smoke.
== See also ==
Cannabis rights
Glossary of cannabis terms
List of books about cannabis
List of celebrities who own cannabis businesses
== References ==
Footnotes
Citations
== Further reading ==
Booth, Martin (2004). Cannabis: A History. Picador. ISBN 978-0-312-42494-7.
Drake, Bill (2002). The Marijuana Food Handbook: A Guide for the Sensuous Connoisseur. Ronin Publishing. ISBN 978-0-914171-99-7.
Grinspoon, Lester (1994). Marihuana Reconsidered. Quick American Archives. ISBN 978-0-932551-13-9.
== External links ==
Media related to Cannabis at Wikimedia Commons
The dictionary definition of marijuana at Wiktionary
"Cannabis". European Union Drugs Agency (EUDA). | Wikipedia/Cannabis_(Drug) |
A tartrate is a salt or ester of the organic compound tartaric acid, a dicarboxylic acid. The formula of the tartrate dianion is O−OC-CH(OH)-CH(OH)-COO− or C4H4O62−.
The main forms of tartrates used commercially are pure crystalline tartaric acid used as an acidulant in non-alcoholic drinks and foods, cream of tartar used in baking, and Rochelle salt, commonly used in electroplating solutions.
== As food additives ==
As food additives, tartrates are used as antioxidants, acidity regulators, and emulsifiers. Examples include
sodium tartrates (E335)
monosodium tartrate
sodium tartrate
sodium ammonium tartrate the compound through which Louis Pasteur discovered chirality
potassium tartrates (E336)
potassium bitartrate (monopotassium tartrate, cream of tartar)
potassium tartrate
potassium sodium tartrate (E337)
calcium tartrate (E354, used as emulsifier)
stearyl tartrate (E483, used as emulsifier)
== In wine ==
In wine, tartrates are the harmless crystalline deposits that separate from wines during fermentation and aging. The principal component of this deposit is potassium bitartrate, a potassium salt of tartaric acid. Small amounts of pulp debris, dead yeast, and precipitated phenolic materials such as tannins make up the impurities contaminating the potassium acid tartrate.
The wine industry is the only source of commercial tartrates, and the crystalline encrustations left inside fermentation vessels are regularly scraped off and purified for commercial use.
Tartrates separate from new wines because they are less soluble in alcohol than in non-alcoholic grape juice. The exact figures vary according to variety and region, but approximately half of the tartrate soluble in grape juice is insoluble in wine. The problem is that the tartrate may remain in a supersaturated state after bottling, only to crystallize at some unpredictable later time.
Tartrates precipitated in red wine usually take on some red pigment and are commonly dismissed as mere sediment; in white wines they can look alarmingly like shards of glass. The modern wine industry has decided that tartrate stabilization is preferable to consumer education.
== As concrete admixture ==
Tartrate is also used as a retarder to delay the setting time of concrete when temperature is too high.
== References == | Wikipedia/Tartrate |
3,4-Methylenedioxyamphetamine (MDA) is an entactogen, stimulant, and psychedelic drug of the amphetamine and MDxx families that is encountered mainly as a recreational drug. In its pharmacology, MDA is a serotonin–norepinephrine–dopamine releasing agent (SNDRA). In most countries, the drug is a controlled substance and its possession and sale are illegal.
MDA is rarely sought as a recreational drug compared to other amphetamines; however, it remains widely used due to it being a primary metabolite, the product of hepatic N-dealkylation, of MDMA. It is also a common adulterant of illicitly produced MDMA.
== Uses ==
=== Recreational ===
MDA is bought, sold, and used as a recreational drug due to its enhancement of mood and empathy. A recreational dose of MDA is sometimes cited as being between 100 and 160 mg. It produces MDMA-like effects, including entactogen and psychedelic effects.
=== Medical ===
MDA currently has no accepted medical use.
== Side effects ==
Side effects of MDA include sympathomimetic effects like increased heart rate and blood pressure as well as increased cortisol and prolactin levels.
== Overdose ==
Symptoms of acute toxicity may include agitation, sweating, increased blood pressure and heart rate, dramatic increase in body temperature, convulsions, and death. Death is usually caused by cardiac effects and subsequent hemorrhaging in the brain (stroke).
== Interactions ==
== Pharmacology ==
=== Pharmacodynamics ===
MDA is a substrate of the serotonin, norepinephrine, dopamine, and vesicular monoamine transporters, and in relation to this, acts as a reuptake inhibitor and releasing agent of serotonin, norepinephrine, and dopamine (that is, it is an SNDRATooltip serotonin–norepinephrine–dopamine releasing agent). It is also an agonist of the serotonin 5-HT2A, 5-HT2B, and 5-HT2C receptors and shows affinity for the α2A-, α2B-, and α2C-adrenergic receptors and serotonin 5-HT1A and 5-HT7 receptors.
In addition to its actions as a monoamine releasing agent, MDA is a potent high-efficacy partial agonist or full agonist of the rodent TAAR1. Conversely, MDA is much weaker in terms of potency as an agonist of the human TAAR1. Moreover, MDA acts as a very weak partial agonist or antagonist of the human TAAR1 rather than as an efficacious agonist. TAAR1 activation is thought to auto-inhibit and constrain the effects of amphetamines that act as TAAR1 agonists, for instance MDMA in rodents.
The (S)-optical isomer of MDA is more potent than the (R)-optical isomer as a psychostimulant, possessing greater affinity for the three monoamine transporters. MDA and its enantiomer (R)-MDA substitute for the psychedelics LSD and DOM in rodent drug discrimination tests. MDA and (R)-MDA produce the head-twitch response, a behavioral proxy of psychedelic-like effects, in rodents. However, the head–twitch response they produce is very weak in magnitude compared to other related psychedelics such as the DOx drugs. On the other hand, the response is more similar in magnitude to that of Ariadne.
In terms of the subjective and behavioral effects of MDA, it is thought that serotonin release is required for its empathogenic effects, dopamine release is required for its euphoriant (rewarding and addictive) effects, dopamine and norepinephrine release is required for its psychostimulant effects, and direct agonism of the serotonin 5-HT2A receptor is required for its mild psychedelic effects.
MDA can produce serotonergic neurotoxic effects in rodents, which might in part be due to transformation into MDA followed by subsequent metabolism. In addition, MDA activates a response of the neuroglia, though this subsides after use.
=== Pharmacokinetics ===
The pharmacokinetics of MDA have been studied. Its duration of action has been reported to be about 6 to 8 hours. The duration of MDA is longer than that of MDMA, about 8 hours for MDA versus 6 hours for MDMA. The elimination half-life of MDA is 10.9 hours. Differences in the duration of MDA versus MDMA may be due pharmacodynamics rather than pharmacokinetics.
== Chemistry ==
MDA is a substituted methylenedioxylated phenethylamine and amphetamine derivative. In relation to other phenethylamines and amphetamines, it is the 3,4-methylenedioxy, α-methyl derivative of β-phenylethylamine, the 3,4-methylenedioxy derivative of amphetamine, and the N-desmethyl derivative of MDMA.
=== Synonyms ===
In addition to 3,4-methylenedioxyamphetamine, MDA is also known by other chemical synonyms such as the following:
α-Methyl-3,4-methylenedioxy-β-phenylethylamine
1-(3,4-Methylenedioxyphenyl)-2-propanamine
1-(1,3-Benzodioxol-5-yl)-2-propanamine
=== Synthesis ===
MDA is typically synthesized from essential oils such as safrole or piperonal. Common approaches from these precursors include:
Reaction of safrole's alkene functional group with a halogen containing mineral acid followed by amine alkylation.
Wacker oxidation of safrole to yield 3,4-methylenedioxyphenylpropan-2-one (MDP2P) followed by reductive amination or via reduction of its oxime.
Henry reaction of piperonal with nitroethane followed by nitro compound reduction.
Darzens reaction on heliotropin was also done by J. Elks, et al. This gives MDP2P, which was then subjected to a Leuckart reaction.
The "two dogs" or "dopeboy" clandestine method, starting with helional as a precursor. First, an oxime is created using hydoxylamine. Then, a Beckmann rearrangement is performed with nickel acetate to form the amide. Then a Hofmann rearrangement is done to form the freebase amine of MDA. Then it is purified with an acid base extraction.
=== Detection in body fluids ===
MDA may be quantitated in blood, plasma or urine to monitor for use, confirm a diagnosis of poisoning or assist in the forensic investigation of a traffic or other criminal violation or a sudden death. Some drug abuse screening programs rely on hair, saliva, or sweat as specimens. Most commercial amphetamine immunoassay screening tests cross-react significantly with MDA and major metabolites of MDMA, but chromatographic techniques can easily distinguish and separately measure each of these substances. The concentrations of MDA in the blood or urine of a person who has taken only MDMA are, in general, less than 10% those of the parent drug.
=== Derivatives ===
MDA constitutes part of the core structure of the β-adrenergic receptor agonist protokylol.
== History ==
MDA was first synthesized by Carl Mannich and W. Jacobsohn in 1910. It was first taken in July 1930 by Gordon Alles at a total dose of 126 mg, who experienced hallucinogenic effects, well-being and euphoria, and peripheral effects. However, he did not subsequently describe these effects until 1959. Alles later licensed the drug to Smith, Kline & French. MDA was first used in animal tests in 1939, and human trials began in 1941 in the exploration of possible therapies for Parkinson's disease. From 1949 to 1957, more than five hundred human subjects were given MDA in an investigation of its potential use as an antidepressant and/or anorectic by Smith, Kline & French. The United States Army also experimented with the drug, code named EA-1298, while working to develop a truth drug or incapacitating agent. Harold Blauer died in January 1953 after being intravenously injected, without his knowledge or consent, with 450 mg of the drug as part of Project MKUltra. MDA was patented as an ataractic by Smith, Kline & French in 1960, and as an anorectic under the trade name "Amphedoxamine" in 1961. MDA began to appear on the recreational drug scene around 1963 to 1964. It was then inexpensive and readily available as a research chemical from several scientific supply houses. Several researchers, including Claudio Naranjo and Richard Yensen, have explored MDA in the field of psychotherapy.
The International Nonproprietary Name (INN) tenamfetamine was recommended by the World Health Organization (WHO) in 1986. It was recommended in the same published list in which the INN of 2,5-dimethoxy-4-bromoamphetamine (DOB), brolamfetamine, was recommended. These events suggest that MDA and DOB were under development as potential pharmaceutical drugs at the time. The Multidisciplinary Association for Psychedelic Studies (MAPS) was also founded in 1986.
Matthew J. Baggott and colleagues conducted some of the first modern clinical studies of MDA in humans and published their findings in the 2010s.
== Society and culture ==
=== Names ===
When MDA was under development as a potential pharmaceutical drug, it was given the International Nonproprietary Name (INN) of tenamfetamine.
=== Legal status ===
==== Australia ====
MDA is schedule 9 prohibited substance under the Poisons Standards. A schedule 9 substance is listed as a "Substances which may be abused or misused, the manufacture, possession, sale or use of which should be prohibited by law except when required for medical or scientific research, or for analytical, teaching or training purposes with approval of Commonwealth and/or State or Territory Health Authorities."
==== United States ====
MDA is a Schedule I controlled substance in the US.
== Research ==
In 2010, the ability of MDA to invoke mystical experiences and alter vision in healthy volunteers was studied. The study concluded that MDA is a "potential tool to investigate mystical experiences and visual perception".
A 2019 double-blind study administered both MDA and MDMA to healthy volunteers. The study found that MDA shared many properties with MDMA including entactogenic and stimulant effects, but generally lasted longer and produced greater increases in psychedelic-like effects like complex imagery, synesthesia, and spiritual experiences.
== See also ==
MDMA
2,3-Methylenedioxyamphetamine
4,4'-Methylenedianiline
Malondialdehyde
== References ==
== External links ==
Erowid MDA Vault
MDA entry in PiHKAL
MDA entry in PiHKAL • info | Wikipedia/MDA_(drug) |
Transform Press is a small publishing company in the area of psychedelics and other psychoactive drugs that is based in Berkeley, California. It is the publisher of the books of Alexander Shulgin and Ann Shulgin and is led by Wendy Tucker, Ann Shulgin's daughter.
The company's published books by the Shulgins include PiHKAL (Phenethylamines I Have Known and Loved) (1991), TiHKAL (Tryptamines I Have Known and Loved) (1997), The Shulgin Index (2011), The Simple Plant Isoquinolines (2002), and The Nature of Drugs (2021). They have also published Ergot Alkaloids: History, Chemistry, and Therapeutic Uses (2023), an English translation by Jitka Nykodemová of Albert Hofmann's 1964 book Die Mutterkornalkaloide: Vom Mutterkorn zum LSD (The Ergot Alkaloids: From Ergot to LSD).
According to Nick Cozzi of the Alexander Shulgin Research Institute (ASRI) in mid-2023, the group is in the process of translating Daniel Trachsel's book Phenethylamine: von der Struktur zur Funktion (Phenethylamines: From Structure to Function) into English, with tentative publication by Transform Press.
== See also ==
Alexander Shulgin Research Institute (ASRI)
== References ==
== External links ==
Transform Press official website
Transform Press - X (formerly Twitter)
Transform Press - Instagram
Transform Press - LinkedIn | Wikipedia/Transform_Press |
MMDA, also known as 3-methoxy-4,5-methylenedioxyamphetamine or as 5-methoxy-MDA, is a psychedelic and entactogen of the amphetamine family.
== Use and effects ==
MMDA was described by Alexander Shulgin in his book PiHKAL. Shulgin lists the dosage range of MMDA as 100 to 250 mg. The first effects appear within 20 to 45 minutes following oral administration. Its duration is described as "moderate".
MMDA produces effects including relaxation, time dilation, empathy, passivity, compassion, changes in music perception, closed-eye visuals such as geometric patterns, open-eye visuals, dream-like states described as "brain movies", and an afterglow. It has been said to be gentler than certain other psychedelics. The drug is said to have similar effects to MDA, but to be to some extent more psychedelic in comparison.
== Side effects ==
Side effects of MMDA have been reported to include restlessness, cold sensations, shivering, nausea, abdominal cramps, disorientation, social withdrawal, feeling ill, and anxiety.
== Interactions ==
== Pharmacology ==
=== Pharmacodynamics ===
MMDA has been shown to act as a non-neurotoxic serotonin releasing agent, with no effects on release of dopamine or probably norepinephrine, and as a serotonin 5-HT2A receptor agonist. The latter property is thought to be responsible for its psychedelic effects, whereas the former action may be involved in its entactogenic effects.
=== Pharmacokinetics ===
MMDA has been found to be formed from myristicin, a component of nutmeg, in rabbits and rats. However, MMDA could not be detected with nutmeg misuse in a human.
== Chemistry ==
Analogues of MMDA include lophophine (MMDPEA), MDA, MDMA, and TMA. Positional isomers of MMDA include MMDA-2, MMDA-3a, MMDA-3b, MMDA-4, and MMDA-5. Further analogues and derivatives of MMDA include DMMDA, DMMDA-2, DMMDA-3, DMMDA-4, DMMDA-5, and DMMDA-6.
== History ==
MMDA was first synthesized and studied by Gordon Alles at the Edgewood Arsenal in the mid-1950s. Its Edgewood Arsenal code name is unknown. Subsequently, Alexander Shulgin synthesized MMDA in 1962 and discovered its psychoactive effects that same year. Shulgin published his findings on MMDA in the scientific literature in 1964. Use of MMDA in psychedelic-assisted psychotherapy was studied by Shulgin, Thornton Sargent, and Claudio Naranjo in the mid-1960s and their findings were published in 1973. Naranjo also described MMDA for these purposes in his 1973 book The Healing Journey: New Approaches to Consciousness. Shulgin subsequently further described MMDA in his book PiHKAL in 1991.
== Society and culture ==
=== Legal status ===
==== International ====
Internationally, MMDA is a Schedule I drug under the Convention on Psychotropic Substances.
==== Australia ====
MMDA is considered a Schedule 9 prohibited substance in Australia under the Poisons Standard (October 2015). A Schedule 9 substance is a substance which may be abused or misused, the manufacture, possession, sale or use of which should be prohibited by law except when required for medical or scientific research, or for analytical, teaching or training purposes with approval of Commonwealth and/or State or Territory Health Authorities.
==== United States ====
MMDA is classified as a Schedule 1 substance in the United States, and is similarly controlled in other parts of the world. MMDA remains illegal, however it is classified differently than the illegality of MDMA.
== See also ==
Substituted methylenedioxyphenethylamine
Substituted methoxyphenethylamine
Methoxymethylenedioxyamphetamine
Dimethoxymethylenedioxyamphetamine
== References ==
== External links ==
MMDA - Isomer Design
MMDA - PiHKAL - Erowid
MMDA - PiHKAL - Isomer Design | Wikipedia/MMDA_(drug) |
Ethnography is a branch of anthropology and the systematic study of individual cultures. It explores cultural phenomena from the point of view of the subject of the study. Ethnography is also a type of social research that involves examining the behavior of the participants in a given social situation and understanding the group members' own interpretation of such behavior.
As a form of inquiry, ethnography relies heavily on participant observation, where the researcher participates in the setting or with the people being studied, at least in some marginal role, and seeking to document, in detail, patterns of social interaction and the perspectives of participants, and to understand these in their local contexts. It had its origin in social and cultural anthropology in the early twentieth century, but has, since then, spread to other social science disciplines, notably sociology.
Ethnographers mainly use qualitative methods, though they may also include quantitative data. The typical ethnography is a holistic study and so includes a brief history, and an analysis of the terrain, the climate, and the habitat. A wide range of groups and organisations have been studied by this method, including traditional communities, youth gangs, religious cults, and organisations of various kinds. While, traditionally, ethnography has relied on the physical presence of the researcher in a setting, there is research using the label that has relied on interviews or documents, sometimes to investigate events in the past such as the NASA Challenger disaster. There is also ethnography done in "virtual" or online environments, sometimes labelled netnography or cyber-ethnography.
== Origins ==
The term ethnography is from Greek (ἔθνος éthnos "folk, people, nation" and γράφω gráphō "I write") and encompasses the ways in which ancient authors described and analyzed foreign cultures. Anthony Kaldellis loosely suggests the Odyssey as a starting point for ancient ethnography, while noting that Herodotus' Histories is the usual starting point; while Edith Hall has argued that Homeric poetry lacks "the coherence and vigour of ethnological science". From Herodotus forward, ethnography was a mainstay of ancient historiography.
Tacitus has ethnographies in the Agricola, Histories, and Germania. Tacitus' Germania "stands as the sole surviving full-scale monograph by a classical author on an alien people." Ethnography formed a relatively coherent subgenre in Byzantine literature.
=== Development as a science ===
While ethnography ("ethnographic writing") was widely practiced in antiquity, ethnography as a science (cf. ethnology) did not exist in the ancient world. There is no ancient term or concept applicable to ethnography, and those writers probably did not consider the study of other cultures as a distinct mode of inquiry from history.
Gerhard Friedrich Müller developed the concept of ethnography as a separate discipline whilst participating in the Second Kamchatka Expedition (1733–43) as a professor of history and geography. Whilst involved in the expedition, he differentiated Völker-Beschreibung as a distinct area of study. This became known as "ethnography", following the introduction of the Greek neologism ethnographia by Johann Friedrich Schöpperlin and the German variant by A. F. Thilo in 1767. August Ludwig von Schlözer and Christoph Wilhelm Jacob Gatterer of the University of Göttingen introduced the term into the academic discourse in an attempt to reform the contemporary understanding of world history.
== Features of ethnographic research ==
According to Dewan (2018), the researcher is not looking for generalizing the findings; rather, they are considering it in reference to the context of the situation. In this regard, the best way to integrate ethnography in a quantitative research would be to use it to discover and uncover relationships and then use the resultant data to test and explain the empirical assumptions.
In ethnography, the researcher gathers what is available, what is normal, what it is that people do, what they say, and how they work.
Ethnography can also be used in other methodological frameworks, for instance, an action research program of study where one of the goals is to change and improve the situation.
Ethnographic research is a fundamental methodology in cultural ecology, development studies, and feminist geography. In addition, it has gained importance in social, political, cultural, and nature-society geography. Ethnography is an effective methodology in qualitative geographic research that focuses on people's perceptions and experiences and their traditionally place-based immersion within a social group.
== Data collection methods ==
According to John Brewer, a leading social scientist, data collection methods are meant to capture the "social meanings and ordinary activities" of people (informants) in "naturally occurring settings" that are commonly referred to as "the field". The goal is to collect data in such a way that the researcher imposes a minimal amount of personal bias in the data. Multiple methods of data collection may be employed to facilitate a relationship that allows for a more personal and in-depth portrait of the informants and their community. These can include participant observation, field notes, interviews and surveys, as well as various visual methods.
Interviews are often taped and later transcribed, allowing the interview to proceed unimpaired of note-taking, but with all information available later for full analysis. Secondary research and document analysis are also used to provide insight into the research topic. In the past, kinship charts were commonly used to "discover logical patterns and social structure in non-Western societies". In the 21st century, anthropology focuses more on the study of people in urban settings and the use of kinship charts is seldom employed.
In order to make the data collection and interpretation transparent, researchers creating ethnographies often attempt to be "reflexive". Reflexivity refers to the researcher's aim "to explore the ways in which [the] researcher's involvement with a particular study influences, acts upon and informs such research".[Marvasti, Amir & Gubrium, Jaber. 2023. Crafting Ethnographic Fieldwork: Sites, Selves & Social Worlds. Routledge. Despite these attempts of reflexivity, no researcher can be totally unbiased. This factor has provided a basis to criticize ethnography.
Traditionally, the ethnographer focuses attention on a community, selecting knowledgeable informants who know the activities of the community well. These informants are typically asked to identify other informants who represent the community, often using snowball or chain sampling. This process is often effective in revealing common cultural denominators connected to the topic being studied. Ethnography relies greatly on up-close, personal experience. Participation, rather than just observation, is one of the keys to this process. Ethnography is very useful in social research.
An inevitability during ethnographic participation is that the researcher experiences at least some resocialization. In other words, the ethnographer to some extent "becomes" what they are studying. For instance, an ethnographer may become skilled at a work activity that they are studying; they may become members of a particular religious group they are interested in studying; or they may even inhabit a familial role in a community they are staying with. Robert M. Emerson, Rachel Fretz, and Linda Shaw summarize this idea in their book Writing Ethnographic Field Notes using a common metaphor: "the fieldworker cannot and should not attempt to be a fly on the wall."
Ybema et al. (2010) examine the ontological and epistemological presuppositions underlying ethnography. Ethnographic research can range from a realist perspective, in which behavior is observed, to a constructivist perspective where understanding is socially constructed by the researcher and subjects. Research can range from an objectivist account of fixed, observable behaviors to an interpretive narrative describing "the interplay of individual agency and social structure." Critical theory researchers address "issues of power within the researcher-researched relationships and the links between knowledge and power."
Another form of data collection is that of the "image". The image is the projection that an individual puts on an object or abstract idea. An image can be contained within the physical world through a particular individual's perspective, primarily based on that individual's past experiences. One example of an image is how an individual views a novel after completing it. The physical entity that is the novel contains a specific image in the perspective of the interpreting individual and can only be expressed by the individual in the terms of "I can tell you what an image is by telling you what it feels like." The idea of an image relies on the imagination and has been seen to be utilized by children in a very spontaneous and natural manner. Effectively, the idea of the image is a primary tool for ethnographers to collect data. The image presents the perspective, experiences, and influences of an individual as a single entity and in consequence, the individual will always contain this image in the group under study.
== Differences across disciplines ==
The ethnographic method is used across a range of different disciplines, primarily by anthropologists/ethnologists but also occasionally by sociologists. Cultural studies, occupational therapy, economics, social work, education, design, psychology, computer science, human factors and ergonomics, ethnomusicology, folkloristics, religious studies, geography, history, linguistics, communication studies, performance studies, advertising, accounting research, nursing, urban planning, usability, political science, social movement, and criminology are other fields which have made use of ethnography.
=== Cultural and social anthropology ===
Cultural anthropology and social anthropology were developed around ethnographic research and their canonical texts, which are mostly ethnographies: e.g. Argonauts of the Western Pacific (1922) by Bronisław Malinowski, Ethnologische Excursion in Johore (1875) by Nicholas Miklouho-Maclay, Coming of Age in Samoa (1928) by Margaret Mead, The Nuer (1940) by E. E. Evans-Pritchard, Naven (1936, 1958) by Gregory Bateson, or "The Lele of the Kasai" (1963) by Mary Douglas. Cultural and social anthropologists today place a high value on doing ethnographic research. The typical ethnography is a document written about a particular people, almost always based at least in part on emic views of where the culture begins and ends. Using language or community boundaries to bound the ethnography is common. Ethnographies are also sometimes called "case studies". Ethnographers study and interpret culture, its universalities, and its variations through the ethnographic study based on fieldwork. An ethnography is a specific kind of written observational science which provides an account of a particular culture, society, or community. The fieldwork usually involves spending a year or more in another society, living with the local people and learning about their ways of life. Ruth Fulton Benedict uses examples of Enthrotyhy in her serious of field work that began in 1922 of Serrano, of the Zuni in 1924, the Cochiti in 1925 and the Pina in 1926. All being people she wished to study for her anthropological data. Benedict's experiences with the Southwest Zuni pueblo is to be considered the basis of her formative fieldwork. The experience set the idea for her to produce her theory of "culture is personality writ large" (modell, 1988). By studying the culture between the different Pueblo and Plain Indians, She discovered the culture isomorphism that would be considered her personalized unique approach to the study of anthropology using ethnographic techniques.
A typical ethnography attempts to be holistic and typically follows an outline to include a brief history of the culture in question, an analysis of the physical geography or terrain inhabited by the people under study, including climate, and often including what biological anthropologists call habitat. Folk notions of botany and zoology are presented as ethnobotany and ethno-zoology alongside references from the formal sciences. Material culture, technology, and means of subsistence are usually treated next, as they are typically bound up in physical geography and include descriptions of infrastructure. Kinship and social structure (including age grading, peer groups, gender, voluntary associations, clans, moieties, and so forth, if they exist) are typically included. Languages spoken, dialects, and the history of language change are another group of standard topics. Practices of child rearing, acculturation, and emic views on personality and values usually follow after sections on social structure. Rites, rituals, and other evidence of religion have long been an interest and are sometimes central to ethnographies, especially when conducted in public where visiting anthropologists can see them.
As ethnography developed, anthropologists grew more interested in less tangible aspects of culture, such as values, worldview and what Clifford Geertz termed the "ethos" of the culture. In his fieldwork, Geertz used elements of a phenomenological approach, tracing not just the doings of people, but the cultural elements themselves. For example, if within a group of people, winking was a communicative gesture, he sought to first determine what kinds of things a wink might mean (it might mean several things). Then, he sought to determine in what contexts winks were used, and whether, as one moved about a region, winks remained meaningful in the same way. In this way, cultural boundaries of communication could be explored, as opposed to using linguistic boundaries or notions about the residence. Geertz, while still following something of a traditional ethnographic outline, moved outside that outline to talk about "webs" instead of "outlines" of culture.
Within cultural anthropology, there are several subgenres of ethnography. Beginning in the 1950s and early 1960s, anthropologists began writing "bio-confessional" ethnographies that intentionally exposed the nature of ethnographic research. Famous examples include Tristes Tropiques (1955) by Lévi-Strauss, The High Valley by Kenneth Read, and The Savage and the Innocent by David Maybury-Lewis, as well as the mildly fictionalized Return to Laughter by Elenore Smith Bowen (Laura Bohannan).
Later "reflexive" ethnographies refined the technique to translate cultural differences by representing their effects on the ethnographer. Famous examples include Deep Play: Notes on a Balinese Cockfight by Clifford Geertz, Reflections on Fieldwork in Morocco by Paul Rabinow, The Headman and I by Jean-Paul Dumont, and Tuhami by Vincent Crapanzano. In the 1980s, the rhetoric of ethnography was subjected to intense scrutiny within the discipline, under the general influence of literary theory and post-colonial/post-structuralist thought. "Experimental" ethnographies that reveal the ferment of the discipline include Shamanism, Colonialism, and the Wild Man by Michael Taussig, Debating Muslims by Michael F. J. Fischer and Mehdi Abedi, A Space on the Side of the Road by Kathleen Stewart, and Advocacy after Bhopal by Kim Fortun.
This critical turn in sociocultural anthropology during the mid-1980s can be traced to the influence of the now classic (and often contested) text, Writing Culture: The Poetics and Politics of Ethnography, (1986) edited by James Clifford and George Marcus. Writing Culture helped bring changes to both anthropology and ethnography often described in terms of being 'postmodern,' 'reflexive,' 'literary,' 'deconstructive,' or 'poststructural' in nature, in that the text helped to highlight the various epistemic and political predicaments that many practitioners saw as plaguing ethnographic representations and practices.
Where Geertz's and Turner's interpretive anthropology recognized subjects as creative actors who constructed their sociocultural worlds out of symbols, postmodernists attempted to draw attention to the privileged status of the ethnographers themselves. That is, the ethnographer cannot escape the personal viewpoint in creating an ethnographic account, thus making any claims of objective neutrality highly problematic, if not altogether impossible. In regards to this last point, Writing Culture became a focal point for looking at how ethnographers could describe different cultures and societies without denying the subjectivity of those individuals and groups being studied while simultaneously doing so without laying claim to absolute knowledge and objective authority. Along with the development of experimental forms such as 'dialogic anthropology,' 'narrative ethnography,' and 'literary ethnography', Writing Culture helped to encourage the development of 'collaborative ethnography.' This exploration of the relationship between writer, audience, and subject has become a central tenet of contemporary anthropological and ethnographic practice. In certain instances, active collaboration between the researcher(s) and subject(s) has helped blend the practice of collaboration in ethnographic fieldwork with the process of creating the ethnographic product resulting from the research.
=== Sociology ===
Sociology is another field which prominently features ethnographies. Urban sociology, Atlanta University (now Clark-Atlanta University), and the Chicago School, in particular, are associated with ethnographic research, with some well-known early examples being The Philadelphia Negro (1899) by W. E. B. Du Bois, Street Corner Society by William Foote Whyte and Black Metropolis by St. Clair Drake and Horace R. Cayton, Jr. Well-known is Jaber F. Gubrium's pioneering ethnography on the experiences of a nursing home, Living and Dying at Murray Manor. Major influences on this development were anthropologist Lloyd Warner, on the Chicago sociology faculty, and to Robert Park's experience as a journalist. Symbolic interactionism developed from the same tradition and yielded such sociological ethnographies as Shared Fantasy by Gary Alan Fine, which documents the early history of fantasy role-playing games. Other important ethnographies in sociology include Pierre Bourdieu's work in Algeria and France.
Jaber F. Gubrium's series of organizational ethnographies focused on the everyday practices of illness, care, and recovery are notable. They include Living and Dying at Murray Manor, which describes the social worlds of a nursing home; Describing Care: Image and Practice in Rehabilitation, which documents the social organization of patient subjectivity in a physical rehabilitation hospital; Caretakers: Treating Emotionally Disturbed Children, which features the social construction of behavioral disorders in children; and Oldtimers and Alzheimer's: The Descriptive Organization of Senility, which describes how the Alzheimer's disease movement constructed a new subjectivity of senile dementia and how that is organized in a geriatric hospital. Another approach to ethnography in sociology comes in the form of institutional ethnography, developed by Dorothy E. Smith for studying the social relations which structure people's everyday lives.
Other notable ethnographies include Paul Willis's Learning to Labour, on working class youth; the work of Elijah Anderson, Mitchell Duneier, and Loïc Wacquant on black America, and Lai Olurode's Glimpses of Madrasa From Africa. But even though many sub-fields and theoretical perspectives within sociology use ethnographic methods, ethnography is not the sine qua non of the discipline, as it is in cultural anthropology.
=== Communication studies ===
Beginning in the 1960s and 1970s, ethnographic research methods began to be widely used by communication scholars. As the purpose of ethnography is to describe and interpret the shared and learned patterns of values, behaviors, beliefs, and language of a culture-sharing group, Harris, (1968), also Agar (1980) note that ethnography is both a process and an outcome of the research. Studies such as Gerry Philipsen's analysis of cultural communication strategies in a blue-collar, working-class neighborhood on the south side of Chicago, Speaking 'Like a Man' in Teamsterville, paved the way for the expansion of ethnographic research in the study of communication.
Scholars of communication studies use ethnographic research methods to analyze communicative behaviors and phenomena. This is often characterized in the writing as attempts to understand taken-for-granted routines by which working definitions are socially produced. Ethnography as a method is a storied, careful, and systematic examination of the reality-generating mechanisms of everyday life (Coulon, 1995). Ethnographic work in communication studies seeks to explain "how" ordinary methods/practices/performances construct the ordinary actions used by ordinary people in the accomplishments of their identities. This often gives the perception of trying to answer the "why" and "how come" questions of human communication. Often this type of research results in a case study or field study such as an analysis of speech patterns at a protest rally, or the way firemen communicate during "down time" at a fire station. Like anthropology scholars, communication scholars often immerse themselves, and participate in and/or directly observe the particular social group being studied.
=== Other fields ===
The American anthropologist George Spindler was a pioneer in applying the ethnographic methodology to the classroom.
Anthropologists such as Daniel Miller and Mary Douglas have used ethnographic data to answer academic questions about consumers and consumption. In this sense, Tony Salvador, Genevieve Bell, and Ken Anderson describe design ethnography as being "a way of understanding the particulars of daily life in such a way as to increase the success probability of a new product or service or, more appropriately, to reduce the probability of failure specifically due to a lack of understanding of the basic behaviors and frameworks of consumers." Sociologist Sam Ladner argues in her book, that understanding consumers and their desires requires a shift in "standpoint", one that only ethnography provides. The results are products and services that respond to consumers' unmet needs.
Businesses, too, have found ethnographers helpful for understanding how people use products and services. By assessing user experience in a "natural" setting, ethnology yields insights into the practical applications of a product or service. It is one of the best ways to identify areas of friction and improve overall user experience. Companies make increasing use of ethnographic methods to understand consumers and consumption, or for new product development (such as video ethnography). The Ethnographic Praxis in Industry (EPIC) conference is evidence of this. Ethnographers' systematic and holistic approach to real-life experience is valued by product developers, who use the method to understand unstated desires or cultural practices that surround products. Where focus groups fail to inform marketers about what people really do, ethnography links what people say to what they do—avoiding the pitfalls that come from relying only on self-reported, focus-group data.
=== Evaluating ethnography ===
The ethnographic methodology is not usually evaluated in terms of philosophical standpoint (such as positivism and emotionalism). Ethnographic studies need to be evaluated in some manner. No consensus has been developed on evaluation standards, but Richardson (2000, p. 254) provides five criteria that ethnographers might find helpful. Jaber F. Gubrium and James A. Holstein's (1997) monograph, The New Language of Qualitative Method, discusses forms of ethnography in terms of their "methods talk".
Substantive contribution: "Does the piece contribute to our understanding of social life?"
Aesthetic merit: "Does this piece succeed aesthetically?"
Reflexivity: "How did the author come to write this text...Is there adequate self-awareness and self-exposure for the reader to make judgments about the point of view?"
Impact: "Does this affect me? Emotionally? Intellectually?" Does it move me?
Expresses a reality: "Does it seem 'true'—a credible account of a cultural, social, individual, or communal sense of the 'real'?"
== Ethics ==
Gary Alan Fine argues that the nature of ethnographic inquiry demands that researchers deviate from formal and idealistic rules or ethics that have come to be widely accepted in qualitative and quantitative approaches in research. Many of these ethical assumptions are rooted in positivist and post-positivist epistemologies that have adapted over time but are apparent and must be accounted for in all research paradigms. These ethical dilemmas are evident throughout the entire process of conducting ethnographies, including the design, implementation, and reporting of an ethnographic study. Essentially, Fine maintains that researchers are typically not as ethical as they claim or assume to be — and that "each job includes ways of doing things that would be inappropriate for others to know". Also see Jaber F. Gubrium concept of "site-specificity" discussed his book co-edited with Amir Marvasti titled CRAFTING ETHNOGRAPHIC FIELDWORK. Routledge, 2023.
Fine is not necessarily casting blame at ethnographic researchers but tries to show that researchers often make idealized ethical claims and standards which are inherently based on partial truths and self-deceptions. Fine also acknowledges that many of these partial truths and self-deceptions are unavoidable. He maintains that "illusions" are essential to maintain an occupational reputation and avoid potentially more caustic consequences. He claims, "Ethnographers cannot help but lie, but in lying, we reveal truths that escape those who are not so bold". Based on these assertions, Fine establishes three conceptual clusters in which ethnographic ethical dilemmas can be situated: "Classic Virtues", "Technical Skills", and "Ethnographic Self".
Much debate surrounding the issue of ethics arose following revelations about how the ethnographer Napoleon Chagnon conducted his ethnographic fieldwork with the Yanomani people of South America.
While there is no international standard on Ethnographic Ethics, many western anthropologists look to the American Anthropological Association for guidance when conducting ethnographic work. In 2009, the Association adopted a code of ethics, stating: Anthropologists have "moral obligations as members of other groups, such as the family, religion, and community, as well as the profession". The code of ethics notes that anthropologists are part of a wider scholarly and political network, as well as human and natural environment, which needs to be reported on respectfully. The code of ethics recognizes that sometimes very close and personal relationship can sometimes develop from doing ethnographic work. The Association acknowledges that the code is limited in scope; ethnographic work can sometimes be multidisciplinary, and anthropologists need to be familiar with ethics and perspectives of other disciplines as well. The eight-page code of ethics outlines ethical considerations for those conducting Research, Teaching, Application and Dissemination of Results, which are briefly outlined below.
"Conducting Research" – When conducting research Anthropologists need to be aware of the potential impacts of the research on the people and animals they study. If the seeking of new knowledge will negatively impact the people and animals they will be studying they may not undertake the study according to the code of ethics.
"Teaching" – When teaching the discipline of anthropology, instructors are required to inform students of the ethical dilemmas of conducting ethnographies and field work.
"Application" – When conducting an ethnography, Anthropologists must be "open with funders, colleagues, persons studied or providing information, and relevant parties affected by the work about the purpose(s), potential impacts, and source(s) of support for the work."
"Dissemination of Results" – When disseminating results of an ethnography, "[a]nthropologists have an ethical obligation to consider the potential impact of both their research and the communication or dissemination of the results of their research on all directly or indirectly involved." Research results of ethnographies should not be withheld from participants in the research if that research is being observed by other people.
=== Classic virtues ===
"The kindly ethnographer" – Most ethnographers present themselves as being more sympathetic than they are, which aids in the research process, but is also deceptive. The identity that we present to subjects is different from whom we are in other circumstances.
"The friendly ethnographer" – Ethnographers operate under the assumption that they should not dislike anyone. When ethnographers find they intensely dislike individuals encountered in the research, they may crop them out of the findings.
"The honest ethnographer" – If research participants know the research goals, their responses will likely be skewed. Therefore, ethnographers often conceal what they know in order to increase the likelihood of acceptance by participants.
=== Technical skills ===
"The Precise Ethnographer" – Ethnographers often create the illusion that field notes are data and reflect what "really" happened. They engage in the opposite of plagiarism, giving undeserved credit through loose interpretations and paraphrasing. Researchers take near-fictions and turn them into claims of fact. The closest ethnographers can ever really get to reality is an approximate truth.
"The Observant Ethnographer" – Readers of ethnography are often led to assume the report of a scene is complete – that little of importance was missed. In reality, an ethnographer will always miss some aspect because of lacking omniscience. Everything is open to multiple interpretations and misunderstandings. As ethnographers' skills in observation and collection of data vary by individual, what is depicted in ethnography can never be the whole picture.
"The Unobtrusive Ethnographer" – As a "participant" in the scene, the researcher will always have an effect on the communication that occurs within the research site. The degree to which one is an "active member" affects the extent to which sympathetic understanding is possible.
=== Ethnographic self ===
The following are commonly misconceived conceptions of ethnographers:
"The Candid Ethnographer" – Where the researcher personally situates within the ethnography is ethically problematic. There is an illusion that everything reported was observed by the researcher.
"The Chaste Ethnographer" – When ethnographers participate within the field, they invariably develop relationships with research subjects/participants. These relationships are sometimes not accounted for within the reporting of the ethnography, although they may influence the research findings.
"The Fair Ethnographer" – Fine claims that objectivity is an illusion and that everything in ethnography is known from a perspective. Therefore, it is unethical for a researcher to report fairness in findings.
"The Literary Ethnographer" – Representation is a balancing act of determining what to "show" through poetic/prosaic language and style, versus what to "tell" via straightforward, 'factual' reporting. The individual skills of an ethnographer influence what appears to be the value of the research.
According to Norman K. Denzin, ethnographers should consider the following seven principles when observing, recording, and sampling data:
The groups should combine symbolic meanings with patterns of interaction.
Observe the world from the point of view of the subject, while maintaining the distinction between everyday and scientific perceptions of reality.
Link the group's symbols and their meanings with the social relationships.
Record all behavior.
The methodology should highlight phases of process, change, and stability.
The act should be a type of symbolic interactionism.
Use concepts that would avoid casual explanations.
== Forms ==
=== Autoethnography ===
Autoethnography is a form of ethnographic research in which a researcher connects personal experiences to wider cultural, political, and social meanings and understandings. According to Adams et al., autoethnography
uses a researcher's personal experience to describe and critique cultural beliefs, practices, and experiences;
acknowledges and values a researcher's relationships with others
uses deep and careful self-reflection—typically referred to as "reflexivity"—to name and interrogate the intersections between self and society, the particular and the general, the personal and the political
shows people in the process of figuring out what to do, how to live, and the meaning of their struggles
balances intellectual and methodological rigor, emotion, and creativity
strives for social justice and to make life better.
Bochner and Ellis have also defined autoethnography as "an autobiographical genre of writing and research that displays multiple layers of consciousness, connecting the personal to the cultural.": 65 They further indicate that autoethnography is typically written in first-person and can "appear in a variety of forms," such as "short stories, poetry, fiction, novels, photographic essays, personal essays, journals, fragmented and layered writing, and social science prose.": 65
=== Genealogical method ===
The genealogical method investigates links of kinship determined by marriage and descent. The method owes its origin from the book of British ethnographer W. H. R. Rivers titled "Kinship and Social Organisation" in 1911. Genealogy or kinship commonly plays a crucial role in the structure of non-industrial societies, determining both social relations and group relationship to the past. Marriage, for example, is frequently pivotal in determining military alliances between villages, clans or ethnic groups.
In the field of epistemology the term is used to characterize the philosophical method employed by such writers as Friedrich Nietzsche and Michel Foucault.
=== Digital ethnography ===
Digital ethnography is also seen as virtual ethnography. This type of ethnography is not so typical as ethnography recorded by pen and pencil. Digital ethnography allows for a lot more opportunities to look at different cultures and societies. Traditional ethnography may use videos or images, but digital ethnography goes more in-depth. For example, digital ethnographers would use social media platforms such as Twitter or blogs so that people's interactions and behaviors can be studied. Modern developments in computing power and AI have enabled higher efficiencies in ethnographic data collection via multimedia and computational analysis using machine learning to corroborate many data sources together to produce a refined output for various purposes. A modern example of this technology in application, is the use of captured audio in smart devices, transcribed to issue targeted adverts (often reconciled vs other metadata, or product development data for designers.
Digital ethnography comes with its own set of ethical questions, and the Association of Internet Researchers' ethical guidelines are frequently used. Gabriele de Seta's paper "Three Lies of Digital Ethnography" explores some of the methodological questions more central to a specific ethnographic approach to internet studies, drawing upon Fine's classic text.
=== Multispecies ethnography ===
Multispecies ethnography in particular focuses on both nonhuman and human participants within a group or culture, as opposed to just human participants in traditional ethnography. A multispecies ethnography, in comparison to other forms of ethnography, studies species that are connected to people and our social lives. Species affect and are affected by culture, economics, and politics.
The study's roots go back to general anthropology of animals. One of the earliest well-known studies was Lewis Henry Morgan's The American Beaver and His Works (1868). His study closely observed a group of beavers in Northern Michigan. Morgan's main objective was to highlight that the daily individual tasks that the beavers performed were complex communicative acts that had been passed down for generations.
In the early 2000s multi-species ethnography took on a huge increase in popularity. The annual meetings of the American Anthropological Association began to host the Multispecies Salon, a collection of discussions, showcases, and other events for anthropologists. The event provided a space for anthropologists and artists to come together and showcase vast knowledge of different organisms and their intertwined systems.
Multispecies ethnography highlights a lot of the negative effects of these shared environments and systems. Not only does multispecies ethnography observe the physical relationships between organisms, it also takes note of the emotional and psychological relationships built between species.
=== Relational ethnography ===
Most ethnographies are conducted in particular settings where the researcher can witness events or behaviors relevant to the study’s focusRelational Ethnography articulates studying fields rather than places or processes rather than processed people. Meaning that relational ethnography doesn't take an object nor a bounded group that is defined by its members shared social features nor a specific location that is delimited by the boundaries of a particular area. But rather the processes involving configurations of relations among different agents or institutions. For instance, such places could be created through an interconnection between the place at hand and the people that live within it and continuously re-create meaning by sharing and changing historic narratives of this place. Applying this form of ethnography to land and landscape, Munira Khayyat suggests that this approach can also help to refocus previous versions of histories, for example the stories of soldiers and their reception in their homes, to those that have been impacted by the wars on the ground (e.g., civilians in Southern Lebanon).
== Notable ethnographers ==
== See also ==
== References ==
=== Bibliography ===
== External links == | Wikipedia/Ethnographer |
Lithium citrate (Li3C6H5O7) is a lithium salt of citric acid that is used as a mood stabilizer in psychiatric treatment of manic states and bipolar disorder. There is extensive pharmacology of lithium, the active component of this salt.
== History ==
Lithium citrate was one of the lithium salts used to add lithium to drinks and water (lithia water) in the late 19th century and the early 20th century, when there was a general health craze for lithium with it believed to be a cure-all. The soft drink 7Up was at one point named "7Up Lithiated Lemon Soda" when it was formulated in 1929 because it claimed to contain lithium citrate. The beverage was a patent medicine marketed as a cure for hangover. In 1936 the federal government forced the manufacturer to remove a number of health claims, and because "lithium was not an actual ingredient", the name was changed to just "7 Up" in 1937.: §2 Many sources repeat an incorrect version of the story where the name is "Bib-Label Lithiated Lemon-Lime Soda" and the removal happened in 1948 due to a Food and Drug Administration ban.
Lithium citrate is used as a mood stabilizer and is used to treat mania, hypomania, depression and bipolar disorder. It can be administered orally in the form of a syrup.
== References == | Wikipedia/Lithium_citrate |
Clinical pharmacy is the branch of pharmacy in which clinical pharmacists provide direct patient care that optimizes the use of medication and promotes health, wellness, and disease prevention. Clinical pharmacists care for patients in all health care settings but the clinical pharmacy movement initially began inside hospitals and clinics. Clinical pharmacists often work in collaboration with physicians, physician assistants, nurse practitioners, and other healthcare professionals. Clinical pharmacists can enter into a formal collaborative practice agreement with another healthcare provider, generally one or more physicians, that allows pharmacists to prescribe medications and order laboratory tests.
== Education and credentialing ==
Clinical pharmacists have extensive education in the biomedical, pharmaceutical, socio-behavioural and clinical sciences. Most clinical pharmacists have a Doctor of Pharmacy (Pharm.D.) degree and many have completed one or more years of post-graduate training (for example, a general and/or specialty pharmacy residency). In the United States, clinical pharmacists can choose to become Board-certified through the Board of Pharmacy Specialties (BPS), which was organized in 1976 as an independent certification agency of the American Pharmacists Association. The BPS certifies pharmacists in the following specialties:
Ambulatory care pharmacy (BCACP)
Critical care pharmacy (BCCCP)
Nuclear pharmacy (BCNP)
Nutrition support pharmacy (BCNSP)
Oncology pharmacy (BCOP)
Pediatric pharmacy (BCPPS)
Geriatric pharmacy (BCGP)
Pharmacotherapy (BCPS)
Infectious disease pharmacy (BCIDP)
Compounded sterile preparations pharmacy (BCSCP)
Cardiology pharmacy (BCCP)
Emergency medicine pharmacy (BCEMP)
Transplant Pharmacist (BCTXP)
Psychiatric pharmacy (BCPP)
There are several types of clinical pharmacists in the United States. In California they are called advanced practice pharmacists (APh). In New Mexico, they are known as Pharmacist Clinicians (PhC) and lastly in Montana and North Carolina they are known as Clinical Pharmacist Practitioners (CPP). Clinical pharmacists in the Veteran Administration are known as Clinical Pharmacy Specialists (CPS).
Role in the health care system
Within the system of health care, clinical pharmacists are experts in the therapeutic use of medications. They routinely provide medication therapy evaluations and recommendations to patients and other health care professionals. Clinical pharmacists are a primary source of scientifically valid information and advice regarding the safe, appropriate, and cost-effective use of medications. Clinical pharmacists are also making themselves more readily available to the public. In the past, access to a clinical pharmacist was limited to hospitals, clinics, or educational institutions. However, clinical pharmacists are making themselves available through a medication information hotline, and reviewing medication lists, all in an effort to prevent medication errors in the foreseeable future. In the United Kingdom, clinical pharmacists are routinely involved in the direct care of patients within hospitals, and increasingly, in doctors surgeries. They also develop post registration professional education, professional curricula for workforce development, provide expertise on the use of medicines to national organizations such as NICE, the Department of Health, and the MHRA, and develop medicines guidelines for use in therapeutic areas.
Clinical pharmacists interact directly with patients in several different ways. They use their knowledge of medication (including dosage, drug interactions, side effects, expense, effectiveness, etc.) to determine if a medication plan is appropriate for their patient. If it is not, the pharmacist will consult the primary physician to ensure that the patient is on the proper medication plan. The pharmacist also works to educate their patients on the importance of taking and finishing their medications. Studies conducted into Pharmacist-led Chronic Disease Management show that it was associated with effects similar to usual care and might improve physiological goal attainment.
In some states in the USA, clinical pharmacists are given prescriptive authority under protocol with a medical provider, and their scope of practice is constantly evolving. In the United Kingdom clinical pharmacists are given independent prescriptive authority.
Basic components of clinical pharmacy practice include prescribing drugs, administering drugs, monitoring prescriptions, managing drug use, and counselling patients.
== See also ==
History of pharmacy
Hospital pharmacy
== References ==
=== Citations ===
=== Sources ===
== External links ==
Academy of Managed Care Pharmacy
American College of Clinical Pharmacy
Board of Pharmacy Specialties
Journal of Clinical Pharmacy and Therapeutics
The British Journal of Clinical Pharmacy
United Kingdom Clinical Pharmacy Association
Clinical Pharmacy Education, Practice and Research | Wikipedia/Clinical_pharmacists |
Model-Informed Precision Dosing (MIPD for short) is the use of pharmacometric models with computer software to optimize drug dosage for an individual patient. Developed in the late 1960s under the impetus of clinical pharmacologists such as Lewis Sheiner and Roger Jelliffe, these approaches involve applying the equations and parameters describing a drug's pharmacokinetics and pharmacodynamics to define the best dosage regimen for a given individual, likely to produce circulating concentrations associated with maximum efficacy and minimum toxicity. Models typically take into account the patient's demographic characteristics (e.g., age, gender, ethnicity), clinical profile (e.g., body measurements, renal and hepatic function, comorbidities, co-medications, dietary habits, substances use) and possibly genetic factors (e.g., polymorphisms affecting cytochromes or drug transporters). When starting a treatment, these models can be used to select a priori the optimal dosage for a patient, based on simulations. During the treatment course, these same models can be used to integrate the results of Therapeutic Drug Monitoring (i.e., the measurement and medical interpretation of circulating drug concentrations) or the measurement of biomarkers of efficacy or toxicity, in an a posteriori approach to dose optimization, derived from Bayesian inference and feedback loops. Practically, these approaches make extensive use of computer software dedicated to the clinical use of pharmacokinetic/pharmacodynamic models, belonging to the computerized clinical decision support tools. They complement Model-Informed Drug Development (MIDD), which is mainly carried out by pharmaceutical industry researchers prior to marketing.
Prescribers are expected to make increasingly regular use of model-driven precision dosing tools for patient treatment and follow-up. Dosage individualization represents the quantitative aspect of precision medicine, while the qualitative aspect lies in the personalized choice of the best drug to treat a given pathology. This optimization of dose selection is especially desirable for drugs with narrow therapeutic index (i.e. effective concentration close to toxic ones). It is also important when a treatment is to be applied to patients with peculiarities, such as children, frail elderly persons, polymorbid patients or those already heavily treated. Technical hurdles still limit the wide implementation of these approaches in clinical practice, but it is to be expected that electronic patient records will pursue their development, thus enabling the increasing integration of model-informed precision dosing into medical practice.
== References == | Wikipedia/Model-Informed_Precision_Dosing |
Drugs.com is an online pharmaceutical encyclopedia that provides drug information for consumers and healthcare professionals, primarily in the United States. It self-describes its information as "accurate and independent" yet limited to being "for educational purposes only and is not intended for medical advice, diagnosis or treatment."
== Website ==
The Drugs.com website is owned and operated by the Drugsite Trust, a privately held Trust administered by two New Zealand pharmacists, Karen Ann and Phillip James Thornton. Operated on the IBM Cloud, Drugs.com provides information on some 24,000 drugs, was visited by 50 million users per month in 2021, and has a download time of one second.
The site contains a library of reference information which includes content from Cerner Multum, Micromedex, Truven Health Analytics, U.S. Food and Drug Administration (FDA), AHFS, Harvard Health Publications, Mayo Clinic, and Animalytics (a veterinary products database).
Drugs.com is certified by the TRUSTe online privacy certification program and the HONcode of Health on the Net Foundation.
The Drugs.com encyclopedia contains drug information for consumers, a portal for drugs based on diseases, a health professionals database of drug monographs, a natural products database, and a poison control center. Drugs.com is not affiliated with any pharmaceutical companies.
== History ==
The domain Drugs.com was originally registered by Bonnie Neubeck in 1994. In 1999 at the height of the dotcom boom, Eric MacIver purchased an option to buy the domain from Neubeck. In August 1999, MacIver sold the domain at auction for US$823,666 to Venture Frogs, a startup incubator run by Tony Hsieh and Alfred Lin, best known for their involvement in LinkExchange and later Zappos.com. Venture Frogs sold the Drugs.com domain name to a private investor in June 2001, allowing Hsieh and Lin to focus on Zappos.com.
The Drugs.com website was officially launched in September 2001. In March 2008, Drugs.com announced the release of Mednotes — an online personal medication record application which connected to Google Health (On June 24, 2011, Google announced it was retiring Google Health on January 1, 2012).
In May 2010, U.S. FDA announced a collaboration with Drugs.com to distribute consumer health updates on the Drugs.com website and mobile platform.
In February 2016, comScore stated that Drugs.com was the sixth most popular health network receiving approximately 23 million visitors for the month, while Searchmetrics listed Drugs.com in the top 100 US websites for search visibility.
In April 2017, The Harris Poll listed Drugs.com as the Health Information Website Brand of the Year.
== References == | Wikipedia/Drugs.com |
The United Kingdom Clinical Pharmacy Association (UKCPA) is a non-profit organisation which actively develops clinical pharmacy practice in medicines management.
== History ==
The organisation was founded in Leicester in 1981 in response to a need to drive clinical pharmacy practice forward in the UK. The organisation is currently focused on supporting and encouraging excellence, leadership, and partnership within clinical pharmacy.
== Functions ==
The UKCPA supports pharmacy practitioners to develop and deliver clinical pharmacy.
The organisation provides the infrastructure to enable pharmacy practitioner peers to deliver professional education and training across a diverse range of practice interest areas (e.g. infection management, anticoagulation, diabetes/endocrinology, pain management, GP practice, critical care, etc). The UKCPA is organised to build and support communities of practice around interest areas - practitioners can talk to each other on a daily basis in order to solve individual clinical problems or create systems, methods and guidelines to deal with clinical scenarios on a local, regional or even national basis.
The UKCPA holds education and training events throughout the UK. The content is provided by coal face clinical practitioners and targeted at various levels of practice, from beginners to expert. The events are accredited by the Royal Pharmaceutical Society. Peer-reviewed research posters are displayed at annual conference.
The UKCPA draws on its membership to provide expertise on the use of medicines to national organisations such as NICE, the Department of Health the MHRA, and other professional organisations.
Expert members are involved in developing professional curricula for workforce development, developing assessment of advanced practice, and are assessors for the Royal Pharmaceutical Society Faculty. The UKCPA is a partner of the Royal Pharmaceutical Society, the professional body for the pharmacy profession in England, Wales and Scotland.
The UKCPA provides a research grant to support its members to develop their research skills. This grant is provided in partnership with Pharmacy Research UK.
== Membership ==
The UKCPA currently has more than 2,500 members in the UK and overseas from all areas of the profession including hospital, community, academia, and industry, as well as pharmacists and pharmacy technicians working at the interface between primary and secondary care.
== Structure ==
The UKCPA is largely run by volunteers – the practitioners themselves. Most UKCPA officers (chair, vice-chair and treasurer) are working pharmacy practitioners. The general secretary and general manager are employed by UKCPA. The general committee makes strategic and financial decisions on behalf of the membership. The business management group makes executive decisions and approves expenditure in consultation with the general committee.
The UKCPA head office is in Leicester where the general manager and administrative team are based.
== Interest groups ==
Cardiology
Care of the Elderly
Community
Critical Care
Diabetes and Endocrinology
Education and Training
Emergency Care
Foundation Pharmacists
Gastroenterology and Hepatology
GP Practice Pharmacists
Haemostasis, Anticoagulation and Thrombosis
Independent Prescribing
Information Technology
Medicines Safety and Quality
Neurosciences
Pain Management
Pharmacy Infection Network
Respiratory
Rheumatology and Dermatology
Surgery and Theatres
Women's Health
== References == | Wikipedia/UK_Clinical_Pharmacy_Association |
Vaccine Act of 1813 was an Act of the Twelfth Congress of the United States to encourage vaccination against smallpox. It was passed 27 February 1813 and repealed 4 May 1822. The Act was the first federal law concerning consumer protection and pharmaceuticals.
Dr. Edward Jenner discovered smallpox vaccine in 1796, and hucksters quickly exploited the demand for vaccine by offering fraudulent versions. The Act made these provisions:
a federal agent charged with preserving genuine vaccine
authority for the agent to distribute vaccine to any US citizen
distribution of legitimate vaccine postage-free (franking privilege)
The Act was repealed in 1822, and the authority to regulate vaccines given to the states. This repeal was the result of an 1821 outbreak of smallpox in North Carolina, which was traced to samples of smallpox, instead of vaccine, accidentally provided by Dr. James Smith while in the capacity of the federal agent charged with preserving and distributing genuine vaccine.
== Text ==
The Act is brief (as compared to modern legislation) and is therefore reproduced in its entirety here:
CHAP. XXXVII.—An Act to encourage Vaccination.
Be it enacted by the Senate and House of Representatives of the United States of America in Congress assembled, That the President of the United States be, and he is hereby authorized to appoint an agent to preserve the genuine vaccine matter, and to furnish the same to any citizen of the United States, whenever it may be applied for, through the medium of the post-office; and such agent shall, previous to his entering upon the execution of the duties assigned to him by this act, and before he shall be entitled to the privilege of franking any letter or package as herein allowed, take and subscribe the following oath or affirmation, before some magistrate, and cause a certificate thereof to be filed in the general post-office: "I, A. B. do swear (or affirm, as the case may be) that I will faithfully use my best exertions to preserve the genuine vaccine matter, and to furnish the same to the citizens of the United States; and also, that I will abstain from every thing prohibited in relation to the establishment of the post-office of the United States." And it shall be the duty of the said agent to transmit to the several postmasters in the United States a copy of this act: and he shall also forward to them a public notice, directing how and where all application shall be made to him for vaccine matter.
SEC. 2. And be it further enacted, That all letters or packages not exceeding half an ounce in weight, containing vaccine matter, or relating to the subject of vaccination, and that alone, shall be carried by the United States' mail free of any postage, either to or from the agent who may be appointed to carry the provisions of this act into effect: Provided always, that the said agent before he delivers any letter for transmission by the mail, shall in his own proper handwriting, on the outside thereof, endorse the word "Vaccination," and thereto subscribe his name, and
shall previously furnish the postmaster of the office where he shall deposit the same with a specimen of his signature; and if said agent shall frank any letter or package, in which shall be contained any thing relative to any subject other than vaccination, he shall, on conviction of every such offence, forfeit and pay a fine of fifty dollars, to be recovered in the same manner as other fines or violations of law establishing the post-office: Provided also, that the discharge of any agent, and the appointment of another in his stead, be at the discretion of the President of the United States.
APPROVED, February 27, 1813.
== References ==
== See also ==
1721 Boston smallpox outbreak
1738–1739 North Carolina smallpox epidemic
1770s Pacific Northwest smallpox epidemic
1775–1782 North American smallpox epidemic
1837 Great Plains smallpox epidemic
1862 Pacific Northwest smallpox epidemic
== Resources ==
"Chapter CLXXIX - An Act to Encourage Vaccination" [Acts passed at the first (and second) session(s) of the Twelfth Congress]. HathiTrust Digital Library. University of Michigan Law School. February 27, 1813. pp. 392–394, IXVIII–IXIX.
"Chapter 502 [CLXXIX] - An Act to Encourage Vaccination" [Laws of the United States of America, from the 4th of March, 1789, to the 4th of March, 1815]. HathiTrust Digital Library. IV. John Bioren and W. John Duane: 508–509, 884, 911. 1816. | Wikipedia/Vaccine_Act_of_1813 |
The Biologics Control Act of 1902, also known as the Virus-Toxin Law, was the first law that implemented federal regulations of biological products such as vaccines in the United States. It was enacted in response to two incidents involving the deaths of 22 children who had contracted tetanus from contaminated vaccines. This law paved the way for further regulation of drug products under the Pure Food and Drug Act of 1906 and the Federal Food, Drug, and Cosmetic Act of 1938. Biologics control is now under the supervision of the U.S. Food and Drug Administration (FDA).
== History ==
When the large scale production of vaccines and anti-toxin serum began in the late 19th century, the United States had no government regulations on biological products. In 1901, a 5-year-old girl died of tetanus in St. Louis, Missouri, after being given a diphtheria anti-toxin. Investigations found that the St. Louis Board of Health produced the contaminated anti-toxin using the blood of a horse infected with tetanus. While the infected horse, Jim, was killed, the Board of Health continued to use the serum to treat diphtheria. It was later discovered that 12 other children had died from the same contaminated anti-toxin serum in St. Louis. That same year, nine children in Camden, New Jersey, died from contaminated smallpox vaccines. These incidents led the Hygienic Laboratory and the Medical Society of the District of Columbia to propose a law regulating the production of biological products. On July 1, 1902, Congress passed the Biologics Control Act.
== Contents of the Act ==
The Biologics Control Act established a board to oversee the implementation of regulations of biological products. The board consisted of the Surgeon-General of the Army, the Surgeon-General of the Navy, and the Surgeon-General of the Marine Hospital Service, and was to be overseen by the Secretary of the Treasury. This board was given the power to issue, suspend, and revoke licenses to produce and sell biological products. The Biologics Control Act also mandated that all products be labeled accurately with the name of the product and the address and license number of the manufacturer. Laboratories could be subjected to unannounced inspections by the Treasury Department. The punishment for the violation of this law was a fine of up to $500 or up to a year in prison.
== Institutions ==
The Laboratory of Hygiene of the Marine Hospital Service, established on Staten Island, NY, in 1887, was in charge of testing biologics before the Biologics Control Act. It was moved to Washington, D.C., in 1891, and renamed the Hygienic Laboratory of the Public Health and Marine Hospital Service in 1902. The Hygienic Laboratory was responsible for renewing licenses annually, testing products, and performing inspections. In 1930, the Ransdell Act transformed the Hygienic Laboratory into the National Institute of Health and gave it a larger role in public health research. In 1948, the name was changed again to the National Institutes of Health, as it encompassed many institutes and centers dedicated to biomedical research. In 1972, biologics regulation was moved to the Food and Drug Administration and later became known as the Center for Biologics Evaluation and Research (CBER).
== Impact ==
The Biologics Control Act set a precedent for the federal regulation of biologics such as vaccines and blood components. With the development of biotechnology, the FDA's Center for Biologics Evaluation and Research (CBER) has taken a larger role in reviewing and approving new biological products intended for medical purposes, including probiotics, xenotransplantation and gene therapy.
== References == | Wikipedia/Biologics_Control_Act |
The Health Sciences Authority (HSA) is a statutory board under the Ministry of Health of the Government of Singapore. It is a multi-disciplinary agency responsible for applying medical, pharmaceutical, and scientific expertise to protect and advance public health and safety.
The organisation serves three key functions: it is the national regulator for health products; it secures the national blood supply through its operation of the national blood bank and management of transfusion medicine standards; and it represents the national expertise in forensic medicine, forensic science and analytical chemistry testing capabilities. These support other regulatory and compliance agencies in the administration of justice and in safeguarding public health.
== History ==
HSA was formed on 1 April 2001 with the integration of five specialised agencies under the Ministry of Health: the Centre for Drug Evaluation; Institute of Science and Forensic Medicine; National Pharmaceutical Administration; Product Regulation Department; and Singapore Blood Transfusion Service.
On 1 April 2019, HSA's food-related duties were absorbed by its successor Singapore Food Agency (SFA) which also absorbed the food-related duties of two other statutory boards namely Agri-Food and Veterinary Authority of Singapore (AVA) and National Environment Agency (NEA). SFA is a statutory board under the Ministry of the Environment and Water Resources.
In February 2022, the HSA became the first regulatory authority in the world to attain the highest maturity level (ML 4) in the World Health Organization's classification of regulatory authorities for medical products. This affirms it as one of the leading regulators at ensuring the quality, safety and efficacy of medical products.
Today, the agency comprises three professional groups: the Health Products Regulation Group; Blood Services Group, and Applied Sciences Group. Each group functions as Divisions comprising branches, units and laboratories. The three professional groups work with the Corporate Services Group which provides strategic direction and corporate support in advancing the organisation.
== Role ==
=== Health products regulation ===
The Health Products Regulation Group ensures that medicines, innovative therapeutics, medical devices and health-related products are wisely regulated and meet appropriate safety, quality and efficacy standards. The agency also contributes to the development of biomedical sciences in Singapore by administering a robust, scientific and responsive regulatory framework.
HSA's risk management system takes into account pre-and-post market precautionary options. On the pre-market front, HSA administers clinical trials for new drugs and grants approvals for these products before they are marketed in Singapore. Audits on good manufacturing and distribution practices are also conducted. Regulation group would evaluate the medical device to determine whether it's acceptable to enter market. The medical device is classified as 4 levels according the product risk from Class A to Class D.
On the post-market front, HSA monitors health products in the market through regular surveillance activities. The agency also carries out investigations and takes enforcement action against illegal activities related to unregistered, counterfeit and adulterated health products. HSA has an established and active pharmacovigilance programme that draws on its network of healthcare professionals and overseas regulators. This allows HSA to initiate targeted and prompt action in response to reported adverse drug reports and expedite the isolation of such problems and minimise harm to public health and safety.
In support of the national objective to reduce smoking, HSA enforces the laws that prohibit tobacco advertisements, smoking by youths under 21 years old as well as the sale of tobacco products to youths in this age group, as well as banning sales of emerging tobacco products such as hookah and electronic cigarettes.
=== National blood service ===
The Blood Services Group is the national blood service of Singapore and is responsible for the adequacy and safety of the country's blood supply. It runs the Bloodbank@HSA in Outram, as well as three satellite blood banks – Bloodbank@Woodlands, Bloodbank@DhobyGhaut and Bloodbank@WestgateTower – which collects, processes, tests and distributes blood and blood components to all hospitals in Singapore. The agency has established a framework to ensure that there is a steady supply of safe blood for day-to-day needs at hospitals and during emergencies. The framework covers the recruitment of voluntary non-remunerated blood donors, stringent blood donation screening criteria, a reliable battery of tests that is conducted on all collected blood, and a comprehensive quality system benchmarked against stringent internationally recognised standards.
The HSA has maintained a strategic partnership with the Singapore Red Cross since 2001 in managing the National Blood Donor Recruitment and Retention Programme.
The agency offers immunohaematology services and tissue typing services to local and regional healthcare institutions, as well as clinical consultative services in the specialty of transfusion medicine. In addition, the agency's cell therapy facility enables one-stop access to cell manufacturing and clinical trial implementation, blood processing and testing services.
=== Forensic and analytical sciences expertise ===
HSA's Applied Sciences Group represents Singapore's national expertise in forensic medicine, forensic sciences, analytical scientific capabilities as well as chemical metrology. This Group supports other regulatory and compliance agencies in the administration of justice and safeguarding public health. The Group comprises: Analytical Science (Chemical Metrology, Food Safety, and Pharmaceutical Divisions), Forensic Medicine and Forensic Science (Biology, Forensic Chemistry & Physics, Illicit Drugs and Analytical Toxicology Divisions).
The range of services cover forensic medical consultancy services in support of death investigation in Singapore; forensic science services such as criminalistics and DNA profiling in support of criminal investigations and illicit drugs control; analytical testing in support of health products regulation, cigarette and tobacco product control; water testing; and food safety testing. Toxicological services are also provided to hospitals.
In collaboration with the Agency for Science, Technology and Research (A*STAR), HSA has been a designated institute for chemical metrology in Singapore since 2008.
== International alliances, affiliations and collaborative efforts ==
HSA has established strong collaborations through Memoranda of Understanding (MOU) with international partners. This is part of its commitment to enhance inter-agency regulatory efforts on the global front. Its international partners include agencies such as the US Food and Drug Administration, Health Canada, Swissmedic, the Australian Therapeutic Goods Administration and China Food and Drug Administration.
HSA's professional groups have been identified as WHO Collaborating Centres in three core areas of expertise - Transfusion Medicine, Drug Quality Assurance and Food Contaminants Monitoring.
HSA has been internationally accredited by the AABB (formerly known as the American Association of Blood Banks), and also the American Society of Histocompatibility & Immunogenetics. It is a founding member of the Asian Pacific Blood Network. As a WHO Collaborating Centre, the agency is an appointed Regional Quality Management Training Centre for Blood Transfusion Services.
It is the first agency outside of the United States of America to be accredited by the National Association of Medical Examiners (NAME), and it also accredited by the American Society of Crime Laboratory Directors/Laboratory Accreditation Board, and the Singapore Laboratory Accreditation Scheme (SINGLAS).
The agency is also a United Nations International Drug Control Programme Reference Laboratory for Biological Specimens and Seized Materials.
== References ==
== External links ==
Official site | Wikipedia/Health_Sciences_Authority |
The pharmaceutical industry is a medical industry that discovers, develops, produces, and markets pharmaceutical goods such as medications and medical devices. Medications are then administered to (or self-administered by) patients for curing or preventing disease or for alleviating symptoms of illness or injury.
Pharmaceutical companies may deal in generic drugs, branded drugs, or both, in different contexts. Generic materials are without the involvement of intellectual property, whereas branded materials are protected by chemical patents. The industry's various subdivisions include distinct areas, such as manufacturing biologics and total synthesis. The industry is subject to a variety of laws and regulations that govern the patenting, efficacy testing, safety evaluation, and marketing of these drugs. The global pharmaceutical market produced treatments worth a total of $1,228.45 billion in 2020. The sector showed a compound annual growth rate (CAGR) of 1.8% in 2021, including the effects of the COVID-19 pandemic.
In historical terms, the pharmaceutical industry, as an intellectual concept, arose in the middle to late 1800s in nation-states with developed economies such as Germany, Switzerland, and the United States. Some businesses engaging in synthetic organic chemistry, such as several firms generating dyestuffs derived from coal tar on a large scale, were seeking out new applications for their artificial materials in terms of human health. This trend of increased capital investment occurred in tandem with the scholarly study of pathology as a field advancing significantly, and a variety of businesses set up cooperative relationships with academic laboratories evaluating human injury and disease. Examples of industrial companies with a pharmaceutical focus that have endured to this day after such distant beginnings include Bayer (based out of Germany) and Pfizer (based out of the U.S.).
The pharmaceutical industry has faced extensive criticism for its marketing practices, including undue influence on physicians through pharmaceutical sales representatives, biased continuing medical education, and disease mongering to expand markets. Pharmaceutical lobbying has made it one of the most powerful influences on health policy, particularly in the United States. There are documented cases of pharmaceutical fraud, including off-label promotion and kickbacks, resulting in multi-billion dollar settlements. Drug pricing continues to be a major issue, with many unable to afford essential prescription drugs. Regulatory agencies like the FDA have been accused of being too lenient due to revolving doors with industry. During the COVID-19 pandemic, major pharmaceutical companies received public funding while retaining intellectual property rights, prompting calls for greater transparency and access.
== History ==
=== Mid-1800s–1945 ===
The modern era of the pharmaceutical industry began with local apothecaries that expanded their traditional role of distributing botanical drugs such as morphine and quinine to wholesale manufacture in the mid-1800s. Intentional drug discovery from plants began with the extraction of morphine – an analgesic and sleep-inducing agent – from opium by the German apothecary assistant Friedrich Sertürner somewhere between 1803 and 1805. Sertürner later named this compound after the Greek god of dreams, Morpheus. Multinational corporations including Merck, Hoffman-La Roche, Burroughs-Wellcome (now part of GSK), Abbott Laboratories, Eli Lilly, and Upjohn (now part of Pfizer) began as local apothecary shops in the mid-1800s. By the late 1880s, German dye manufacturers had perfected the purification of individual organic compounds from tar and other mineral sources and had also established rudimentary methods in organic chemical synthesis. The development of synthetic chemical methods allowed scientists to systematically vary the structure of chemical substances, and growth in the emerging science of pharmacology expanded their ability to evaluate the biological effects of these structural changes.
==== Epinephrine, norepinephrine, and amphetamine ====
By the 1890s, the profound effect of adrenal extracts on many different tissue types had been discovered, setting off a search both for the mechanism of chemical signaling and efforts to exploit these observations for the development of new drugs. The blood pressure raising and vasoconstrictive effects of adrenal extracts were of particular interest to surgeons as hemostatic agents and as a treatment for shock, and several companies developed products based on adrenal extracts containing varying purities of the active substance. In 1897, John Abel at the Johns Hopkins University identified the active substance as epinephrine, which he isolated in an impure state as the sulfate salt. Industrial chemist Jōkichi Takamine later developed a method for obtaining epinephrine in a pure state and licensed the technology to Parke-Davis. Parke-Davis marketed epinephrine under the trade name Adrenalin. Injected epinephrine proved to be especially efficacious for the acute treatment of asthma attacks, and an inhaled version was sold in the United States until 2011 (Primatene Mist). By 1929 epinephrine had been formulated into an inhaler for use in the treatment of nasal congestion.
While highly effective, the requirement for injection limited the use of epinephrine and orally active derivatives were sought. A structurally similar compound, ephedrine, was identified by Japanese chemists in the Ma Huang plant and marketed by Eli Lilly as an oral treatment for asthma. Following the work of Henry Dale and George Barger at Burroughs-Wellcome, academic chemist Gordon Alles synthesized amphetamine and tested it in asthma patients in 1929. The drug proved to have only modest anti-asthma effects but produced sensations of exhilaration and palpitations. Amphetamine was developed by Smith, Kline and French as a nasal decongestant under the trade name Benzedrine Inhaler. Amphetamine was eventually developed for the treatment of narcolepsy, post-encephalitic parkinsonism, and mood elevation in depression and other psychiatric indications. It received approval as a New and Nonofficial Remedy from the American Medical Association for these uses in 1937, and remained in common use for depression until the development of tricyclic antidepressants in the 1960s.
==== Discovery and development of the barbiturates ====
In 1903, Hermann Emil Fischer and Joseph von Mering disclosed their discovery that diethylbarbituric acid, formed from the reaction of diethylmalonic acid, phosphorus oxychloride and urea, induces sleep in dogs. The discovery was patented and licensed to Bayer pharmaceuticals, which marketed the compound under the trade name Veronal as a sleep aid beginning in 1904. Systematic investigations of the effect of structural changes on potency and duration of action led to the discovery of phenobarbital at Bayer in 1911 and the discovery of its potent anti-epileptic activity in 1912. Phenobarbital was among the most widely used drugs for the treatment of epilepsy through the 1970s, and as of 2014, remains on the World Health Organization's list of essential medications.
==== Restrictions in use of amphetamines and barbiturates ====
The 1950s and 1960s saw increased awareness of the addictive properties and abuse potential of barbiturates and amphetamines and led to increasing restrictions on their use and growing government oversight of prescribers. Today, amphetamine is largely restricted to use in the treatment of attention deficit disorder and phenobarbital in the treatment of epilepsy.
==== Benzodiazepines ====
In 1958, Leo Sternbach discovered the first benzodiazepine, chlordiazepoxide (Librium). Dozens of other benzodiazepines have been developed and are in use, some of the more popular drugs being diazepam (Valium), alprazolam (Xanax), clonazepam (Klonopin), and lorazepam (Ativan). Due to their far superior safety and therapeutic properties, benzodiazepines have largely replaced the use of barbiturates in medicine, except in certain special cases. When it was later discovered that benzodiazepines, like barbiturates, significantly lose their effectiveness and can have serious side effects when taken long-term, Heather Ashton researched benzodiazepine dependence and developed a protocol to discontinue their use.
==== Insulin ====
A series of experiments performed from the late 1800s to the early 1900s revealed that diabetes is caused by the absence of a substance normally produced by the pancreas. In 1869, Oskar Minkowski and Joseph von Mering found that diabetes could be induced in dogs by surgical removal of the pancreas. In 1921, Canadian professor Frederick Banting and his student Charles Best repeated this study and found that injections of pancreatic extract reversed the symptoms produced by pancreas removal. Soon, the extract was demonstrated to work in humans, but the development of insulin therapy as a routine medical procedure was delayed by difficulties in producing the material in sufficient quantity and with reproducible purity. The researchers sought assistance from industrial collaborators at Eli Lilly and Co. based on the company's experience with large-scale purification of biological materials. Chemist George B. Walden of Eli Lilly and Company found that careful adjustment of the pH of the extract allowed a relatively pure grade of insulin to be produced. Under pressure from Toronto University and a potential patent challenge by academic scientists who had independently developed a similar purification method, an agreement was reached for the non-exclusive production of insulin by multiple companies. Before the discovery and widespread availability of insulin therapy, the life expectancy of diabetics was only a few months.
==== Early anti-infective research: salvarsan, prontosil, penicillin and vaccines ====
The development of drugs for the treatment of infectious diseases was a major focus of early research and development efforts; in 1900, pneumonia, tuberculosis, and diarrhea were the three leading causes of death in the United States and mortality in the first year of life exceeded 10%.
In 1911 arsphenamine, the first synthetic anti-infective drug, was developed by Paul Ehrlich and chemist Alfred Bertheim of the Institute of Experimental Therapy in Berlin. The drug was given the commercial name Salvarsan. Ehrlich, noting both the general toxicity of arsenic and the selective absorption of certain dyes by bacteria, hypothesized that an arsenic-containing dye with similar selective absorption properties could be used to treat bacterial infections. Arsphenamine was prepared as part of a campaign to synthesize a series of such compounds and exhibited partially selective toxicity. Arsphenamine proved to be the first effective treatment for syphilis, a disease that until then had been incurable and led inexorably to severe skin ulceration, neurological damage, and death.
Ehrlich's approach of systematically varying the chemical structure of synthetic compounds and measuring the effects of these changes on biological activity was pursued broadly by industrial scientists, including Bayer scientists Josef Klarer, Fritz Mietzsch, and Gerhard Domagk. This work, also based on the testing of compounds available from the German dye industry, led to the development of Prontosil, the first representative of the sulfonamide class of antibiotics. Compared to arsphenamine, the sulfonamides had a broader spectrum of activity and were far less toxic, rendering them useful for infections caused by pathogens such as streptococci. In 1939, Domagk received the Nobel Prize in Medicine for this discovery. Nonetheless, the dramatic decrease in deaths from infectious diseases that occurred before World War II was primarily the result of improved public health measures such as clean water and less crowded housing, and the impact of anti-infective drugs and vaccines was significant mainly after World War II.
In 1928, Alexander Fleming discovered the antibacterial effects of penicillin, but its exploitation for the treatment of human disease awaited the development of methods for its large-scale production and purification. These were developed by a U.S. and British government-led consortium of pharmaceutical companies during World War II.
There was early progress toward the development of vaccines throughout this period, primarily in the form of academic and government-funded basic research directed toward the identification of the pathogens responsible for common communicable diseases. In 1885, Louis Pasteur and Pierre Paul Émile Roux created the first rabies vaccine. The first diphtheria vaccines were produced in 1914 from a mixture of diphtheria toxin and antitoxin (produced from the serum of an inoculated animal), but the safety of the inoculation was marginal and it was not widely used. The United States recorded 206,000 cases of diphtheria in 1921, resulting in 15,520 deaths. In 1923, parallel efforts by Gaston Ramon at the Pasteur Institute and Alexander Glenny at the Wellcome Research Laboratories (later part of GlaxoSmithKline) led to the discovery that a safer vaccine could be produced by treating diphtheria toxin with formaldehyde. In 1944, Maurice Hilleman of Squibb Pharmaceuticals developed the first vaccine against Japanese Encephalitis. Hilleman later moved to Merck, where he played a key role in the development of vaccines against measles, mumps, chickenpox, rubella, hepatitis A, hepatitis B, and meningitis.
==== Unsafe drugs and early industry regulation ====
Prior to the 20th century, drugs were generally produced by small scale manufacturers with little regulatory control over manufacturing or claims of safety and efficacy. To the extent that such laws did exist, enforcement was lax. In the United States, increased regulation of vaccines and other biological drugs was spurred by tetanus outbreaks and deaths caused by the distribution of contaminated smallpox vaccine and diphtheria antitoxin. The Biologics Control Act of 1902 required that federal government grant premarket approval for every biological drug and for the process and facility producing such drugs. This Act was followed in 1906 by the Pure Food and Drugs Act, which forbade the interstate distribution of adulterated or misbranded foods and drugs. A drug was considered misbranded if it contained alcohol, morphine, opium, cocaine, or any of several other potentially dangerous or addictive drugs, and if its label failed to indicate the quantity or proportion of such drugs. The government's attempts to use the law to prosecute manufacturers for making unsupported claims of efficacy were undercut by a Supreme Court ruling restricting the federal government's enforcement powers to cases of incorrect specification of the drug's ingredients.
In 1937 over 100 people died after ingesting "Elixir Sulfanilamide" manufactured by S.E. Massengill Company of Tennessee. The product was formulated in diethylene glycol, a highly toxic solvent that is now widely used as antifreeze. Under the laws extant at that time, prosecution of the manufacturer was possible only under the technicality that the product had been called an "elixir", which implied a solution in ethanol. In response to this episode, the U.S. Congress passed the Federal Food, Drug, and Cosmetic Act of 1938 (FD&C Act), which for the first time required pre-market demonstration of safety before a drug could be sold, and explicitly prohibited false therapeutic claims.
=== 1945–1970 ===
==== Further advances in anti-infective research ====
The aftermath of World War II saw an explosion in the discovery of new classes of antibacterial drugs including the cephalosporins (developed by Eli Lilly based on the seminal work of Giuseppe Brotzu and Edward Abraham), streptomycin (discovered during a Merck-funded research program in Selman Waksman's laboratory), the tetracyclines (discovered at Lederle Laboratories, now a part of Pfizer), erythromycin (discovered at Eli Lilly and Co.) and their extension to an increasingly wide range of bacterial pathogens. Streptomycin, discovered during a Merck-funded research program in Selman Waksman's laboratory at Rutgers in 1943, became the first effective treatment for tuberculosis. At the time of its discovery, sanitoriums for the isolation of tuberculosis-infected people were a ubiquitous feature of cities in developed countries, with 50% dying within 5 years of admission.
A Federal Trade Commission report issued in 1958 attempted to quantify the effect of antibiotic development on American public health. The report found that over the period 1946–1955, there was a 42% drop in the incidence of diseases for which antibiotics were effective and only a 20% drop in those for which antibiotics were not effective. The report concluded that "it appears that the use of antibiotics, early diagnosis, and other factors have limited the epidemic spread and thus the number of these diseases which have occurred". The study further examined mortality rates for eight common diseases for which antibiotics offered effective therapy (syphilis, tuberculosis, dysentery, scarlet fever, whooping cough, meningococcal infections, and pneumonia), and found a 56% decline over the same period. Notable among these was a 75% decline in deaths due to tuberculosis.
During the years 1940–1955, the rate of decline in the U.S. death rate accelerated from 2% per year to 8% per year, then returned to the historical rate of 2% per year. The dramatic decline in the immediate post-war years has been attributed to the rapid development of new treatments and vaccines for infectious disease that occurred during these years.
Vaccine development continued to accelerate, with the most notable achievement of the period being Jonas Salk's 1954 development of the polio vaccine under the funding of the non-profit National Foundation for Infantile Paralysis. The vaccine process was never patented but was instead given to pharmaceutical companies to manufacture as a low-cost generic. In 1960 Maurice Hilleman of Merck Sharp & Dohme identified the SV40 virus, which was later shown to cause tumors in many mammalian species. It was later determined that SV40 was present as a contaminant in polio vaccine lots that had been administered to 90% of the children in the United States. The contamination appears to have originated both in the original cell stock and in monkey tissue used for production. In 2004 the National Cancer Institute announced that it had concluded that SV40 is not associated with cancer in people.
Other notable new vaccines of the period include those for measles (1962, John Franklin Enders of Children's Medical Center Boston, later refined by Maurice Hilleman at Merck), Rubella (1969, Hilleman, Merck) and mumps (1967, Hilleman, Merck) The United States incidences of rubella, congenital rubella syndrome, measles, and mumps all fell by >95% in the immediate aftermath of widespread vaccination. The first 20 years of licensed measles vaccination in the U.S. prevented an estimated 52 million cases of the disease, 17,400 cases of mental retardation, and 5,200 deaths.
==== Development and marketing of antihypertensive drugs ====
Hypertension is a risk factor for atherosclerosis, heart failure, coronary artery disease, stroke, renal disease, and peripheral arterial disease, and is the most important risk factor for cardiovascular morbidity and mortality, in industrialized countries. Prior to 1940 approximately 23% of all deaths among persons over age 50 were attributed to hypertension. Severe cases of hypertension were treated by surgery.
Early developments in the field of treating hypertension included quaternary ammonium ion sympathetic nervous system blocking agents, but these compounds were never widely used due to their severe side effects, because the long-term health consequences of high blood pressure had not yet been established, and because they had to be administered by injection.
In 1952 researchers at CIBA (Gesellschaft für Chemische Industrie in Basel, predecessor to Novartis) discovered the first orally available vasodilator, hydralazine. A major shortcoming of hydralazine monotherapy was that it lost its effectiveness over time (tachyphylaxis). In the mid-1950s Karl H. Beyer, James M. Sprague, John E. Baer, and Frederick C. Novello of Merck and Co. discovered and developed chlorothiazide, which remains the most widely used antihypertensive drug today. This development was associated with a substantial decline in the mortality rate among people with hypertension. The inventors were recognized by a Public Health Lasker Award in 1975 for "the saving of untold thousands of lives and the alleviation of the suffering of millions of victims of hypertension".
A 2009 Cochrane review concluded that thiazide antihypertensive drugs reduce the risk of death (RR 0.89), stroke (RR 0.63), coronary heart disease (RR 0.84), and cardiovascular events (RR 0.70) in people with high blood pressure. In the ensuing years other classes of the antihypertensive drug were developed and found wide acceptance in combination therapy, including loop diuretics (Lasix/furosemide, Hoechst Pharmaceuticals, 1963), beta blockers (ICI Pharmaceuticals, 1964) ACE inhibitors, and angiotensin receptor blockers. ACE inhibitors reduce the risk of new-onset kidney disease [RR 0.71] and death [RR 0.84] in diabetic patients, irrespective of whether they have hypertension.
==== Oral contraceptives ====
Prior to World War II, birth control was prohibited in many countries, and in the United States even the discussion of contraceptive methods sometimes led to prosecution under Comstock laws. The history of the development of oral contraceptives is thus closely tied to the birth control movement and the efforts of activists Margaret Sanger, Mary Dennett, and Emma Goldman. Based on fundamental research performed by Gregory Pincus and synthetic methods for progesterone developed by Carl Djerassi at Syntex and by Frank Colton at G.D. Searle & Co., the first oral contraceptive, Enovid, was developed by G.D. Searle & Co. and approved by the FDA in 1960. The original formulation incorporated vastly excessive doses of hormones and caused severe side effects. Nonetheless, by 1962, 1.2 million American women were on the pill, and by 1965 the number had increased to 6.5 million. The availability of a convenient form of temporary contraceptive led to dramatic changes in social mores including expanding the range of lifestyle options available to women, reducing the reliance of women on men for contraceptive practice, encouraging the delay of marriage, and increasing pre-marital co-habitation.
==== Thalidomide and the Kefauver-Harris amendments ====
In the U.S., a push for revisions of the FD&C Act emerged from Congressional hearings led by Senator Estes Kefauver of Tennessee in 1959. The hearings covered a wide range of policy issues, including advertising abuses, questionable efficacy of drugs, and the need for greater regulation of the industry. While momentum for new legislation temporarily flagged under extended debate, a new tragedy emerged that underscored the need for more comprehensive regulation and provided the driving force for the passage of new laws.
On 12 September 1960, an American licensee, the William S. Merrell Company of Cincinnati, submitted a new drug application for Kevadon (thalidomide), a sedative that had been marketed in Europe since 1956. The FDA medical officer in charge of reviewing the compound, Frances Kelsey, believed that the data supporting the safety of thalidomide was incomplete. The firm continued to pressure Kelsey and the FDA to approve the application until November 1961, when the drug was pulled off the German market because of its association with grave congenital abnormalities. Several thousand newborns in Europe and elsewhere suffered the teratogenic effects of thalidomide. Without approval from the FDA, the firm distributed Kevadon to over 1,000 physicians there under the guise of investigational use. Over 20,000 Americans received thalidomide in this "study," including 624 pregnant patients, and about 17 known newborns suffered the effects of the drug.
The thalidomide tragedy resurrected Kefauver's bill to enhance drug regulation that had stalled in Congress, and the Kefauver-Harris Amendment became law on 10 October 1962. Manufacturers henceforth had to prove to the FDA that their drugs were effective as well as safe before they could go on the US market. The FDA received authority to regulate the advertising of prescription drugs and to establish good manufacturing practices. The law required that all drugs introduced between 1938 and 1962 had to be effective. A collaborative study by the FDA and the National Academy of Sciences showed that nearly 40 percent of these products were not effective. A similarly comprehensive study of over-the-counter products began ten years later.
=== 1970–1990s ===
==== Statins ====
In 1971, Akira Endo, a Japanese biochemist working for the pharmaceutical company Sankyo, identified mevastatin (ML-236B), a molecule produced by the fungus Penicillium citrinum, as an inhibitor of HMG-CoA reductase, a critical enzyme used by the body to produce cholesterol. Animal trials showed very good inhibitory effects as in clinical trials, however a long-term study in dogs found toxic effects at higher doses and as a result, mevastatin was believed to be too toxic for human use. Mevastatin was never marketed, because of its adverse effects of tumors, muscle deterioration, and sometimes death in laboratory dogs.
P. Roy Vagelos, chief scientist and later CEO of Merck & Co, was interested and made several trips to Japan starting in 1975. By 1978, Merck had isolated lovastatin (mevinolin, MK803) from the fungus Aspergillus terreus, first marketed in 1987 as Mevacor.
In April 1994, the results of a Merck-sponsored study, the Scandinavian Simvastatin Survival Study, were announced. Researchers tested simvastatin, later sold by Merck as Zocor, on 4,444 patients with high cholesterol and heart disease. After five years, the study concluded that patients saw a 35% reduction in their cholesterol, and their chances of dying of a heart attack were reduced by 42%. In 1995, Zocor and Mevacor both made Merck over US$1 billion. Endo was awarded the 2006 Japan Prize, and the Lasker-DeBakey Clinical Medical Research Award in 2008 for his "pioneering research into a new class of molecules" for "lowering cholesterol".
=== 21st Century ===
Since several decades, biologics have been rising in importance in comparison with small molecule treatments. The biotech subsector, animal health and the Chinese pharmaceutical sector have also grown substantially. On the organisational side, big international pharmaceutical corporations have experienced a substantial decline of their value share. Also, the core generic sector (substitutions for off-patent brands) has been down valued due to competition.
Torreya estimated the pharmaceutical industry to have a market valuation of US$7.03 trillion by February 2021 from which US$6.1 trillion is the value of the publicly traded companies. Small Molecules modality had 58.2% of the valuation share down from 84.6% in 2003. Biologics was up at 30.5% from 14.5%. The valuation share of Chinese Pharma grew from 2003 to 2021 from 1% to 12% overtaking Switzerland who is now ranked number 3 with 7.7%. The United States had still by far the most valued pharmaceutical industry with 40% of global valuation. 2023 was a year of layoffs for at least 10,000 people across 129 public biotech firms globally, albeit mostly small firms; this was a significant increase in reductions versus 2022 in part due to worsening global financial conditions and a reduction in investment by "generalist investors". Private firms also saw a significant reduction in venture capital investment in 2023, continuing a downward trend started in 2021, which also led to a reduction in initial public offerings being floated.
=== Impact of mergers and acquisitions ===
A 2022 article articulated this notion succinctly by saying "In the business of drug development, deals can be just as important as scientific breakthroughs", typically referred to as pharmaceutical M&A (for mergers and acquisitions). It highlighted that some of the most impactful of the remedies of the early 21st Century were only made possible through M&A activities, specifically noting Keytruda and Humira.
== Research and development ==
Drug discovery is the process by which potential drugs are discovered or designed. In the past, most drugs have been discovered either by isolating the active ingredient from traditional remedies or by serendipitous discovery. Modern biotechnology often focuses on understanding the metabolic pathways related to a disease state or pathogen, and manipulating these pathways using molecular biology or biochemistry. A great deal of early-stage drug discovery has traditionally been carried out by universities and research institutions.
Drug development refers to activities undertaken after a compound is identified as a potential drug in order to establish its suitability as a medication. Objectives of drug development are to determine appropriate formulation and dosing, as well as to establish safety. Research in these areas generally includes a combination of in vitro studies, in vivo studies, and clinical trials. The cost of late stage development has meant it is usually done by the larger pharmaceutical companies. The pharmaceuticals and biotechnology industry spends more than 15% of its net sales for Research & Development which is in comparison with other industries by far the highest share.
Often, large multinational corporations exhibit vertical integration, participating in a broad range of drug discovery and development, manufacturing and quality control, marketing, sales, and distribution. Smaller organizations, on the other hand, often focus on a specific aspect such as discovering drug candidates or developing formulations. Often, collaborative agreements between research organizations and large pharmaceutical companies are formed to explore the potential of new drug substances. More recently, multi-nationals are increasingly relying on contract research organizations to manage drug development.
=== The cost of innovation ===
Drug discovery and development are very expensive; of all compounds investigated for use in humans only a small fraction are eventually approved in most nations by government-appointed medical institutions or boards, who have to approve new drugs before they can be marketed in those countries. In 2010 18 NMEs (New Molecular Entities) were approved and three biologics by the FDA, or 21 in total, which is down from 26 in 2009 and 24 in 2008. On the other hand, there were only 18 approvals in total in 2007 and 22 back in 2006. Since 2001, the Center for Drug Evaluation and Research has averaged 22.9 approvals a year.
This approval comes only after heavy investment in pre-clinical development and clinical trials, as well as a commitment to ongoing safety monitoring. Drugs which fail part-way through this process often incur large costs, while generating no revenue in return. If the cost of these failed drugs is taken into account, the cost of developing a successful new drug (new chemical entity, or NCE), has been estimated at US$1.3 billion (not including marketing expenses). Professors Light and Lexchin reported in 2012, however, that the rate of approval for new drugs has been a relatively stable average rate of 15 to 25 for decades.
Industry-wide research and investment reached a record $65.3 billion in 2009. While the cost of research in the U.S. was about $34.2 billion between 1995 and 2010, revenues rose faster (revenues rose by $200.4 billion in that time).
A study by the consulting firm Bain & Company reported that the cost for discovering, developing and launching (which factored in marketing and other business expenses) a new drug (along with the prospective drugs that fail) rose over a five-year period to nearly $1.7 billion in 2003. According to Forbes, by 2010 development costs were between $4 billion to $11 billion per drug.
Some of these estimates also take into account the opportunity cost of investing capital many years before revenues are realized (see Time-value of money). Because of the very long time needed for the discovery, development, and approval of pharmaceuticals, these costs can accumulate to nearly half the total expense. A direct consequence within the pharmaceutical industry value chain is that major pharmaceutical multinationals tend to increasingly outsource risks related to fundamental research, which somewhat reshapes the industry ecosystem with biotechnology companies playing an increasingly important role, and overall strategies being redefined accordingly. Some approved drugs, such as those based on re-formulation of an existing active ingredient (also referred to as Line-extensions) are much less expensive to develop.
== Product approval ==
In the United States, new pharmaceutical products must be approved by the Food and Drug Administration (FDA) as being both safe and effective. This process generally involves the submission of an Investigational New Drug (IND) filing with sufficient pre-clinical data to support proceeding with human trials. Following IND approval, three phases of progressively larger human clinical trials may be conducted. Phase I generally studies toxicity using healthy volunteers. Phase II can include pharmacokinetics and dosing in patients, and Phase III is a very large study of efficacy in the intended patient population. Following the successful completion of Phase III testing, a New Drug Application is submitted to the FDA. The FDA reviews the data and if the product is seen as having a positive benefit-risk assessment, approval to market the product in the US is granted.
A fourth phase of post-approval surveillance is also often required due to the fact that even the largest clinical trials cannot effectively predict the prevalence of rare side effects. Postmarketing surveillance ensures that after marketing the safety of a drug is monitored closely. In certain instances, its indication may need to be limited to particular patient groups, and in others, the substance is withdrawn from the market completely.
The FDA provides information about approved drugs at the Orange Book site.
In the UK, the Medicines and Healthcare products Regulatory Agency (MHRA) approves and evaluates drugs for use. Normally an approval in the UK and other European countries comes later than one in the USA. Then it is the National Institute for Health and Care Excellence (NICE), for England and Wales, who decides if and how the National Health Service (NHS) will allow (in the sense of paying for) their use. The British National Formulary is the core guide for pharmacists and clinicians.
In many non-US western countries, a 'fourth hurdle' of cost effectiveness analysis has developed before new technologies can be provided. This focuses on the 'efficacy price tag' (in terms of, for example, the cost per QALY) of the technologies in question. In England and Wales NICE decides whether and in what circumstances drugs and technologies will be made available by the NHS, whilst similar arrangements exist with the Scottish Medicines Consortium in Scotland, and the Pharmaceutical Benefits Advisory Committee in Australia. A product must pass the threshold for cost-effectiveness if it is to be approved. Treatments must represent 'value for money' and a net benefit to society.
=== Orphan drugs ===
There are special rules for certain rare diseases ("orphan diseases") in several major drug regulatory territories. For example, diseases involving fewer than 200,000 patients in the United States, or larger populations in certain circumstances are subject to the Orphan Drug Act. Because medical research and development of drugs to treat such diseases is financially disadvantageous, companies that do so are rewarded with tax reductions, fee waivers, and market exclusivity on that drug for a limited time (seven years), regardless of whether the drug is protected by patents.
== Global sales ==
In 2011, global spending on prescription drugs topped $954 billion, even as growth slowed somewhat in Europe and North America. The United States accounts for more than a third of the global pharmaceutical market, with $340 billion in annual sales followed by the EU and Japan. Emerging markets such as China, Russia, South Korea and Mexico outpaced that market, growing a huge 81 percent.
The top ten best-selling drugs of 2013 totaled $75.6 billion in sales, with the anti-inflammatory drug Humira being the best-selling drug worldwide at $10.7 billion in sales. The second and third best selling were Enbrel and Remicade, respectively. The top three best-selling drugs in the United States in 2013 were Abilify ($6.3 billion,) Nexium ($6 billion) and Humira ($5.4 billion). The best-selling drug ever, Lipitor, averaged $13 billion annually and netted $141 billion total over its lifetime before Pfizer's patent expired in November 2011.
IMS Health publishes an analysis of trends expected in the pharmaceutical industry in 2007, including increasing profits in most sectors despite loss of some patents, and new 'blockbuster' drugs on the horizon.
=== Patents and generics ===
Depending on a number of considerations, a company may apply for and be granted a patent for the drug, or the process of producing the drug, granting exclusivity rights typically for about 20 years. However, only after rigorous study and testing, which takes 10 to 15 years on average, will governmental authorities grant permission for the company to market and sell the drug. Patent protection enables the owner of the patent to recover the costs of research and development through high profit margins for the branded drug. When the patent protection for the drug expires, a generic drug is usually developed and sold by a competing company. The development and approval of generics are less expensive, allowing them to be sold at a lower price. Often the owner of the branded drug will introduce a generic version before the patent expires in order to get a head start in the generic market. Restructuring has therefore become routine, driven by the patent expiration of products launched during the industry's "golden era" in the 1990s and companies' failure to develop sufficient new blockbuster products to replace lost revenues.
=== Prescriptions ===
In the U.S., the value of prescriptions increased over the period of 1995 to 2005 by 3.4 billion annually, a 61 percent increase. Retail sales of prescription drugs jumped 250 percent from $72 billion to $250 billion, while the average price of prescriptions more than doubled from $30 to $68.
== Marketing ==
Advertising is common in healthcare journals as well as through more mainstream media routes. In some countries, notably the US, they are allowed to advertise directly to the general public. Pharmaceutical companies generally employ salespeople (often called 'drug reps' or, an older term, 'detail men') to market directly and personally to physicians and other healthcare providers. In some countries, notably the US, pharmaceutical companies also employ lobbyists to influence politicians. Marketing of prescription drugs in the US is regulated by the federal Prescription Drug Marketing Act of 1987. The pharmaceutical marketing plan incorporates the spending plans, channels, and thoughts which will take the drug association, and its items and administrations, forward in the current scene.
=== To healthcare professionals ===
The book Bad Pharma also discusses the influence of drug representatives, how ghostwriters are employed by the drug companies to write papers for academics to publish, how independent the academic journals really are, how the drug companies finance doctors' continuing education, and how patients' groups are often funded by industry.
=== Direct to consumer advertising ===
Since the 1980s, new methods of marketing prescription drugs to consumers have become important. Direct-to-consumer media advertising was legalised in the FDA Guidance for Industry on Consumer-Directed Broadcast Advertisements.
== Controversies ==
=== Drug marketing and lobbying ===
There have been many controversies surrounding pharmaceutical marketing and influence. There have been accusations and findings of influence on doctors and other health professionals through drug representatives including the constant provision of marketing 'gifts' and biased information to health professionals. As well as highly prevalent advertising in journals and conferences, funding independent healthcare organizations and health promotion campaigns, being at a time the most lobbied industry in the US, sponsorship of medical schools or nurse training, sponsorship of continuing educational events, with influence on the curriculum, and hiring physicians and doctors as paid consultants on medical advisory boards.
Some advocacy groups, such as No Free Lunch and AllTrials, have criticized the effect of drug marketing to physicians because they say it biases physicians to prescribe the marketed drugs even when others might be cheaper or better for the patient.
There have been related accusations of disease mongering (over-medicalising) to expand the market for medications. An inaugural conference on that subject took place in Australia in 2006. In 2009, the Government-funded National Prescribing Service launched the "Finding Evidence – Recognising Hype" program, aimed at educating GPs on methods for independent drug analysis.
Meta-analyses have shown that psychiatric studies sponsored by pharmaceutical companies are several times more likely to report positive results, and if a drug company employee is involved the effect is even larger. Influence has also extended to the training of doctors and nurses in medical schools, which is being fought.
It has been argued that the design of the Diagnostic and Statistical Manual of Mental Disorders and the expansion of the criteria represents an increasing medicalization of human nature, or "disease mongering", driven by drug company influence on psychiatry. The potential for direct conflict of interest has been raised, partly because roughly half the authors who selected and defined the DSM-IV psychiatric disorders had or previously had financial relationships with the pharmaceutical industry.
In the US, starting in 2013, under the Physician Financial Transparency Reports (part of the Sunshine Act), the Centers for Medicare & Medicaid Services has to collect information from applicable manufacturers and group purchasing organizations in order to report information about their financial relationships with physicians and hospitals. Data are made public on the Centers for Medicare & Medicaid Services website. The expectation is that the relationship between doctors and the Pharmaceutical industry will become fully transparent.
In a report conducted by OpenSecrets, there were more than 1,100 lobbyists working in some capacity for the pharmaceutical business in 2017. In the first quarter of 2017, the health products and pharmaceutical industry spent $78 million on lobbying members of the United States Congress.
=== Medication pricing ===
The pricing of pharmaceuticals is becoming a major challenge for health systems. A November 2020 study by the West Health Policy Center stated that more than 1.1 million senior citizens in the U.S. Medicare program is expected to die prematurely over the next decade because they will be unable to afford their prescription medications, requiring an additional $17.7 billion to be spent annually on avoidable medical costs due to health complications.
=== Regulatory issues ===
Ben Goldacre has argued that regulators – such as the Medicines and Healthcare products Regulatory Agency (MHRA) in the UK, or the Food and Drug Administration (FDA) in the United States – advance the interests of the drug companies rather than the interests of the public due to revolving door exchange of employees between the regulator and the companies and friendships develop between regulator and company employees. He argues that regulators do not require that new drugs offer an improvement over what is already available, or even that they be particularly effective.
Others have argued that excessive regulation suppresses therapeutic innovation and that the current cost of regulator-required clinical trials prevents the full exploitation of new genetic and biological knowledge for the treatment of human disease. A 2012 report by the President's Council of Advisors on Science and Technology made several key recommendations to reduce regulatory burdens to new drug development, including 1) expanding the FDA's use of accelerated approval processes, 2) creating an expedited approval pathway for drugs intended for use in narrowly defined populations, and 3) undertaking pilot projects designed to evaluate the feasibility of a new, adaptive drug approval process.
=== Pharmaceutical fraud ===
Pharmaceutical fraud involves deceptions that bring financial gain to a pharmaceutical company. It affects individuals and public and private insurers. There are several different schemes used to defraud the health care system which are particular to the pharmaceutical industry. These include: Good Manufacturing Practice (GMP) Violations, Off Label Marketing, Best Price Fraud, CME Fraud, Medicaid Price Reporting, and Manufactured Compound Drugs. Of this amount $2.5 billion was recovered through False Claims Act cases in FY 2010. Examples of fraud cases include the GlaxoSmithKline $3 billion settlement, Pfizer $2.3 billion settlement and Merck & Co. $650 million settlement. Damages from fraud can be recovered by use of the False Claims Act, most commonly under the qui tam provisions which reward an individual for being a "whistleblower", or relator (law).
Every major company selling atypical antipsychotics—Bristol-Myers Squibb, Eli Lilly and Company, Pfizer, AstraZeneca and Johnson & Johnson—has either settled recent government cases, under the False Claims Act, for hundreds of millions of dollars or is currently under investigation for possible health care fraud. Following charges of illegal marketing, two of the settlements set records in 2009 for the largest criminal fines ever imposed on corporations. One involved Eli Lilly's antipsychotic Zyprexa, and the other involved Bextra, an anti-inflammatory medication used for arthritis. In the Bextra case, the government also charged Pfizer with illegally marketing another antipsychotic, Geodon; Pfizer settled that part of the claim for $301 million, without admitting any wrongdoing.
In July 2012, GlaxoSmithKline pleaded guilty to criminal charges and agreed to a $3 billion settlement of the largest health-care fraud case in the U.S. and the largest payment by a drug company. The settlement is related to the company's illegal promotion of prescription drugs, its failure to report safety data, bribing doctors, and promoting medicines for uses for which they were not licensed. The drugs involved were Paxil, Wellbutrin, Advair, Lamictal, and Zofran for off-label, non-covered uses. Those and the drugs Imitrex, Lotronex, Flovent, and Valtrex were involved in the kickback scheme.
The following is a list of the four largest settlements reached with pharmaceutical companies from 1991 to 2012, rank ordered by the size of the total settlement. Legal claims against the pharmaceutical industry have varied widely over the past two decades, including Medicare and Medicaid fraud, off-label promotion, and inadequate manufacturing practices.
=== Physician roles ===
In May 2015, the New England Journal of Medicine emphasized the importance of pharmaceutical industry-physician interactions for the development of novel treatments and argued that moral outrage over industry malfeasance had unjustifiably led many to overemphasize the problems created by financial conflicts of interest. The article noted that major healthcare organizations, such as National Center for Advancing Translational Sciences of the National Institutes of Health, the President's Council of Advisors on Science and Technology, the World Economic Forum, the Gates Foundation, the Wellcome Trust, and the Food and Drug Administration had encouraged greater interactions between physicians and industry in order to improve benefits to patients.
=== Response to COVID-19 ===
In November 2020 several pharmaceutical companies announced successful trials of COVID-19 vaccines, with efficacy
of 90 to 95% in preventing infection. Per company announcements and data reviewed by external analysts, these vaccines are priced at $3 to $37 per dose. The Wall Street Journal ran an editorial calling for this achievement to be recognized with a Nobel Peace Prize.
Doctors Without Borders warned that high prices and monopolies on medicines, tests, and vaccines would prolong the pandemic and cost lives. They urged governments to prevent profiteering, using compulsory licenses as needed, as had already been done by Canada, Chile, Ecuador, Germany, and Israel.
On 20 February, 46 US lawmakers called for the US government not to grant monopoly rights when giving out taxpayer development money for any coronavirus vaccines and treatments, to avoid giving exclusive control of prices and availability to private manufacturers.
In the United States, the government signed agreements in which research and development or the building of manufacturing plants for potential COVID-19 therapeutics was subsidized. Typically, the agreement involved the government taking ownership of a certain number of doses of the product without further payment. For example, under the auspices of Operation Warp Speed in the United States, the government subsidized research related to COVID-19 vaccines and therapeutics at Regeneron, Johnson and Johnson, Moderna, AstraZeneca, Novavax, Pfizer, and GSK. Typical terms involved research subsidies of $400 million to $2 billion, and included government ownership of the first 100 million doses of any COVID-19 vaccine successfully developed.
American pharmaceutical company Gilead sought and obtained orphan drug status for remdesivir from the US Food and Drug Administration (FDA) on 23 March 2020. This provision is intended to encourage the development of drugs affecting fewer than 200,000 Americans by granting strengthened and extended legal monopoly rights to the manufacturer, along with waivers on taxes and government fees. Remdesivir is a candidate for treating COVID-19; at the time the status was granted, fewer than 200,000 Americans had COVID-19, but numbers were climbing rapidly as the COVID-19 pandemic reached the US, and crossing the threshold soon was considered inevitable. Remdesivir was developed by Gilead with over $79 million in U.S. government funding. In May 2020, Gilead announced that it would provide the first 940,000 doses of remdesivir to the federal government free of charge. After facing strong public reactions, Gilead gave up the "orphan drug" status for remdesivir on 25 March. Gilead retains 20-year remdesivir patents in more than 70 countries. In May 2020, the company further announced that it was in discussions with several generics companies to provide rights to produce remdesivir for developing countries, and with the Medicines Patent Pool to provide broader generic access.
== Developing world ==
=== Patents ===
Patents have been criticized in the developing world, as they are thought to reduce access to existing medicines. Reconciling patents and universal access to medicine would require an efficient international policy of price discrimination. Moreover, under the TRIPS agreement of the World Trade Organization, countries must allow pharmaceutical products to be patented. In 2001, the WTO adopted the Doha Declaration, which indicates that the TRIPS agreement should be read with the goals of public health in mind, and allows some methods for circumventing pharmaceutical monopolies: via compulsory licensing or parallel imports, even before patent expiration.
In March 2001, 40 multi-national pharmaceutical companies brought litigation against South Africa for its Medicines Act, which allowed the generic production of antiretroviral drugs (ARVs) for treating HIV, despite the fact that these drugs were on-patent. HIV was and is an epidemic in South Africa, and ARVs at the time cost between US$10,000 and US$15,000 per patient per year. This was unaffordable for most South African citizens, and so the South African government committed to providing ARVs at prices closer to what people could afford. To do so, they would need to ignore the patents on drugs and produce generics within the country (using a compulsory license), or import them from abroad. After an international protest in favour of public health rights (including the collection of 250,000 signatures by Médecins Sans Frontières), the governments of several developed countries (including The Netherlands, Germany, France, and later the US) backed the South African government, and the case was dropped in April of that year.
In 2016, GlaxoSmithKline (the world's sixth largest pharmaceutical company) announced that it would be dropping its patents in poor countries so as to allow independent companies to make and sell versions of its drugs in those areas, thereby widening the public access to them. GlaxoSmithKline published a list of 50 countries they would no longer hold patents in, affecting one billion people worldwide.
=== Charitable programs ===
In 2011 four of the top 20 corporate charitable donations and eight of the top 30 corporate charitable donations came from pharmaceutical manufacturers. The bulk of corporate charitable donations (69% as of 2012) comes by way of non-cash charitable donations, the majority of which again were donations contributed by pharmaceutical companies.
Charitable programs and drug discovery & development efforts by pharmaceutical companies include:
"Merck's Gift", wherein billions of river blindness drugs were donated in Africa
Pfizer's gift of free/discounted fluconazole and other drugs for AIDS in South Africa
GSK's commitment to give free albendazole tablets to the WHO for, and until, the elimination of lymphatic filariasis worldwide.
In 2006, Novartis committed US$755 million in corporate citizenship initiatives around the world, particularly focusing on improving access to medicines in the developing world through its Access to Medicine projects, including donations of medicines to patients affected by leprosy, tuberculosis, and malaria; Glivec patient assistance programs; and relief to support major humanitarian organisations with emergency medical needs.
== See also ==
List of industrial complexes – Economic conceptPages displaying short descriptions of redirect targets
Big Pharma conspiracy theories – Conspiracy theories about the pharmaceutical industry
Clinical trial – Phase of clinical research in medicine
Drug development – Process of bringing a new pharmaceutical drug to the market
Drug discovery – Pharmaceutical procedure
Legal drug trade – manufacture and sale of pharmaceutical drugs in compliance with the lawPages displaying wikidata descriptions as a fallback
List of pharmaceutical companies
Licensed production – Production under license of technology developed elsewhere
Outsourcing – Contracting internal tasks to an external organization
Pharmaceutical marketing – Advertising by pharmaceutical companies
Pharmacy – Clinical health science
Pharmacy benefit management – Administration of prescription drug programs in the United States
Unitaid – Global health initiative
Valuation (finance) § Valuation of intangible assets
== References ==
== External links ==
Quotations related to Pharmaceutical industry at Wikiquote
"Global Medicines Use in 2020". IMS Institute for Healthcare Informatics. November 2015.
"The pharmaceutical industry and global health – Facts & figures 2017" (PDF). International Federation of Pharmaceutical Manufacturers & Associations. February 2017. Archived from the original (PDF) on 12 December 2020. Retrieved 18 November 2020.
"Licensing Agreements in the Pharmaceutical Industry".
"The Pharmaceutical Industry in Figures – Key Data 2018" (PDF). European Federation of Pharmaceutical Industries and Associations. | Wikipedia/Drug_company |
President of the United States George W. Bush signed the Food and Drug Administration Amendments Act of 2007 (FDAAA) on September 27, 2007. This law reviewed, expanded, and reaffirmed several existing pieces of legislation regulating the FDA. These changes allow the FDA to perform more comprehensive reviews of potential new drugs and devices. It was sponsored by Reps. Joe Barton and Frank Pallone and passed unanimously by the Senate.
The FDAAA extended the authority to levy fees to companies applying for approval of drugs, expanded clinical trial guidelines for pediatric drugs, and created the priority review voucher program, amongst other items.
== Title I: Prescription Drug User Fee Amendments of 2007 ==
Title I amends the Federal Food, Drug, and Cosmetic Act to include post-marketing safety activities in the review of drug application. This included developing and using improved adverse event data collection systems and improved analytical tools to assess potential safety problems and conducting screenings of the Adverse Event Reporting System database and reporting on new safety concerns.
It also reauthorizes the Prescription Drug User Fee Act. The PFUDA was first enacted in 1992 to allow the FDA to collect application fees from pharmaceutical companies when applying for approval for a drug. Since then, it has been reauthorized three times; first in 1997, then 2002, and most recently with the passage of the FDAAA in 2007. The purpose of these fees is to provide resources to the FDA that help them more effectively review potential new drugs. The most recent reauthorization will further expand on the previous policy. It aims to broaden and upgrade the drug safety program, allocate more resources for television advertising, and theoretically allow the FDA to more efficiently review and approve safe and effective new drugs for consumers.
It requires the FDA, through the authority of the Secretary of Health and Human Services to provide a partial refund of an applicant's user fees if the application is withdrawn without a waiver before filing.
It sets forth special rules for positron emission tomography drugs, including subjecting an applicant in a drug application for a PET drug to one-sixth of the annual prescription drug establishment fee.
It exempts approved drugs or biological products designated for a rare disease (orphan drugs) from product and establishment fees if certain requirements are met, including that the drug is owned/licensed and marketed by a company having gross worldwide revenues that fall below a certain amount.
== Title II: Medical Device User Fee Amendments of 2007 ==
Title II is given the short title of "Medical Device User Fee Amendments" (MDUFA). It defines terms relating to fees for medical devices. "30-day notice" is defined as a notice of a supplement to an approved application that is limited to a request to make modifications to manufacturing procedures or methods affecting the safety and effectiveness of the device.
It makes changes to medical device fees, including establishing a fee for a 30-day notice, a request for classification information, and periodic reporting for a class III device.
It extends the authority of accredited people (third parties) to review premarket reports for devices and make recommendations to the FDA regarding the classification of devices.
It requires any establishment in a foreign country engaged in the manufacturing or processing of a drug or device that is imported into the US to annually register with the FDA.
== Title III: Pediatric Medical Device Safety and Improvement Act of 2007 ==
Title III requires applications for a humanitarian device exemption, an application for premarket approval of a medical device, or a product development protocol for a medical device to include, if available, a description of any pediatric subpopulations that suffer from the disease that the device is intended for, and the number of affected pediatric patients.
It requires the FDA to submit an annual report to congressional committees that includes: (1) the number of devices approved in the preceding year for which there is a pediatric subpopulation that suffers from the disease; (2) the number of approved devices labeled for use in pediatric patients; (3) the number of fee-exempt devices approved; and (4) the review time for each approved device.
It authorizes the FDA to determine that adult data on medical devices may be used to support claims of effectiveness in pediatric populations if the course of the disease and the effects of the device are sufficiently similar in adults and pediatric patients.
It excludes a person granted a humanitarian device exemption from the prohibition against selling the device for an amount that exceeds its research and development, fabrication, and distribution costs if: (1) the device is intended to treat or diagnose a disease or condition that occurs in pediatric patients; (2) the device was not approved for pediatric patients prior to enactment of this Act; (3) the number of devices distributed does not exceed an annual distribution number specified by the Secretary; and (4) the request for exemption is submitted on or before October 1, 2012.
== Title IV: Pediatric Research Equity Act of 2007 ==
Title IV requires an applicant seeking to defer submission of some or all pediatric assessments of the safety and effectiveness of a new drug or biological product to submit to the FDA a timeline for the completion of pediatric studies. It also sets forth annual reporting requirements for an applicant following the approval of such a deferral.
It requires that an applicant seeking waiver of pediatric assessment submission requirements on the grounds that a pediatric formulation cannot be developed, to submit documentation detailing why a pediatric formulation cannot be developed. It also authorizes the FDA to require submission of a pediatric assessment if the Secretary finds that adequate pediatric labeling could confer a benefit on pediatric patients or the absence of adequate pediatric labeling could pose a significant risk to pediatric patients.
== Title V: Best Pharmaceuticals for Children Act of 2007 ==
Title V has the short title "Best Pharmaceuticals for Children Act".
It amends the Federal Food, Drug, and Cosmetic Act to revise provisions regarding market exclusivity for pediatric drug studies on new or already approved drugs, including to change the definition of "pediatric studies" to authorize the Secretary to include preclinical studies, to require the studies to be completed using appropriate formulations for each age group for which such a study is requested, and to prohibit the FDA from extending the period of market exclusivity later than nine months prior to the expiration of the period.
It requires an applicant that does not agree to the request for a pediatric study to submit to the Secretary the reasons such pediatric formulations cannot be developed, and requires an applicant that agrees to the request to provide the Secretary with all post-marketing adverse event reports regarding the drug.
It directs the FDA to: (1) publish a notice identifying any drug for which a pediatric formulation was developed, studied, and found to be safe and effective in the pediatric population if the pediatric formulation is not introduced onto the market within one year after the determination regarding market exclusivity; (2) utilize the internal review committee to review all written requests for pediatric studies issued; (3) track and make publicly available information on the pediatric studies conducted; (4) order the labeling of a product to include information about the results of the study and a statement that a pediatric study does or does not demonstrate that the drug is safe and effective in pediatric populations; and (5) ensure that all adverse event reports that have been received for a drug are referred to the Office of Pediatric Therapeutics. It prescribes actions for the FDA to take if pediatric studies have not been completed and there is a continuing need for information relating to the use of the drug in the pediatric population.
It requires the pediatric subcommittee of the Oncologic Drugs Advisory Committee to provide recommendations to the internal review committee that reviews pediatric research requests with respect to the treatment of pediatric cancer.
The Pediatric Trials Network serves as the mechanism by which many studies on off-patent drugs are performed, in keeping with the BPCA objective of ensuring accurate drug labeling for children.
== Title VI: Reagan-Udall Foundation ==
Title VI establishes the Reagan-Udall Foundation for the Food and Drug Administration as a nonprofit corporation to advance the mission of the FDA to modernize product development, accelerate innovation, and enhance product safety. It requires the Foundation to: (1) identify unmet needs in the development, manufacture, and evaluation of the safety and effectiveness of such products; (2) establish goals and priorities; (3) identify federal research and development programs and minimize duplication; (4) award grants to scientists and entities to efficiently and effectively advance such goals and priorities; and (5) provide objective clinical and scientific information to the FDA and other federal agencies.
It requires the FDA to establish an Office of the Chief Scientist to: (1) oversee, coordinate, and ensure quality and regulatory focus of FDA intramural research programs; (2) track and coordinate intramural research awards made by each FDA center or science-based office; (3) develop and advocate for a budget to support intramural research; (4) develop a peer review process by which intramural research can be evaluated; (5) identify and solicit intramural research proposals from across the FDA; and (6) develop additional post-marketing safety performance measures.
== Title VII: Conflicts of Interest ==
Title VII places limits on who can serve on an FDA advisory committee. It directs the FDA to implement strategies on effective outreach to potential members of advisory committees and to review the expertise and financial disclosure report of an individual when considering an appointment to an advisory committee. It prohibits any member of an advisory committee from participating with respect to any matter in which the member has a financial interest, unless the member is granted a waiver in order to afford the advisory committee essential expertise. The number of waivers is limited and decreases as a percentage of committee members over several years.
== Title VIII: Clinical Trials Databases ==
Title VIII is in regard to clinicaltrials.gov. It amends the Public Health Service Act to require the FDA, acting through the Director of NIH, to expand the clinical trials registry data bank. It requires the Director to ensure that the data bank is made publicly available through the Internet and requires the FDA to ensure that the data bank includes links to results information for those clinical trials that form the primary basis of an efficacy claim or are conducted after the drug or device involved is approved or cleared.
== Title IX: Enhanced Authorities Regarding Postmarket Safety of Drugs ==
Title IX prohibits a "responsible person" from introducing into interstate commerce a new drug, if the person is in violation of a requirement related to post-approval clinical trials or labeling changes.
It authorizes the FDA to require a responsible person for a drug to conduct a post-approval study or clinical trial of the drug to assess a known serious risk or signals of a serious risk or to identify an unexpected serious risk, to require a postapproval study or clinical trial for an already approved drug only if the Secretary becomes aware of new safety information, and to issue an order directing a responsible person or holder of an approved application to make a labeling change to address new safety information.
It prohibits a person from introducing into interstate commerce a new drug or biological product for which a risk evaluation and mitigation strategy is required if the person fails to maintain compliance with the requirements of such strategy.
It requires a proposed risk evaluation and management strategy to include a timetable for assessment of the strategy and allows the FDA to require such a strategy to include additional elements, including distribution to each patient of a Medication Guide and a patient package insert, a communication plan to health care providers, and assurances of safe use.
It establishes the Drug Safety Oversight Board.
It authorizes the FDA to require the submission of any TV advertisement for a drug for review before it can be broadcast, to make recommendations with respect to information included in the label of the drug or on statements for inclusion in advertisements but not require changes in such advertisements, and to require inclusion in advertisements of certain disclosures about a serious risk listed in the labeling of the drug.
It requires the FDA to issue special guidance for clinical trials of antibiotics.
It prohibits interstate commerce of any food that has an approved drug, licensed biological product, or certain other drugs or biological products added, unless the drug or biological product was marketed in food prior to approval, licensure, or clinical investigation, the FDA has approved the use of such drug or biological product in the food, or the use of the drug or the biological product is to enhance the safety or preservation of the food and not intended to have biological or therapeutic effects and the use is in conformity with specified regulations.
It requires the FDA to develop standards to secure the drug supply chain against counterfeit, diverted, substandard, adulterated, misbranded, or expired drugs, to prioritize and develop standards for the identification and validation of prescription drugs, to develop a standardized numerical identifier for prescription drugs, and to expand resources and facilities for securing the drug supply chain.
It requires the Advisory Committee on Risk Communication to regularly perform a comprehensive review of the types of risk information provided on the website and to recommend ways for the FDA to work with outside entities to help facilitate communication of risk.
It requires that certain information related to a new drug application be published on the FDA's website, including documents related to the review of an application and a summary of conclusions from all reviewing disciplines about the drug. It stipulates that a scientific review of an application is considered the work of the reviewer and prohibits the altering of such work by management or the reviewer once it is final.
It directs the FDA to publish and update quarterly a complete list of all authorized generic drugs on the FDA's website.
== Title X: Food Safety ==
Title X requires the FDA to work with companies, professional associations, and other organizations during an ongoing recall of food regulated by the FDA to collect and aggregate information, to use existing networks to enhance the quality and speed of public communication, and to post information regarding recalled food on the FDA's website in a single location.
It requires the FDA to work with states to assist in improving the safety of food. It requires a responsible person who determines that an article of food is a reportable food to submit a report to the FDA within 24 hours and to investigate the cause of the adulteration if the adulteration may have originated with the responsible person. It requires the FDA to immediately notify the Secretary of Homeland Security if the FDA believes food reported to the registry may have been deliberately adulterated.
It requires the FDA to produce a report on any environmental risks associated with genetically engineered seafood products and sets forth reporting requirements with respect to food products regulated by the FDA.
== Title XI: Other Provisions ==
Title XI requires the FDA to identify and periodically update clinically susceptible concentrations (specific values that characterize bacteria as clinically susceptible, intermediate, or resistant to the drug tested).
It directs the FDA to convene a public meeting regarding which infectious diseases potentially qualify for available grants and contracts under the Orphan Drug Act or other incentives for development, and amends the Orphan Drug Act to reauthorize appropriations for grants and contracts to defray the costs of testing for the development of drugs, medical devices, and medical foods for rare diseases.
It allows an applicant for a non-racemic drug containing as an active ingredient a single enantiomer that is contained in a racemic drug approved in another application to elect to have the single enantiomer considered the same active ingredient as that contained in the approved racemic drug under certain circumstances.
It requires the HHS Secretary to enter into a contract with the Institute of Medicine to conduct a study to assess the overall safety and quality of genetic tests and prepare a report that includes recommendations to improve federal oversight and regulation of genetic tests.
=== Priority review voucher program ===
Title XI also created the priority review voucher program. This requires the FDA to award a transferable, priority review voucher to the sponsor of a tropical disease product application upon approval by the Secretary of such application and establish a priority review user fee program. In this Act, only tropical diseases were covered under this program to incentivize the development of neglected tropical diseases. In 2012, this was expanded to include rare pediatric conditions. As of 2017, 13 priority review vouchers have been awarded.
== See also ==
U.S. Food and Drug Administration
Food and Drug Administration Safety and Innovation Act
== References ==
== External links ==
fda.gov
fda.gov | Wikipedia/Food_and_Drug_Administration_Amendments_Act_of_2007 |
The Prescription Drug User Fee Act (PDUFA) was a law passed by the United States Congress in 1992 which allowed the Food and Drug Administration (FDA) to collect fees from drug manufacturers to fund the new drug approval process. The Act provided that the FDA was entitled to collect a substantial application fee from drug manufacturers at the time a New Drug Application (NDA) or Biologics License Application (BLA) was submitted, with those funds designated for use only in Center for Drug Evaluation and Research (CDER) or Center for Biologics Evaluation and Research (CBER) drug approval activities. In order to continue collecting such fees, the FDA is required to meet certain performance benchmarks, primarily related to the speed of certain activities within the NDA review process.
== History ==
The move towards imposing user fees to pay for the regulatory review of new medicines was the result of dissatisfaction among consumers, industry, and the FDA. All three groups felt that drug approvals were taking far too long. Pharmaceutical companies had to wait to begin to recoup the costs of research and development. The FDA estimated that a delay of one month in a review’s completion cost its sponsor $10 million. The FDA argued that it needed additional staff to end its back-log of drugs awaiting approval for market. The FDA had not received sufficient appropriations from Congress to hire them. For decades the FDA had asked for permission to implement user fees and the pharmaceutical industry generally opposed them, fearing that the funds would not be used to speed drug review. The 1992 law became possible when the FDA and industry agreed on setting target completion times for reviews and the promise these fees would supplement federal appropriations instead of replacing them.
=== AIDS epidemic ===
The length of the drug approval process fell under severe scrutiny during the early years of the AIDS epidemic. In the late 1980s, ACT-UP and other HIV activist organizations accused the FDA of unnecessarily delaying the approval of medications to fight HIV and opportunistic infections, and staged large protests, such as a confrontational October 11, 1988, action at the FDA headquarters which resulted in roughly 180 arrests. In August 1990, Louis Lasagna, then chairman of a presidential advisory panel on drug approval, estimated that thousands of lives were lost each year due to delays in approval and marketing of drugs for cancer and AIDS. Partly in response to these criticisms, the FDA introduced expedited approval of drugs for life-threatening diseases and expanded pre-approval access to drugs for patients with limited treatment options. All of the initial drugs approved for the treatment of HIV/AIDS were approved through accelerated approval mechanisms. For example, a "treatment IND" was issued for the first HIV drug, AZT, in 1985, and approval was granted 2 years later, in 1987.
AIDS activists, desperate for new treatments, were outraged at the cost of those first drugs and the slow pace of drug development. These activists bombarded the government and drug companies with complaints and public protests. The activists won a major victory in 1989, when Burroughs Wellcome implemented a 20% price cut on AZT, then still the only treatment for HIV. Even after this price concession, the 12-pill-per-day AZT regimen cost patients $6,400 a year. AIDS activists expressed their anger by trashing booths at medical conventions and continuing vocal public protests. Gradually, drug companies established relationships with AIDS activists and the two sides came together to improve clinical trials. By August 1991, relations had warmed up so much that ACT-UP founder Larry Kramer wrote Bristol-Myers Squibb chief Richard Gelb a letter of congratulations on the imminent approval of Videx. AIDS groups fought for the reauthorization of the Orphan Drug Act and the passage of the Prescription Drug User Fee Act in 1992.
=== PDUFA I ===
The Prescription Drug User Fee Act (PDUFA) was first enacted in 1992. PDUFA gives the Food and Drug Administration (FDA) a revenue source, fees paid by pharmaceutical companies seeking the approval of new drugs, to supplement but not replace direct appropriations from Congress. PDUFA was passed in order to shorten the length of time from a manufacturer’s submission of a New Drug Application or a Biologics License Application to an FDA decision approval or licensure.
Congress created three kinds of user fees via PDUFA and required that they each make up one-third of the total fees collected. These include application review fees paid by the sponsor for each drug or biologic application submitted, establishment fees paid by manufacturers annually for each of its facilities, and product fees paid annually for each product on the market covered by PDUFA. For 1993, the application review fee was about $100,000. The law provided exemptions and waivers for applications from small businesses, drugs aimed at orphan diseases, or unmet public health needs.
In order to avoid listing specific performance goals in statutory language Congress stated in the bill’s “Findings” that, "3) the fees authorized by this title will be dedicated toward expediting the review of human drug applications as set forth in the goals identified in the letters of September 14, 1992, and September 21, 1992, from the Commissioner of Food and Drugs to the Chairman of the Energy and Commerce Committee of the House of Representatives and the Chairman of the Labor and Human Resources Committee of the Senate, as set forth at 138 Cong. Rec. H9099-H9100 (daily ed. September 22, 1992)."
=== PDUFA II ===
In its 1997 reauthorization of PDUFA, Congress enacted stricter performance goals, required increased transparency in the drug review process, and tried to facilitate better communication between drug makers and patient advocacy groups. Congress expanded the scope of the legislation to include the investigational phases of a new drug’s development. PDUFA II was passed as Title I of the Food and Drug Administration Modernization Act.
When Congress was debating the legislation that implemented PDUFA II Rep. Billy Tauzin, who later became head of PhRMA and one of those leading the call for a further streamlined review process, told a story of how a family friend had to travel to Mexico to obtain drugs that helped him overcome prostate cancer. "We continue to have problems with the fact that approved medicines in other countries can't get approved here. But what I particularly can't understand at all are situations where you have people suffering terminal illnesses, and they can't get the experimental drugs that might save their lives."
In testimony before Congress, James Swire, an AIDS activist and health educator who became infected with HIV in 1990, said the FDA has dramatically reduced the time needed to approve life-saving drugs using the money from PDUFA. Swire said, "I'm here because people really pushed the review process for AIDS and HIV treatments. There still is not a cure, but because of some of the new drugs, a lot of us have been able to get back to work."
=== PDUFA III ===
PDUFA III, part of the Public Health and Bioterrorism Preparedness Act, made appropriations for increased postmarket monitoring of new products and allowed the FDA to hire additional personnel to speed the reviews of new drugs. Another 2002 statute extended user fee policies to cover the approval process for medical devices.
During the period that PDUFA III was in effect the FDA's requirement that drug companies pay user fees for 505(b)(2) applications to switch drugs from requiring a prescription to being sold over-the-counter became a source of controversy. The drug industry claimed that the FDA misinterpreted the section of PDUFA III authorizing user fees when deciding to charge for reviewing 505(b)(2) applications. Specifically, they said Congress only intended user fees to be paid on new indications for a new active ingredient and that switching a drug to over-the-counter status was an exception to the rule requiring user fees.
In February 2007 the FDA exempted drugs used in the President's Emergency Plan for AIDS Relief (PEPFAR) from user fees in order to reduce the financial burden of developing new AIDS drugs.
=== PDUFA IV ===
The FDA requested and received fee increases to cover increased reviewer workload and expanded post-marketing safety initiatives, as well as the authority to apply user fees to the monitoring of direct-to-consumer drug advertising. President Bush signed the reauthorization of PDUFA into law on 27 September 2007.
In 2007, the FDA was expected to collect $259,300,000 in industry user fees.
=== PDUFA V ===
The reauthorization process for PDUFA V began with a public hearing in April 2010. The Pharmaceutical Research and Manufacturers of America (PhRMA) strongly supported reauthorization of PDUFA, saying at the time that “PDUFA V can play a critical role in making more life-saving medicines available to patients in a timely manner, strengthening the scientific base of the FDA and providing a steady, reliable stream of resources for Agency scientists."
PDUFA was reauthorized in July 2012. PDUFA's fifth reauthorization calls for upgrading benefit/risks assessments of new medicines as well as call for more patient perspectives in the review process.
=== PDUFA VI ===
On August 18, 2017, President Trump signed into law the Food and Drug Administration Reauthorization Act (FDARA), which includes the reauthorization of PDUFA through September 2022. PDUFA VI will provide for the continued timely review of new drug and biologic license applications.
== Effectiveness ==
=== Increased staffing ===
A 2002 U.S. Government Accountability Office (GAO) report found that PDUFA funds allowed the FDA to increase the number of new drug reviewers by 77 percent in the first eight years of the act, and the median approval time for non-priority new drugs dropped from 27 months to 14 months over the same period.
=== Review times ===
A major PDUFA goal is for the FDA to review and provide a ruling on applications within one year unless significant changes are made to the application during the last three months of the review cycle. In a 1997 speech given prior to leaving the FDA David Kessler said, "So far we have reviewed 95% of the 1995 group on time. We won't reach 100%, however, because we did make a mistake: we misread a deadline on a computer printout and we missed one deadline by three days." The PDUFA goal for the 1995 group called for a 70% on-time record. The 95% on-time rate more than doubled the pre-PDUFA on-time level of about 40%. Kessler said the FDA achieved similar positive results with other PDUFA goals, including in its review time for efficacy supplements (requests to add a new indication or a new group of patients to an already approved drug), submissions for manufacturing supplements (for making significant changes in the way a drug is made or using a new manufacturing facility) and resubmissions (responses provided to questions or alleged deficiencies raised by the FDA).
From 1993 through 1996, the years PDUFA I was in effect, the approval time for new drugs declined significantly while the number of new products increased. The approval time for NDAs in the 8 years before the implementation of PDUFA I was roughly 31.3 months. During this period, the approval time exceeded 30 months in every year except 1990 when it was 27.7 months and 1992 when it was 29.9 months. From 1993 through 1996, the average approval time fell to 20.8 months. During this period, the approval time for new drugs never exceeded 30 months. According to the Pharmaceutical Research and Manufacturers of America drug review time was cut roughly in half after the passage of PDUFA I.
=== Drug launches ===
Faster drug approval times and other PDUFA-related changes have led to pharmaceutical companies targeting more drugs for first launch in the United States thus increasing patient access to new medicines. Faster drug review from 1990 to 2001 were found to increase the probability of a drug being launched first in the United States by 14%. Other changes made under PDUFA such as the increased probability of approval and shortened development periods increased the probability of a drug being first launched in the United States by 31 percent at the end of PDUFA I and 27 percent at the end of PDUFA II.
During the eight years before PDUFA took effect, an average of 24 new drugs were approved each year. The number of approvals ranged from 20 in 1988 to 30 in 1991. During the four years that PDUFA I was in effect, an average of 32 drugs were approved each year, ranging from 22 in 1994 to 53 in 1996. The average number of new drugs approved by the FDA each year increased by one-third.
First drug launches making use of new chemical entities in the United States increased from 44 from 1982 through 1992 to 156 in from 1993 through 2003 period. The increase in first drug launches in the United States from 1993 through 2003 is particularly interesting given that the European Union harmonized its regulatory regime for new drugs with those of other major markets in order to reduce barriers for drug approvals during the same period.
=== Regulator-industry communication ===
David Kessler described improved communication between the FDA and the drug industry on what data should be included in NDAs as an important benefit of PDUFA. He said, "For example, in fiscal year 1993, 34 of the new applications that came into the FDA were sent back to the company because they were poorly prepared or missing critical information. In fiscal year 1996 six applications were refused for these reasons – a more than fivefold improvement."
== PDUFA dates ==
PDUFA dates are deadlines for the FDA to review new drugs. The FDA is normally given 10 months to review new drugs. If a drug is selected for priority review, the FDA is allotted 6 months to review the drug. These time frames begin on the date that an NDA is accepted by the FDA as complete.
== Scale of fees ==
FDA calculates fees based on an annual basis. For fiscal year 2021, drug application fees are:
$3,117,218 per full application requiring clinical data,
$1,558,609 per application not requiring clinical data or per supplement requiring clinical data.
$369,413 for programs
The FDA estimates that operating costs for the year 2017 will be $878,590,000. The FD&C Act specifies that one-third of the total fee revenue is to be derived from application fees, one-third from establishment fees, and one-third from product fees (see section 736(b)(2) of the FD&C Act). FDA estimates that in 2016, 2,646 products will have been billed for product fees and 523 establishments will have been billed for establishment fees.
In 2015, 132.5 full application equivalents (FAEs) were charged an application fee. FAEs are calculated by counting a full application as one FAE and an application not requiring clinical data or a clinical data supplement as half an FAE.
An application that is withdrawn, or refused for filing, counts as one quarter of the original FAE. For a full application this is one quarter FAE, and for an application without clinical data or a clinical data supplement this is an eighth of an FAE.
== FDA budget ==
User fees imposed under PDUFA are expected to add $707 million to the FDA budget in 2011, roughly a quarter of the agency's total spending. User fees cover roughly 65 percent of the drug approval process.
== References == | Wikipedia/Prescription_Drug_User_Fee_Act |
The United States Food and Drug Administration Modernization Acts (FDAMA) are amendments to the Federal Food, Drug, and Cosmetic Act, which regulated products by the FDA. The first bill, the FDA Modernization Act of 1997, reduced the timeline for approving new pharmaceutical drugs. It also loosened rules around broadcast pharmaceutical advertising.
In 2022, the Act was updated with the FDA Modernization Act 2.0, which cancelled a 1938 mandate to require animal testing for every drug development protocol.
== History ==
Congressman Richard Burr and Senator James M. Jeffords were the chairperson sponsors of the Food and Drug Administration Regulatory Modernization Act of 1997 or FDA Modernization Act of 1997. The U.S. legislation was signed by Bill Clinton on 21 November 1997, and fully enacted by 1 April 1999, putting into law reforms begun under the National Partnership for Reinventing Government. One result of the passing of the act was a reduction in the time for the approval of new pharmaceutical drugs. Critics questioned whether the shortened time frame for the approval of prescription drugs would do more harm than good.
In 2022, the Act was updated with the FDA Modernization Act 2.0. Signed into law by President Joe Biden, the act cancelled an earlier mandate (set by the Federal Food, Drug, and Cosmetics Act of 1938) to require animal testing in drug development.
== FDA Modernization Act of 1997 ==
The following are the most significant provisions of the 1997 act:
=== Prescription drug user fees ===
The act reauthorized, for five more years, the Prescription Drug User Fee Act of 1992 (PDUFA). This enabled the FDA to reduce the average time required for a drug review from 30 months to 15 months.
=== FDA initiatives and programs ===
The law enacted FDA initiatives undertaken under Vice President Al Gore's Reinventing Government program. The initiatives include measures to modernize the regulation of biological products by bringing them in harmony with the regulations for drugs and eliminating the need for establishment license application; eliminate the batch certification and monograph requirements for insulin and antibiotics; streamline the approval processes for drug and biological manufacturing changes; and reduce the need for environmental assessment as part of a product application.
The act also codified FDA regulations and practice to increase patient access to experimental drugs and medical devices and to accelerate review of important new medications. In addition, the law provided for an expanded database on clinical trials, ClinicalTrials.gov.
=== Information on off-label use and drug economics ===
The law abolishes the long-standing prohibition of broadcasting by manufacturers of information about unapproved uses of drugs and medical devices. The act allows a firm to circulate peer-reviewed journal articles about an off-label indication of its product, providing the company is also committing itself to file proof of research within a certain amount of time.
The act also allows drug companies to provide economic information about their products to formulary committees, managed care organizations, and similar large-scale buyers of health-care products. The law, however, does not permit the spreading of economic information that could affect prescribing choices to individual medical practitioners.
=== Pharmacy compounding ===
The act creates a special exemption to ensure continued availability of compounded drug products prepared by pharmacists to provide patients with individualized therapies not available commercially. The law, however, seeks to prevent manufacturing under the guise of compounding by establishing parameters within which the practice is appropriate and lawful.
=== Risk-based regulation of medical devices ===
The act complements and builds on the FDA's measures to focus its resources on medical devices that present the greatest risks to patients. The law also directs the FDA to focus its post market surveillance on higher risk devices, and allows the agency to implement a reporting system that concentrates on a representative sample of user facilities—such as hospitals and nursing homes—that experience deaths and serious illnesses or injuries linked with the use of devices.
Finally, the law expands an ongoing pilot program under which the FDA accredits outside—so-called "third party"—experts to conduct the initial review of all low-to-intermediate risk class I and II devices. The act, however, specifies that an accredited person may not review devices that are permanently implantable, life-supporting, life sustaining, or for which clinical data are required.
=== Food safety and labeling ===
The act eliminates the requirement of the FDA's premarket approval for most packaging and other substances that come in contact with food and may migrate into it. Instead, the law establishes a process whereby the manufacturer can notify the agency of its intent to use certain food contact substances and, unless the FDA objects within 120 days, the manufacturer may proceed with the marketing of the new product. Implementation of the notification process is contingent on additional appropriations to cover its cost to the agency. The act also expands procedures under which the FDA can authorize health claims and nutrient content claims without reducing the statutory standard.
=== Standards for medical products ===
In the area of drugs, the law codifies the agency's current practice of allowing in certain circumstances one clinical investigation as the basis for product approval. The act, however, does preserve the presumption that, as a general rule, two adequate and well-controlled studies are needed to prove the product's safety and effectiveness.
In the area of medical devices, the act specifies that the FDA may keep out of the market products whose manufacturing processes are so deficient that they could present a serious health hazard. The law also gives the agency authority to take appropriate action if the technology of a device suggests that it is likely to be used for a potentially harmful unlabeled use.
== FDA Modernation Act 2.0 ==
In 2022, the FDA Modernization Act 2.0 was approved and signed into law by President Joe Biden. The FDA Modernization Act of 2.0 removed the requirement for animal testing in drug development, making it optional. This enabled further development of new alternative technologies such as cell assays, computer modeling, and bioprinting.
== See also ==
Food and Drug Administration Amendments Act of 2007
== References ==
== External links ==
FDA page on the FDAMA
FDAMA Implementation Chart of Completed Items | Wikipedia/Food_and_Drug_Administration_Modernization_Act |
The Marketed Health Products Directorate (MHPD) is the Canadian federal authority that monitors the safety and effectiveness of health products marketed in Canada. These include:
Prescription and non-prescription medications
Biologic medical products, including fractionated blood products
Therapeutic and diagnostic vaccines
Natural health products;
Radiopharmaceutical products
Medical devices
Cells, tissues and organs
As part of Health Canada, MHPD collects and analyzes reports of adverse health product reactions through its network of regional reporting centres and disseminates new health product safety information.
== References ==
== External links ==
Marketed Health Products Directorate (official website)
Health Canada. "Marketed Health Products Directorate: Retrospective - The First Five Years | 2002-2007" | Wikipedia/Marketed_Health_Products_Directorate |
The Food and Drug Administration Safety and Innovation Act of 2012 (FDASIA) is a piece of American regulatory legislation signed into law on July 9, 2012. It gives the United States Food and Drug Administration (FDA) the authority to collect user fees from the medical industry to fund reviews of innovator drugs, medical devices, generic drugs and biosimilar biologics. It also creates the breakthrough therapy designation program and extends the priority review voucher program to make eligible rare pediatric diseases. The measure was passed by 96 senators voting for and one voting against.
== Title I: Fees Relating to Drugs ==
Title I extends through FY2017 the authority of the FDA, through the authority of the Secretary of Health and Human Services, to collect drug application and supplement fees, prescription drug establishment fees, and prescription drug product fees to support the FDA process for reviewing human drug applications.
It requires the FDA to submit annually to the House Committee on Energy and Commerce and the Senate Committee on Health, Education, Labor, and Pensions, a report on the progress of the FDA in achieving the goals of the administration, future plans of the FDA, and the progress of the Center for Drug Evaluation and Research and Center for Biologics Evaluation and Research in achieving such goals. The report should include the number of: (1) new drug applications and biologics license applications filed, (2) priority new drug and biologics applications filed, (3) standard efficacy supplements, (4) priority efficacy supplements, (5) applications filed for review under accelerated approval, (6) applications filed for review as fast track products, (7) applications filed for orphan-designated products, and (8) breakthrough designations.
== Title II: Fees Relating to Devices ==
Title II extends through FY2017 the authority of the FDA to assess and collect fees for medical device applications and submissions. It authorizes the FDA to grant a full or partial waiver of medical device user fees if the FDA finds that the waiver is in the interest of public health.
== Title III: Fees Relating to Generic Drugs ==
Title III directs the FDA to assess and collect fees related to generic drugs: (1) a one-time backlog fee for abbreviated new drug applications pending on October 1, 2012; (2) a drug master file fee; (3) an abbreviated new drug application and prior approval supplement filing fee, as well as an additional fee for certain active pharmaceutical ingredient information; and (4) a generic drug facility fee and active pharmaceutical ingredient facility fee.
== Title IV: Fees Relating to Biosimilar Biological Products ==
Similarly to Title III, Title IV directs the FDA to assess and collect the following fees related to biosimilar biological products: (1) biosimilar program development fees, encompassing an initial biosimilar development fee, an annual biosimilar development fee, and a reactivation fee; (2) a biosimilar product application and supplement fee; (3) a biosimilar product establishment fee; and (4) a biosimilar product fee. Fees are waived for the first biosimilar application of a small business.
== Title V: Pediatric Drugs and Devices ==
Title V makes permanent the Best Pharmaceuticals for Children Act, granting extended market exclusivity for new and already-marketed drugs for the pediatric population, and the Pediatric Research Equity Act of 2003 for research into pediatric uses for existing drugs. Exclusivity will be granted only upon a written request.
It also grants authority to the FDA to extend a deadline for a pediatric drug study. It requires an applicant for a pediatric drug to submit an initial pediatric study plan to the FDA prior to the submission of drug safety assessments.
== Title VI: Medical Device Regulatory Improvements ==
Title VI prohibits the FDA from rejecting an application for approval of a medical device for investigational use on the basis that: (1) the investigation may not support a substantial equivalence or de novo classification determination or approval of the device; (2) the investigation may not meet a requirement, including a data requirement, relating to the approval or clearance of a device; or (3) an additional or different investigation may be necessary to support clearance or approval of the device.
It requires the FDA to establish a program to assess information relating to recalls of medical devices, and document the basis for termination by the FDA of a device recall. It authorizes the FDA to prohibit the sponsor of an investigation of the effectiveness of a medical device from conducting such investigation (issuing a clinical hold) if the FDA makes a determination that the device represents an unreasonable risk to the safety of the participants of the clinical trial.
It authorizes the FDA to classify certain new medical devices without first issuing a determination that such devices are not substantially equivalent to existing devices and change the classification of a medical device based upon new information about such device by administrative order instead of by regulation.
It expands the exemption from the prohibition on profit for medical devices that have been granted humanitarian device exemptions to include devices intended for use in adults, if such a device is intended for the treatment or diagnosis of a disease or condition that does not occur in pediatric patients, or that occurs in such numbers that the device's development is impossible, highly impracticable, or unsafe.
It authorizes the FDA to order post-marketing surveillance for medical devices at the time of their approval or clearance or at any time thereafter and requires device manufacturers to start surveillance not later than 15 months after the date the FDA issues an order. Medical devices for small or unique populations that are created or modified to comply with the order of an individual physician and that are designed to treat a unique pathology or physiological condition that no other device is domestically available to treat are exempted from post-marketing approval requirements.
== Title VII: Drug Supply Chain ==
Title VII imposes FDA registration requirements for domestic and foreign drug establishments. It expands drug product listing information to include information on drug excipient establishments, including all establishments used in the production of such excipient, a unique facility identifier of such establishment, and an e-mail address for each excipient manufacturer. It requires the FDA to maintain an electronic database for the purposes of risk-based inspections and to conduct risk-based inspections of registered drug establishments, including inspections for medical devices, and post a report on the FDA website on the number of domestic and foreign establishments registered in the previous fiscal year, the number of inspections of such establishments, and the percentage of the FDA budget used to fund such inspections.
It requires an establishment that is engaged in the manufacture or preparation of a drug to provide the FDA with records or other information in advance of an inspection. A drug is deemed adulterated if the establishment in which such drug was manufactured, processed, packed, or held does not comply with inspections.
It authorizes the FDA to destroy counterfeit or adulterated imported drug products that have minor monetary value or a reasonable probability of causing serious adverse health consequences or death. It authorizes the FDA to detain drugs found during inspection to be adulterated or misbranded. It exempts the FDA from freedom of information disclosure requirements with respect to information about drugs obtained from a foreign government if the information alerts the FDA to a potential need for a safety investigation, the information is provided to the FDA voluntarily on the condition that it is not released to the public, and the information is subject to a written agreement between the FDA and the foreign government. It authorizes the FDA to require importers of drugs to provide certain information to allow the FDA to assess the risk of importing such drugs and it requires the registration of commercial drug importers with the FDA.
It requires the FDA to publish regulations to establish good importer practices that specify the measures an importer shall take to ensure that imported drugs are in compliance. It requires a manufacturer or distributor to notify the FDA if they know that the use of a drug may result in serious injury or death, of a significant loss or theft of such drug intended for use in the US, or that a drug has been or is being counterfeited and sold in the US, or a drug has been or could be imported into the US.
An amendment proposed by John McCain to allow consumers to obtain drugs from Canada was rejected.
== Title VIII: Generating Antibiotic Incentives Now ==
Title VIII is referred to as the GAIN Act, and was passed to incentivize the development of new antibiotics in response to the growing threat of antibiotic resistance and a lack of antibiotic products in pharmaceutical manufacturers' pipelines. It extends the exclusivity period for qualified infectious disease products by five years. The extra five years of market protection is in addition to any other existing exclusivity, including those available under the Hatch-Waxman Act (3 to 5 years), orphan drug (7 years), or pediatric exclusivity (6 months).
A "qualified infectious disease product" is defined as an antibacterial or antifungal drug intended to treat serious or life-threatening infections. It requires the FDA to establish and maintain a list of pathogens qualifying for the program and makes qualified infectious disease products eligible for priority and fast track review. As of Sept. 2013, the FDA had issued 24 QIDP designations for 16 chemical entities.
In response to the GAIN Act, the FDA announced in Sept. 2012 that they were creating The Antibacterial Drug Development Task Force to assist in developing and revising guidance related to antibacterial drug development. The task force consisted of a multi-disciplinary group of 19 CDER scientists and clinicians who were charged with identifying priority areas and developing and implementing possible solutions to the challenges of antibacterial drug development.
== Title IX: Drug Approval and Patient Access ==
Title IX states that the FDA should apply accelerated approval and fast track provisions to expedite the development of treatments for serious or life-threatening diseases, while maintaining safety and effectiveness standards for such treatments. It requires the FDA, at the request of a drug sponsor, to expedite the review of a drug if the drug treats a serious or life-threatening disease or condition and the drug demonstrates substantial improvement over existing therapies. This created the breakthrough therapy designation.
It also extends through FY2017 the authorization of appropriations for grants and contracts for the development of drugs for rare diseases and conditions (orphan drugs). It directs the FDA to award a priority review voucher to a sponsor of a rare pediatric disease product application, and establish a user fee program for such sponsors.
=== Breakthrough therapy ===
Breakthrough Therapy Designation was created for drugs that may be significantly better treatments for serious diseases or conditions. On November 13, 2013, the FDA approved obinutuzumab (trade name Gazyva) by Hoffmann-La Roche for chronic lymphocytic leukemia making it the first drug to receive the breakthrough therapy designation.: 358
== Title X: Drug Shortages ==
Title X revises requirements for notifying the FDA of drug shortages. It requires the FDA to establish a task force to develop and implement a plan for enhancing the FDA's response to preventing and mitigating drug shortages. It requires the FDA to maintain an up-to-date list of drugs determined to be in shortage, including the name of each drug in shortage, the name of each manufacturer of a drug in shortage, the reason for the shortage, and the estimated duration of the shortage.
It amends the Controlled Substances Act to require the Attorney General to review requests to increase quotas of controlled substances and make a determination within 30 days if a request pertains to a drug in shortage. It allows a hospital that is owned and operated by the same entity and that shares access to databases with drug order information for its patients to repackage a drug in shortage (i.e., divide its volume into smaller amounts) and transfer it to another hospital within the same health system without incurring otherwise applicable FDA registration requirements.
== Title XI: Other Provisions ==
Title XI includes several provisions. It provides for expanded FDA regulation of medical gases.
It requires the FDA to work with other regulatory authorities and international organizations to encourage uniform clinical trial standards for medical products worldwide, and accept data from clinical investigations conducted outside of the US in determining whether to approve a drug.
It requires the FDA to issue a final determination on any petition filed by a generic drug applicant for determining whether a drug was withdrawn for a safety or effectiveness reason no later than 270 days after the filing of any such petition.
It amends the Controlled Substances Act to add as a Schedule I controlled substance any material, compound, mixture, or preparation which contains specified cannabimimetic agents (or the salts, isomers, or salts of isomers thereof), and specified additional hallucinogenic substances.
=== Synthetic drug abuse prevention ===
The Synthetic Drug Abuse Prevention Act of 2012 bans synthetic compounds commonly found in synthetic marijuana ("K2" or "Spice"), synthetic cathinones ("bath salts") MDPV and methylone, as well as hallucinogenic drugs 2C-C, 2C-D, 2C-E, 2C-I. 2C-H, 2C-N, 2C-P, and 2C-T-2 by placing them under Schedule I of the Controlled Substances Act.
== Proposed amendments ==
Several proposed amendments were rejected.
By 28 yeas to 67 nays, Bingaman Amendment No. 2111, to allegedly provide cost savings by fostering competition among generic pharmaceutical manufacturers and ensuring that anti-competitive "pay-for-delay" settlements between brand-name and generic pharmaceutical manufacturers do not block generic drugs from entering the market.
By 46 yeas to 50 nays, Murkowski Amendment No. 2108, to prohibit approval by the Food and Drug Administration of genetically engineered fish unless the National Oceanic and Atmospheric Administration concurs with such approval.
By 43 yeas to 54 nays, McCain Amendment No. 2107, to allow the importation by individuals of safe and affordable drugs from Canada.
By 9 yeas to 88 nays, Sanders Amendment No. 2109, to revoke the exclusivity of certain entities that are responsible for violations of the Federal Food, Drug, and Cosmetic Act, the False Claims Act, and other certain laws.
Two measures were tabled: an amendment to require manufacturers of dietary supplements to register dietary supplement products with the Food and Drug Administration, and an amendment to amend the Federal Food, Drug, and Cosmetic Act concerning claims about the effects of foods and dietary supplements on health-related conditions and disease, to prohibit employees of the Food and Drug Administration from carrying firearms and making arrests without warrants, and to adjust the mens rea of certain prohibited acts under the Federal Food, Drug, and Cosmetic Act to knowing and willful.
== References ==
== External links ==
Food and Drug Administration Safety and Innovation Act (PDF/details) as amended in the GPO Statute Compilations collection
Food and Drug Administration Safety and Innovation Act as enacted in the US Statutes at Large
Regulatory Information: Food and Drug Administration Safety and Innovation Act
Full Text of the Synthetic Drug Abuse Prevention Act of 2012
FDA Expedited programs guidance e.g. Fast track, breakthrough therapy, accelerated approval, priority review. | Wikipedia/Food_and_Drug_Administration_Safety_and_Innovation_Act |
The regulation of food and dietary supplements by the U.S. Food and Drug Administration is a process governed by various statutes enacted by the United States Congress and interpreted by the U.S. Food and Drug Administration ("FDA"). Pursuant to the Federal Food, Drug, and Cosmetic Act ("the Act") and accompanying legislation, the FDA has authority to oversee the quality of substances sold as food in the United States, and to monitor claims made in the labeling about both the composition and the health benefits of foods.
Substances which the FDA regulates as food are subdivided into various categories, including foods, food additives, added substances (man-made substances which are not intentionally introduced into food, but nevertheless end up in it), and dietary supplements. The specific standards which the FDA exercises differ from one category to the next. Furthermore, the FDA has been granted a variety of means by which it can address violations of the standards for a given category of substances.
== History of legislation ==
=== Pure Food and Drug Act ===
The Pure Food and Drug Act of 1906 was the first of a series of significant consumer protection laws enacted by the Federal Government in the twentieth century and led to the creation of the Food and Drug Administration. Its main purpose was to ban foreign and interstate traffic in adulterated or mislabeled food and drug products, and it directed the U.S. Bureau of Chemistry to inspect products and refer offenders to prosecutors. It required that active ingredients be placed on the label of a drug's packaging and that drugs could not fall below purity levels established by The United States Pharmacopeia or The National Formulary. The Jungle by Upton Sinclair was an inspirational piece that kept the public's attention on the important issue of unsanitary meat processing plants that later formed the Pure Food and Drug Act.
=== Federal Food, Drug, and Cosmetic Act ===
The United States Federal Food, Drug, and Cosmetic Act (abbreviated as FFDCA, FDCA, or FD&C), is a set of laws passed by Congress in 1938 giving authority to the U.S. Food and Drug Administration (FDA) to oversee the safety of food, drugs, and cosmetics. A principal author of this law was Royal S. Copeland, a three-term U.S. Senator from New York. In 1968, the Electronic Product Radiation Control provisions were added to the FD&C. Also in that year the FDA formed the Drug Efficacy Study Implementation (DESI) to incorporate into FD&C regulations the recommendations from a National Academy of Sciences investigation of effectiveness of previously marketed drugs. The act has been amended many times, most recently to add requirements about bioterrorism preparations.
The introduction of this act was influenced by the death of more than 100 patients due to a sulfanilamide medication where diethylene glycol was used to dissolve the drug and make a liquid form. See Elixir Sulfanilamide disaster. It replaced the earlier Pure Food and Drug Act of 1906.
=== Food Additives Amendment of 1958 ===
The Food Additives Amendment of 1958 is a 1958 amendment to the Food, Drugs, and Cosmetic Act of 1938. It was a response to concerns about the safety of new food additives. The amendment established the designation of "generally recognized as safe", which refers to chemicals or substances which can be used as food additives without further evaluation or testing just because they have been long used and there is broad acceptance of their use. New food additives would be subject to testing including by the "Delaney clause". The Delaney clause was a provision in the amendment which said that if a substance were found to cause cancer in man or animal, then it could not be used as a food additive.
=== Dietary Supplement Health and Education Act of 1994 ===
The Dietary Supplement Health and Education Act of 1994 is a 1994 statute of United States Federal legislation which defines and regulates dietary supplements. Under the act, supplements are mainly unregulated, without proof of effectiveness or safety needed to market a supplement, as well as dietary supplements being classified as foods instead of as drugs.
== Food ==
Food is defined in the Act to be:
articles used for food or drink for man or other animals,
chewing gum, and
articles used for components of any such article.
The first definition offered is self-referential, defining food in part as "articles used for food", leaving it to the FDA and the courts to determine what exactly constitutes food. This determination is particularly important because the definition of a "drug" under the act includes a section defining drugs as "articles (other than food) intended to affect the structure or any function of the body of man or other animals". Thus, the definition of food is important not only in determining what is covered by the regulatory regime for food, but in determining what is excluded from the regulatory regime for drugs. For example, in the 1983 case of Nutrilab, Inc. v. Schweiker, the United States Court of Appeals for the Seventh Circuit found that starch blockers, though derived from kidney beans, were drugs rather than food under the meaning of the Act. The starch blockers were sold as tablets, and "not consumed primarily for taste, aroma, or nutritive value". Products that are normally considered to be foods may also be regulated as drugs if the parties responsible for their manufacture or sale make claims as to their ability to treat diseases, although the FDA now permits advertising addressing the disease-fighting qualities in foods where those qualities have been endorsed by the scientific community.
The standards for food sold in the United States are set forth in Chapter IV of the Act. These standards set forth two main areas of food that violates the Act: adulterated food and misbranded food. These categories are independent of one another; food can be completely free of adulteration and otherwise healthy to consume, and still be in violation of the act if it is misbranded. Likewise, food that has completely accurate labels, including warnings about dangers that it may pose to health, may nevertheless be deemed adulterated.
=== Adulterated food ===
The Act sets forth several circumstances under which food will be deemed adulterated. The primary definition set forth is that food is adulterated if:
...it bears or contains any poisonous or deleterious substance which may render it injurious to health; but in case the substance is not an added substance such food shall not be considered adulterated under this clause if the quantity of such substance in such food does not ordinarily render it injurious to health.
Added substances are treated separately by the FDA, meaning that the sale of an article or substance as food will generally be permitted if that article or substance is not ordinarily injurious to health.
Food is also deemed adulterated "if it consists in whole or in part of any filthy, putrid, or decomposed substance, or if it is otherwise unfit for food"; if it was "prepared, packed, or held under insanitary conditions whereby it may have become contaminated with filth, or whereby it may have been rendered injurious to health"; if it was produced from "a diseased animal or of an animal which has died otherwise than by slaughter"; if it was packaged in a poisonous material; or if it was intentionally irradiated outside of irradiation guidelines set forth by the Act. These definitions are also independent, meaning that food that is "filthy" or has been "held under insanitary conditions" is still in violation of the Act and subject to condemnation even if the owner can demonstrate that it poses no actual threat to health. The phrase "otherwise unfit for food", although seeming to be a catch-all, has rarely been invoked. It would apply to a circumstance such as a seller offering wood chips as food, which might be safe to consume and prepared under sanitary conditions, but would be impossible to chew.
==== Inspections for adulteration ====
The FDA has the authority to inspect any establishment in which food is manufactured, processed, packed, or held. In searching for contamination, the FDA typically uses organoleptic inspection methods – investigators trained to distinguish contamination and decomposition by sight and smell. Upon completion of such an inspection, the FDA will generate an "Establishment Inspection Report" (EIR) detailing any problems found. Where problems are found, the FDA will instruct the owner of the inspected facility how to proceed in resolving those problems. FDA inspectors may take photographs of an establishment unless they are expressly told not to do so, and the owner of the establishment must provide an employee to answer questions that arise during the inspection. If the owner of an establishment refuses to permit FDA inspectors to enter a covered establishment, or any part of one, then the FDA may obtain a search warrant to enter.
Courts have held that, so long as the owner has not objected to the inspection and prevented the inspectors from entering, the FDA does not require a warrant to seize materials that are in violations of the Act. Furthermore, such materials may be used at trial against the owner without raising unreasonable search and seizure issues under the Fourth Amendment to the United States Constitution because the industry at issue has been found to be heavily regulated, meaning that the owner of such an establishment has no expectation of privacy with respect to premises of the type covered by the Act.
==== Action levels ====
The presence of some degree of contamination is inevitable in almost all food. Technically, the FDA could inspect all food under a microscope and prohibit the sale of every article containing any discernible trace of mold, insect fragments, rodent hairs, and the like – effectively barring the sale of all food. In order to avoid this outcome, the FDA sets "action levels", which specify minimum amounts of particular contaminants that must be found in a food sample before the FDA will take action with respect to that sample. The FDA maintains a listing of all current action levels on its website. The FDA also establishes action levels for man-made chemicals such as aflatoxin, lead, and mercury, and maintains these on its website.
=== Misbranded food ===
The primary basis under which food may be deemed misbranded under the Act is if "its labeling is false or misleading in any particular". Labeling is defined elsewhere in the Act, and includes:
...all labels and other written, printed, or graphic matter
upon any article or any of its containers or wrappers
accompanying such article
Under the second part of this definition, it has been held that a food substance sold in conjunction with a book or pamphlet which makes false claims about the benefits of that substance is misbranded. If books making false claims about a food are sold in conjunction with that food, the books themselves may also be seized and destroyed – even if the author had no intention of selling the book in conjunction with the food. However, if a store happens to be selling both a food and a book which makes false claims about that food, and is selling the items separately, then no misbranding occurs. This is so even if the book and the food are both produced by the same company, and even if the maker of the food encourages the seller to carry the book.
In terms of determining whether food is misbranded, the FDA only monitors labeling, and not advertising, which instead falls under the authority of the Federal Trade Commission. However, the FDA will review the advertising of a product to determine whether it is to be regulated as a food or as a drug, based on the claims that the manufacturer or seller makes about its properties.
==== Standards of identity ====
The FDA is authorized to issue a standard of identity for any food. This is a description of what, exactly, must be in that food in order for it to be identified under a certain name. For example, a court has upheld an FDA ruling that for a product to be sold as cream cheese, it must contain a specified minimum percentage of milk fat, and a maximum level of moisture. Incorrectly identifying a food by a name for which a standard of identity has been established is considered a form of misbranding. The FDA has set forth nearly 300 such standards. However, in recent decades, companies marketing new types of food items have diminished the importance of these standards by simply coining new names for foodstuffs that do not conform to an existing standard, with examples including Cool Whip and Cheetos.
==== Health claims ====
There are two kinds of health claims that can be made about foods other than dietary supplements: structure/function claims and disease claims. Structure/function claims are claims that do not suggest that the food can diagnose, treat, or prevent any particular disease, but that it can, for example, maintain, regulate, or promote normal healthy bodily functions. Where such claims are made, foods are generally required to carry a disclaimer on their label indicating that the claim has not been evaluated by the FDA.
Disease claims suggest that the food can help prevent specific diseases. Such claims are only permitted where the FDA finds that there is "significant scientific agreement", or where the claim has been approved by another federal health agency or the National Academy of Sciences.
== Food additives ==
Food additives are defined in the Act to be:
...any substance the intended use of which results or may reasonably be expected to result, directly or indirectly, in its becoming a component or otherwise affecting the characteristics of any food...
The definition goes on to capture several broad categories of things not traditionally thought of as "food", including "any substance intended for use in producing, manufacturing, packing, processing, preparing, treating, packaging, transporting, or holding food". The definition only applies if the substance in question is not "generally recognized as safe" by qualified experts, and also exempts substances that were in common use as food prior to January 1, 1958.
The Act sets forth certain exemptions for substances which are treated under different regulatory schemes, including pesticide chemicals and their residue, color additives, substances previously approved under other statutes, new animal drugs, and dietary supplements. The statute directs that food additives are generally to be presumed to be unsafe (and therefore prohibited) until they have been proven to be safe. However, the statute then sets out a regulatory scheme under which a person intending to use a heretofore unapproved food additive may petition for "the issuance of a regulation prescribing the conditions under which such additive may be safely used".
=== Delaney clause ===
The Delaney clause, initially enacted in 1958, prohibits the FDA from approving food additives shown to cause cancer. At the time of the passage of the amendment, little was known about the carcinogenic propensities of a wide variety of additives. Following the enactment of this amendment, more and more substances were shown to be potentially carcinogenic, albeit in experiments wherein test animals were subjected to doses far in excess to the proportions which humans were likely to consume. In 1982, the FDA responded to this trend by adopting a rule that a food additive would not be denied approval under the Delaney clause unless the additive itself, and not just the constituent chemicals used to make it, was shown to cause cancer. This policy was later challenged in court following FDA approval of a food coloring manufactured with a compound known to be carcinogenic, after separate testing indicated that the food coloring itself did not cause cancer in test animals. The United States Court of Appeals for the Sixth Circuit upheld the FDA's approval of the food coloring.
== Added substances ==
Added substances are not separately defined in the act, but are understood to be different from food itself based on the definition of adulterated food, and a later section authorizing the FDA to set forth tolerance limits for "[a]ny poisonous or deleterious substance added to any food...". Such substances are prohibited, "except where such substance is required in the production thereof or cannot be avoided by good manufacturing practice". Because added substances often can not be avoided in food, such as the presence of environmental pollutants in fish, the FDA is required to "promulgate regulations limiting the quantity therein or thereon to such extent as [is] necessary for the protection of public health". The action levels discussed above with respect to poisonous or deleterious substances address these added substances. Added substances differ from food additives, discussed above, in that the latter applies to things which are intentionally added to food, and therefore require FDA approval prior to being added to food.
== Dietary supplements ==
The Dietary Supplement Health and Education Act of 1994 mandated that the FDA regulate dietary supplements as foods, rather than as drugs. Consequently, dietary supplements are defined as a kind of food under the statute, with the caveat that this does not exempt them from being treated as drugs in the way that other foods are exempted, if circumstances permit it.
Like other food substances, dietary supplements are not subject to the safety and efficacy testing requirements imposed on drugs, and unlike drugs they do not require prior approval by the FDA; however, they are subject to the FDA regulations regarding adulteration and misbranding. The FDA can take action against dietary supplements only after they are proven to be unsafe. Dietary supplements may be deemed to be misbranded if they are marketed in a way that characterizes them as a drug, without having undergone the clinical trials to which new drugs are subjected. Manufacturers of dietary supplements are permitted to make specific claims of health benefits, referred to as "structure or function claims" on the labels of these products. They may not claim to treat, diagnose, cure, or prevent disease and must include a disclaimer on the label. Where a manufacturer makes a structure or function claim in connection with the sale of a dietary supplement, the manufacturer must notify the FDA within 30 days after it has introduced that product to the market.
Claims that either a food or dietary supplement acts to prevent a disease are permitted, so long as there is "significant scientific agreement" for the claim, or it has been approved in an "authoritative statement" by "a scientific body with official responsibility for the public health protection or research directly relating to human nutrition" such as the National Academy of Sciences.
Consumer Reports, a consumer protection advocacy and product testing group, stated:
They can be ineffective, contaminated with microbes or heavy metals, dangerously mislabeled, or intentionally spiked with illegal or prescription drugs. They can also cause harmful side effects by themselves and interact with prescription medication in ways that make those drugs less effective. [...] According to a 2015 nationally representative Consumer Reports survey, almost half of American adults think that supplement makers test their products for efficacy, and more than half believe that manufacturers prove their products are safe before selling them.
In February 2019 FDA commissioner Scott Gottlieb said that the agency needed stronger powers over health claims and the FDA warned a dozen companies to stop claiming their products can cure diseases. The present law, established in 1994, requires the agency to prove that a product is unsafe. Manufacturers have to notify the agency of new products, but not of their ingredients. In 2019 there were between 50,000 and 80,000 dietary supplements on the American market, beyond the agency's capacity to monitor. The industry group Council for Responsible Nutrition opposed any suggestion that the sector needed stronger regulation.
== Prohibitions and treatment of violations ==
The Act expressly prohibits the "introduction, or delivery for introduction into interstate commerce of food... that is adulterated or misbranded", as well as the actual adulteration or misbranding of food. The Act further sets forth a broad range of powers that the FDA may exercise in order to prevent distribution of adulterated or misbranded food. In addition to the express powers set forth in the statute, the FDA exercises certain implied powers, such as the issuance of Warning Letters and recall orders.
The steps which the FDA may take in response to a violation include the following:
Sending an "untitled letter" to the violator indicating the concern and requesting a response detailing how the concern will be addressed by the violator.
Sending a Warning Letter to the violator specifically identifying the violation and requiring a response detailing how the violation will be addressed.
Issuing a press release, holding a press conference, having notices posted, or taking similar action to alert the public to the violation. Use of publicity is expressly authorized by the Act, and courts have held that the FDA need not give the alleged violator any notice or opportunity to be heard prior to the use of this measure. A party who feels that the FDA has wrongfully maligned its goods may file a lawsuit for defamation, but no such suit has ever succeeded.
Ordering the violator to recall the adulterated or misbranded products. The FDA has no formal authority to order a recall, but companies that receive such an order almost always comply with it to avoid invoking the FDA's more severe enforcement powers.
Ordering the violator to disgorge its products from sales of products to third parties, and provide restitution to those parties. The FDA also lacks statutory authority for this practice, but is able to coerce violators to disgorge profits through consent decrees. Courts have also found that they have the equitable power to order disgorgement and restitution as requested.
Petitioning a United States district courts to issue an injunction against the violation, as permitted by the Act, and to order the seizure of foods which violate the Act. The FDA has an easier burden to obtain both preliminary and permanent injunctive relief that does a private litigant, because the FDA is always acting in the public interest, and the injury sought to be prevented – violation of the laws designed to protect the public from harmful or misleading products – is presumed to be irreparable.
Seizing the offending food without first obtaining a court order, if the FDA has probable cause to believe that a misbranded food is dangerous to health or is fraudulent in a way that would cause commercial injury to the consumer. Where this occurs, the owner of the food may later seek to recover the seized food by initiating a proceeding in the local United States district court.
Seeking criminal penalties which may be imposed on violators, including imprisonment for up to a year and a fine of up to $1,000 for a first offense. Controversially, the president of a company that violates the Act may be found criminally liable for those violations even if he had no personal knowledge of the violations. Although the Act provides for civil penalties for certain violations relating to applications for approval of new drugs, it does not provide for civil penalties for violations involving food.
Where food is found to be adulterated, the FDA also has the option to offer the owner the opportunity to "recondition" the food – that is, to remove all traces and contamination, and submit that food for a reinspection by the FDA, at which time it may be approved for sale. Similarly, where food is found to be misbranded, the FDA has the option of offering the owner the opportunity to correct the labeling, and put the food back on the market with new labels that are not misleading.
== See also ==
Regulation of tobacco by the U.S. Food and Drug Administration
== References == | Wikipedia/Regulation_of_food_and_dietary_supplements_by_the_U.S._Food_and_Drug_Administration |
The Committee on Energy and Commerce is one of the oldest standing committees of the United States House of Representatives. Established in 1795, it has operated continuously—with various name changes and jurisdictional changes—for more than 200 years. The two other House standing committees with such continuous operation are the House Ways and Means Committee and the House Rules Committee. The committee has served as the principal guide for the House in matters relating to the promotion of commerce and to the public's health and marketplace interests, with the relatively recent addition of energy considerations among them. Due to its broad jurisdiction, it is considered one of the most powerful committees in the House.
== Role of the committee ==
The House Committee on Energy and Commerce has developed what is arguably the broadest (non-tax-oriented) jurisdiction of any congressional committee. The committee maintains principal responsibility for legislative oversight relating to telecommunications, consumer protection, food and drug safety, public health, air quality and environmental health, the supply and delivery of energy, and interstate and foreign commerce. This jurisdiction extends over five Cabinet-level departments and seven independent agencies—from the Department of Energy, Health and Human Services, the Transportation Department to the Federal Trade Commission, Food and Drug Administration, and Federal Communications Commission—and sundry quasi-governmental organizations.
== Jurisdiction ==
The Energy and Commerce Committee has the broadest jurisdiction of any authorizing committee in Congress. It legislates on a wide variety of issues, including:
health care, including mental health and substance abuse
health insurance, including Medicare and Medicaid
biomedical research and development
food, drug, device and cosmetic safety
environmental protection
clean air and climate change
safe drinking water
toxic chemicals and hazardous waste
national energy policy
renewable energy and conservation
nuclear facilities
electronic communications and the internet
broadcast and cable television
privacy, cybersecurity and data security
consumer protection and product safety
motor vehicle safety
travel, tourism and sports
interstate and foreign commerce
== Members, 119th Congress ==
Resolutions electing members: H.Res. 13 (Chair), H.Res. 14 (Ranking Member), H.Res. 21 (R), H.Res. 22 (D), H.Res. 40 (Menendez)
== Subcommittees ==
To manage the wide variety of issues it encounters, the committee relies on the front-line work of six subcommittees, one more than during the 111th Congress. During the 111th Congress, Chairman Henry Waxman combined the traditionally separate energy and environment subcommittees into a single subcommittee. New Chairman Fred Upton restored them as separate subcommittees at the start of the 112th Congress, and they have been retained to this day.
== Historical membership rosters ==
=== 118th Congress ===
Resolutions electing members: H.Res. 14 (Chair), H.Res. 15 (Ranking Member), H.Res. 56 (R), H.Res. 57 (D), H.Res. 1133 (R)
Subcommittees
=== 117th Congress ===
Resolutions electing members: H.Res. 9 (Chair), H.Res. 10 (Ranking Member), H.Res. 62 (D), H.Res. 63 (R)
Subcommittees
=== 116th Congress ===
Sources: H.Res. 7 (Chair), H.Res. 8 (Ranking Member), H.Res. 42 (D), H.Res. 68 (R)
Subcommittees
=== 115th Congress ===
Sources: H.Res. 6 (Chair), H.Res. 7 (Ranking Member), H.Res. 29 (R) and H.Res. 45 (D).
=== 114th Congress ===
== History ==
The committee was originally formed as the Committee on Commerce and Manufactures on December 14, 1795. Prior to this, legislation was drafted in the Committee of the Whole or in special ad hoc committees, appointed for specific limited purposes. However the growing demands of the new nation required that Congress establish a permanent committee to manage its constitutional authority under the Commerce Clause to "regulate Commerce with foreign Nations, and among the several States."
From this time forward, as the nation grew and Congress dealt with new public policy concerns and created new committees, the Energy and Commerce Committee has maintained its central position as Congress's monitor of commercial progress—a focus reflected in its changing jurisdiction, both in name and practice.
In 1819, the committee's name was changed to the Committee on Commerce, reflecting the creation of a separate Manufacturers Committee and also the increasing scope of and complexity of American commercial activity, which was expanding the committee's jurisdiction from navigational aids and the nascent general health service to foreign trade and tariffs. Thomas J. Bliley, who chaired the committee from 1995 to 2000, chose to use this traditional name, which underscores the committee's role for Congress on this front.
In 1891, in emphasis of the committee's evolving activities, the name was again changed to the Committee on Interstate and Foreign Commerce—a title it maintained until 1981, when, under incoming Chairman John Dingell, the committee first assumed what is now its present name to emphasize its lead role in guiding the energy policy of the United States. Dingell regained chairmanship of the committee in 2007 after having served as ranking member since 1995. In late 2008, Henry Waxman initiated a successful challenge to unseat Dingell as chairman. His challenge was unusual as the party caucus traditionally elects chairmen based on committee seniority. Waxman formally became chairman at the start of the 111th Congress.
== Previous chairs ==
=== Committee on Commerce and Manufactures ===
=== Committee on Commerce ===
=== Committee on Interstate and Foreign Commerce ===
=== Committee on Energy and Commerce ===
== See also ==
List of current United States House of Representatives committees
== References ==
== External links ==
Official website (Archive)
House Energy and Commerce Committee. Legislation activity and reports, Congress.gov.
House Energy and Commerce Committee Hearings and Meetings Video. Congress.gov | Wikipedia/House_Energy_and_Commerce_Committee |
Drug Efficacy Study Implementation (DESI) was a program begun by the Food and Drug Administration (FDA) in the 1960s after the requirement (in the Kefauver-Harris Drug Control Act) that all drugs be efficacious as well as safe, was made part of US law. The DESI program was intended to classify all pre-1962 drugs that were already on the market as either effective, ineffective, or needing further study. The Drug Efficacy Study Implementation (DESI) evaluated over 3,000 separate products and over 16,000 therapeutic claims. By 1984, final action had been completed on 3,443 products; of these, 2,225 were found to be effective, 1,051 were found not effective, and 167 were pending.
One of the early effects of the DESI study was the development of the Abbreviated New Drug Application (ANDA).
== See also ==
Estes Kefauver
Federal Food, Drug, and Cosmetic Act
Inverse benefit law
Regulation of therapeutic goods
== References ==
== External links ==
National Academies of Sciences archives. The Drug Efficacy Study of the National Research Council’s Division of Medical Sciences, 1966-1969
Chhabra R, Kremzner ME, Kiliany BJ. FDA policy on unapproved drug products: past, present, and future. Ann Pharmacother. 2005 Jul-Aug;39(7-8):1260-4. PMID 15956239
This article incorporates public domain material from websites or documents of the United States Department of Health and Human Services. | Wikipedia/Drug_Efficacy_Study_Implementation |
Gaucher's disease or Gaucher disease () (GD) is a genetic disorder in which glucocerebroside (a sphingolipid, also known as glucosylceramide) accumulates in cells and certain organs. The disorder is characterized by bruising, fatigue, anemia, low blood platelet count and enlargement of the liver and spleen, and is caused by a hereditary deficiency of the enzyme glucocerebrosidase (also known as glucosylceramidase), which acts on glucocerebroside. When the enzyme is defective, glucocerebroside accumulates, particularly in white blood cells and especially in macrophages (mononuclear leukocytes, which is often a target for intracellular parasites). Glucocerebroside can collect in the spleen, liver, kidneys, lungs, brain, and bone marrow.
Manifestations may include enlarged spleen and liver, liver malfunction, skeletal disorders or bone lesions that may be painful, severe neurological complications, swelling of lymph nodes and (occasionally) adjacent joints, distended abdomen, a brownish tint to the skin, anemia, low blood platelet count, and yellow fatty deposits on the white of the eye (sclera). Persons seriously affected may also be more susceptible to infection. Some forms of Gaucher's disease may be treated with enzyme replacement therapy.
The disease is caused by a recessive mutation in the GBA gene located on chromosome 1 and affects both males and females. About one in 100 people in the United States are carriers of the most common type of Gaucher disease. The carrier rate among Ashkenazi Jews is 8.9% while the birth incidence is 1 in 450.
Gaucher's disease is the most common of the lysosomal storage diseases. It is a form of sphingolipidosis (a subgroup of lysosomal storage diseases), as it involves dysfunctional metabolism of sphingolipids.
The disease is named after the French physician Philippe Gaucher, who originally described it in 1882.
== Signs and symptoms ==
Painless hepatomegaly and splenomegaly: the size of the spleen can be 1,500–3,000 g (3.3–6.6 lb), as opposed to the normal size of 50–200 g (0.11–0.44 lb). Splenomegaly may decrease the affected individual's capacity for eating by exerting pressure on the stomach. While painless, enlargement of the spleen increases the risk of splenic rupture.
Hypersplenism and pancytopenia, the rapid and premature destruction of blood cells, leads to anemia, neutropenia, leukopenia, and thrombocytopenia (with an increased risk of infection and bleeding).
Cirrhosis of the liver is rare.
Severe pain associated with joints and bones occurs, frequently presenting in hips and knees.
While Gaucher disease is a spectrum disorder, it can be split into Neuronopathic and non-neuronopathic forms. Neurological symptoms occur only in some types of Gaucher's (see below):
Type II: Seizures, hypertonia, developmental delay, difficulty swallowing, apnea and other brainstem function abnormalities.
Type III: muscle twitches known as myoclonus, seizures, slowed horizontal saccadic eye movement, and in some cases, cognitive impairment.
Parkinson's disease is recognized as being more common in Gaucher's disease patients and their heterozygous carrier relatives.
Osteoporosis: 75% of patients develop visible bony abnormalities due to the accumulated glucosylceramide. A deformity of the distal femur in the shape of an Erlenmeyer flask is commonly described.
Yellowish-brown skin pigmentation
== Genetics ==
The three types of Gaucher's disease are autosomal recessive. Both parents must be carriers for a child to be affected. If both parents are carriers, the chance of the disease is one in four, or 25%, with each pregnancy for an affected child.
Each type has been linked to particular mutations. In all, about 80 known GBA gene mutations are grouped into three main types:
Type I (N370S homozygote), the most common, also called the "non-neuropathic" type occurs mainly in Ashkenazi Jews, at 100 times the occurrence in the general populace. The median age at diagnosis is 28 years of age, and life expectancy is mildly decreased.
Type II (one or two alleles L444P) is characterized by neurological problems in small children. The enzyme is hardly released into the lysosomes. The prognosis is poor: most die before the age of three.
Type III (also one or two copies of L444P, possibly delayed by protective polymorphisms) occurs in Swedish patients from the Norrbotten region. This group develops the disease somewhat later, but most die before their 30th birthday.
The Gaucher-causing mutations may have entered the Ashkenazi Jewish gene pool in the early Middle Ages (48–55 generations ago).
== Pathophysiology ==
The disease is caused by a defect in the housekeeping gene for lysosomal glucocerebrosidase (also known as beta-glucosidase, EC 3.2.1.45, PDB: 1OGS) on the first chromosome (1q22). The enzyme is a 55.6-kilodalton, 497-amino acid-long protein that catalyses the breakdown of glucocerebroside, a cell membrane constituent of red and white blood cells. In Gaucher disease, the enzyme is unable to function correctly and glucocerebroside accumulates. The macrophages that clear these cells are unable to eliminate the waste product, which accumulates in fibrils and turn into 'Gaucher cells', which appear on light microscopy to resemble crumpled-up paper.
The exact mechanism of neurotoxicity is not understood, but it is thought to involve a reaction to glucosylsphingosine.
Different mutations in the GBA (beta-glucosidase) gene determine the remaining activity of the enzyme. In type I, there is some residual activity of the enzyme, accounting for the lack of neuropathology in this type. Although there is some correlation between genotype and phenotype, neither the amount of stored lipids nor the residual enzyme activity correlates well with disease symptoms. This circumstance has called for alternative explanations accounting for disease symptoms including
jamming of the endo/lysosomal system
ER stress
altered lipid composition of membranes throughout the cell, including the plasma membrane, and consequent changes in the dynamic and signaling properties of the cell membrane
inflammation caused by cytokine secretion as a result of sphingolipid accumulation, and neurodegeneration caused by the accumulation of glucosylsphingosine, a neurotoxin
Heterozygotes for particular acid beta-glucosidase mutations carry about a five-fold risk of developing Parkinson's disease, making this the most common known genetic risk factor for Parkinson's.
Cancer risk may be increased, particularly myeloma. This is thought to be due to accumulation of glucosylceramide and complex glycosphingolipids.
The role of inflammatory processes in Gaucher disease is poorly elucidated. However, sphingolipids are known to participate in inflammation and apoptosis, and markers of macrophage activation are elevated in people with Gaucher disease. These markers include angiotensin-converting enzyme, cathepsin S, chitotriosidase, and CCL18 in the blood plasma; and tumor necrosis factor alpha in splenic Gaucher cells (engorged macrophages).
== Diagnosis ==
Gaucher disease is suggested based on the overall clinical picture. Initial laboratory testing may include enzyme testing. As a result, lower than 15% of mean normal activity is considered to be diagnostic. Decreased enzyme levels will often be confirmed by genetic testing. Numerous different mutations occur; sequencing of the beta-glucosidase gene is sometimes necessary to confirm the diagnosis. Prenatal diagnosis is available and is useful when a known genetic risk factor is present.
A diagnosis can also be implied by biochemical abnormalities such as high alkaline phosphatase, angiotensin-converting enzyme, and immunoglobulin levels, or by cell analysis showing "crinkled paper" cytoplasm and glycolipid-laden macrophages.
Some lysosomal enzymes are elevated, including tartrate-resistant acid phosphatase, hexosaminidase, and a human chitinase, chitotriosidase. This latter enzyme has proved to be very useful for monitoring Gaucher's disease activity in response to treatment and may reflect the severity of the disease
=== Classification ===
Gaucher's disease (GD) has three common clinical subtypes. These subtypes have come under some criticism for not taking account of the full spectrum of observable symptoms (the phenotypes). Also, compound heterozygous variations occur which considerably increase the complexity of predicting disease course.
GD type I (non-neuropathic) is the most common and least severe form of the disease. Symptoms may begin early in life or adulthood and mainly affect the liver, spleen, and bone. Enlarged liver and grossly enlarged spleen (together hepatosplenomegaly) are common; the spleen can rupture and cause additional complications. Skeletal weakness and bone disease may be extensive. Spleen enlargement and bone marrow replacement cause anemia, thrombocytopenia, and leukopenia. The brain and nervous system are not affected pathologically, but lung and, rarely, kidney impairment may occur. Patients in this group usually bruise easily (due to low levels of platelets) and experience fatigue due to low numbers of red blood cells. Depending on disease onset and severity, type I patients may live well into adulthood. The range and severity of symptoms can vary dramatically between patients.
GD type II (acute infantile neuropathic) typically begins within six months of birth and has an incidence rate of around 1 in 100,000 live births. Symptoms include an enlarged liver and spleen, extensive and progressive brain damage, eye movement disorders, spasticity, seizures, limb rigidity, and a poor ability to suck and swallow. Affected children usually die by age two.
GD type III (chronic neuropathic) can begin at any time in childhood or even in adulthood and occurs in about 1 in 100,000 live births. It is characterized by slowly progressive, but milder neurologic symptoms compared to the acute or type II version. Major symptoms include an enlarged spleen and/or liver, seizures, poor coordination, skeletal irregularities, eye movement disorders, blood disorders including anemia, and respiratory problems. Patients often live into their early teen years and adulthood.
== Treatment ==
For those with type-I and most type-III, enzyme replacement treatment with intravenous recombinant glucocerebrosidase can decrease liver and spleen size, reduce skeletal abnormalities, and reverse other manifestations. This treatment costs about US$200,000 annually for a single person and should be continued for life. The rarity of the disease means dose-finding studies have been difficult to conduct, so controversy remains over the optimal dose and dosing frequency. Due to the low incidence, this has become an orphan drug in many countries, meaning a government recognizes and accommodates the financial constraints that limit research into drugs that address a small population.
The first drug for Gaucher's was alglucerase (Ceredase), which was a version of glucocerebrosidase that was harvested from human placental tissue and then modified with enzymes. It was approved by the FDA in 1991 and has been withdrawn from the market due to the approval of similar drugs made with recombinant DNA technology instead of being harvested from tissue; drugs made recombinantly are preferable since there is no concern about diseases being transmitted from the tissue used in harvesting, there are fewer risks of variations in enzyme structure from batch to batch, and they are less expensive to manufacture.
Available recombinant glucocerebrosidases are:
Imiglucerase (approved in 1995)
Velaglucerase (approved in 2010)
Taliglucerase alfa (Elelyso) (approved in 2012)
Miglustat is a small molecule, oral medication that was first approved for Gaucher's disease in Europe in 2002. It works by preventing the formation of glucocerebroside, the substance that builds up and causes harm in Gaucher's. This approach is called substrate reduction therapy.
Eliglustat (Cerdelga) (approved in 2014) is also a small molecule. The compound is believed to work by inhibition of glucosylceramide synthase.
== Epidemiology ==
The National Gaucher Foundation (United States) states the incidence of Gaucher's disease is about one in 20,000 live births. Around one in 100 people in the general US population is a carrier for type I Gaucher's disease, giving a prevalence of one in 40,000. Among Ashkenazi Jews, the rate of carriers is considerably higher, at roughly one in 15.
Type II Gaucher's disease shows no particular preference for any ethnic group.
Type III Gaucher's disease is especially common in the population of the northern Swedish region of Norrbotten, where the incidence of the disease is one in 50,000.
== History ==
The disease was first recognized by the French doctor Philippe Gaucher, who originally described it in 1882 and lent his name to the condition. In 1902, its mode of inheritance was discovered by Nathan Brill. The neuronal damage associated with the disease was discovered in the 1920s, and the biochemical basis for the disease was elucidated in the 1960s by Roscoe Brady. The first effective treatment for the disease, the drug alglucerase (Ceredase), was approved by the FDA in April 1991. An improved drug, imiglucerase (Cerezyme), was approved by the FDA in May 1994 and has replaced the use of Ceredase.
October is National Gaucher's Disease Awareness Month in the United States.
== Society and culture ==
=== Prominent people with disease ===
Wallace Chapman; New Zealand radio and television personality
Anne Begg; Scottish politician
== See also ==
== References ==
== External links ==
Gaucher Disease at NINDS | Wikipedia/Gaucher's_disease |
The Agency for Toxic Substances and Disease Registry (ATSDR) is a federal public health agency within the U.S. Department of Health and Human Services (HHS). The agency focuses on minimizing human health risks associated with exposure to hazardous substances. It works closely with other federal, state, and local agencies; tribal governments; local communities; and healthcare providers. Its mission is to "Serve the public through responsive public health actions to promote healthy and safe environments and prevent harmful exposures." ATSDR was created as an advisory, nonregulatory agency by the Superfund legislation and was formally organized in 1985.
Although ATSDR is an independent operating agency within HHS, the Centers for Disease Control and Prevention (CDC) performs many of its administrative functions. The CDC director also serves as the ATSDR administrator, and ATSDR has a joint Office of the Director with the National Center for Environmental Health (NCEH). The ATSDR headquarters are located in Atlanta, Georgia, at the CDC Chamblee campus. In fiscal year 2010, ATSDR had an operating budget of $76.8 million and had roughly 300 full-time employees (not including contractors).
The ATSDR is formally and administratively overseen by the Director of the Centers for Disease Control and Prevention (CDC), currently Mandy Cohen since July 10, 2023 Direction is provided by ATSDR's Director, currently Patrick N. Breysse, who ranks below the Administrator, and ATSDR's Associate Director, currently Christopher M. Reh.
As part of the announced 2025 HHS reorganization, ATSDR is planned to be integrated into the new Administration for a Healthy America.
== Overview ==
ATSDR is an agency within the US Department of Health and Human Services concerned with the effects of hazardous substances on human health. ATSDR is charged with assessing the presence and nature of health hazards at specific Superfund sites, as well as helping prevent or reduce further exposure and the illnesses that can result from such exposures. ATSDR is an oversight agency created to ensure that public health protection and environmental regulation work hand in hand.
ATSDR functions include public health assessments of National Priority List (NPL or Superfund) hazardous waste sites; petitioned health consultations or assessments concerning specific waste sites or industrial facilities that US citizens have requested further action upon; the conduct of health studies (including surveillance and registries) to determine the long-term impact of these facilities; response to emergency releases of hazardous substances, applied research in support of public health assessments, information development and dissemination, and education and training concerning hazardous substances. ATSDR also prepares toxicological profiles for hazardous substances found at National Priorities List sites, as well as at federal sites administered by the Department of Defense and Department of Energy.
== Goals ==
ATSDR has seven goals:
Protect the public from environmental hazards and toxic exposures.
Promote healthy environments.
Advance the science of environmental public health.
Support environmental public health practice.
Educate communities, partners, and policy makers about environmental health risks and protective measures.
Promote environmental justice and reduce health disparities associated with environmental exposures.
Provide unique scientific and technical expertise to advance public health science and practice.
== Authority ==
Unlike the Environmental Protection Agency (EPA), ATSDR is an advisory, nonregulatory agency. ATSDR conducts research on the health impacts of hazardous waste sites and provides information and recommendations to federal and state agencies, community members, and other interested parties. However, ATSDR is not involved in cleanup of those sites, nor can ATSDR provide or fund medical treatment for people who have been exposed to hazardous substances.
== History ==
In response to the environmental disasters at Love Canal and Times Beach, Missouri, Congress passed the Comprehensive Environmental Response, Compensation, and Liability Act of 1980 (CERCLA), commonly known as the Superfund legislation. CERCLA gave EPA primary responsibility for identifying, investigating, and cleaning up hazardous waste sites. CERCLA also authorized the establishment of ATSDR to assess the presence and nature of health hazards to communities living near Superfund sites, to help prevent or reduce harmful exposures, and to expand the knowledge base about the health effects that result from exposure to hazardous substances.
A 1982 lawsuit litigated by Chemical Manufacturers Association and the American Petroleum Institute forced the creation of ATSDR, which was created as an agency under the Department of Health and Human Services on April 19, 1983. James O. Mason served as the agency's first administrator. The Hazardous and Solid Waste Amendments of 1984 to the Resource Conservation and Recovery Act (RCRA) gave ATSDR additional authority related to hazardous waste storage facilities. ATSDR was charged with conducting public health assessments at these sites when requested by EPA, states, or individuals, as well as assisting EPA to determine which substances should be regulated and the levels at which chemicals may pose a threat to human health. ATSDR was formally organized as an agency on June 11, 1985. The Superfund Amendments and Reauthorization Act of 1986 (SARA) broadened ATSDR's responsibilities in the areas of public health assessments, establishment and maintenance of toxicological databases, information dissemination, and medical education.
In 2003, the position of assistant administrator was replaced with a director who is shared with NCEH.
== Organization ==
=== Administration ===
CDC Director Mandy Cohen serves concurrently/ex officio as ATSDR administrator and CDC director, heading the Office of the Administrator. Patrick N. Breysse, PhD. serves as director of NCEH/ATSDR, heading the Office of the Director. The ATSDR administrator/CDC director, who provides overall leadership of the agency, is appointed by the president of the United States; the appointment does not require Senate approval. The ATSDR administrator appoints the NCEH/ATSDR director, who is responsible for managing the agency's programs and activities.
=== Organizational structure ===
Office of the Administrator (also CDC Director)
Office of the Director (also NCEH (National Center for Environmental Health) head)
Office of Communications
Office of Science
Office of Management and Analytics
Office of Policy, Partnerships, and Planning
Office of the Associate Director
Office of Innovation and Analytics (OIA)
Office of Community Health Hazard Assessment (OCHHA)
Office of Capacity Development and Applied Prevention Science (OCDAPS)
The Office of the Director (of ASTDR) is joint with that of NCEH; it also contains seven functional units, five offices, five program-specific divisions to support and implement six program areas:
Public Health Assessments
Toxicological Profiles
Emergency Response
Exposure and Disease Registries
Health Effects Research
Health Education
=== Regional offices ===
The Division of Community Health Investigations manages an office in Washington, D.C., as well as offices in each of the 10 EPA regions:
Boston (Region 1: Connecticut, Maine, Massachusetts, New Hampshire, Rhode Island, Vermont)
New York and Edison, New Jersey (Region 2: New Jersey, New York, Puerto Rico, U.S. Virgin Islands)
Philadelphia (Region 3: Delaware, District of Columbia, Maryland, Pennsylvania, Virginia, West Virginia)
Atlanta (Region 4: Alabama, Florida, Georgia, Kentucky, Mississippi, North Carolina, South Carolina, Tennessee)
Chicago (Region 5: Illinois, Indiana, Michigan, Minnesota, Ohio, Wisconsin)
Dallas (Region 6: Arkansas, Louisiana, New Mexico, Oklahoma, Texas)
Kansas City, Kansas (Region 7: Iowa, Kansas, Missouri, Nebraska)
Denver and Helena, Montana (Region 8: Colorado, Montana, North Dakota, South Dakota, Utah, Wyoming)
San Francisco (Region 9: American Samoa, Arizona, California, Guam, Hawaii, Nevada, Northern Mariana Islands, Trust Territories)
Seattle and Anchorage, Alaska (Region 10: Alaska, Idaho, Oregon, Washington)
The regional offices work cooperatively with EPA, state and local health departments, health professionals, community groups, and other partners to implement programs and initiatives.
== Programs ==
=== Public health assessments and health consultations ===
One of ATSDR's primary responsibilities is conducting public health assessments and health consultations. The agency conducts public health assessments for all current or proposed sites on the National Priorities List (commonly known as Superfund sites). The purpose of public health assessments is to examine whether hazardous substances at a site pose a human health hazard and to issue recommendations about limiting or stopping exposure to those substances. ATSDR also conducts health consultations, often in response to requests from EPA and state and local agencies. Health consultations examine specific health questions, such as the health effects of exposure to a specific chemical at a site. Health consultations are more limited in scope than public health assessments. ATSDR also conducts public health assessments and health consultations in response to petitions from members of the public. To conduct public health assessments and health consultations, ATSDR relies on its own scientists or establishes cooperative agreements with states, providing technical assistance to state health departments. ATSDR issued more than 200 public health assessments in 2009 and provides about 1,000 health consultations each year.
When investigating sites, ATSDR examines environmental data, health data, and information from community members about how the site affects their quality of life. ATSDR normally does not collect its own environmental data; rather, it usually relies on partner organizations, such as EPA, to conduct testing and gather data. This environmental data provides information on the amount of contamination and possible ways humans could be exposed to the hazardous substances at the site. The health data provides information on rates of illness, disease, and death in the local community. Since ATSDR is an advisory agency, the conclusions in its public health assessments and health consultations are often in the form of recommendations to state and national environmental and health agencies, such as EPA, that have regulatory authority. Other agencies and the general public rely on ATSDR to provide trusted information on the health effects of hazardous substances at contaminated sites.
=== Toxicology research ===
Another major responsibility of ATSDR is producing toxicological profiles for the most common substances that are found at Superfund sites. The toxicological profiles summarize important studies on the substances' health effects. ATSDR also publishes ToxFAQs, ToxGuides, and public health statements, which summarize the health information in toxicological profiles for use by the general public and health professionals. The agency maintains a Toxic Substances Portal that compiles all of the agency's toxicology information and allows users to search by chemical. ATSDR has published toxicological profiles for more than 250 hazardous substances.
ATSDR has a computational toxicology laboratory that conducts research and modeling on the effects of toxic substances on human health. The agency's toxicology work involves pharmacokinetic/pharmacodynamic modeling, quantitative structure–activity relationship methods, and benchmark dose modeling, as well as establishing minimal risk levels for human exposure to hazardous substances. One model developed by the toxicology laboratory showed that children were much more susceptible than adults to chemical exposure from inhalation and oral exposure. In the aftermath of chemical spills and emergencies, the laboratory also conducts research for state and local health departments on the health effects of the chemicals involved.
=== Health registries ===
ATSDR maintains registries of people who were exposed to certain toxic substances or have certain diseases. Participation in these registries is voluntary, and individual data and personal information is kept private. The information collected is used by epidemiologists and other researchers to examine long-term health outcomes or risk factors for illness. It can also help doctors diagnose those health conditions in other individuals and treat them earlier. The agency also uses registries to contact registered individuals with important health information.
==== Tremolite Asbestos Registry ====
The Tremolite Asbestos Registry contains people who lived in or worked in Libby, Montana, while vermiculite was mined there; these people were at risk for exposure to the tremolite asbestos that was naturally occurring in the vermiculite. ATSDR began addressing public health concerns in Libby in 1999 and created the registry in 2004. The purpose of the registry was to monitor the long-term health effects of people in Libby exposed to tremolite asbestos and to assist with communicating important health information to registrants. Researchers have used the registry to study how asbestos exposure affects human health. This research has yielded several important findings. Registry data was used to conduct the first study of the relationship between asbestos exposure and respiratory problems in children. Another study using registry data found a significant relationship between asbestos exposure and death from cardiovascular disease.
==== World Trade Center Health Registry ====
The World Trade Center Health Registry was established in 2002 by ATSDR and the New York City Department of Health and Mental Hygiene to track the long-term physical and mental health effects of the September 11 attacks. The registry contains more than 71,000 people who lived, worked, or went to school near the World Trade Center site, as well as emergency response personnel who were involved in rescue and recovery efforts. It is the largest post-disaster health registry in the United States. Researchers use the registry to study the health effects of the disaster and to develop public health recommendations for future disasters. A 2009 study based on registry data found that posttraumatic stress disorder and asthma were the two most commonly reported conditions among registry participants five to six years after the disaster. The study found that 19% of adult participants reported new posttraumatic stress symptoms, and 10% of adult participants reported developing new asthma.
==== ALS Registry ====
As of 2008, ATSDR is starting a new registry for people with amyotrophic lateral sclerosis (also known as ALS or Lou Gehrig's Disease). President George W. Bush signed the ALS Registry Act, which provided for establishment of the registry, on October 8, 2008. It is hoped that the registry will provide information on the prevalence of ALS and lead to a better understanding of factors that may be associated with the disease. The agency began registering people for the registry on October 20, 2010.
=== Surveillance ===
ATSDR conducts surveillance by maintaining projects to collect and analyze information on diseases and chemical exposures. Research using that information and data can then be used to prevent future and control injury, disease, and death.
==== Hazardous Substances Emergency Events Surveillance Program ====
One of the most notable surveillance projects was the Hazardous Substances Emergency Events Surveillance (HSEES) program, which lasted from 1990 to 2009. ATSDR partnered with 15 states to collect information for HSEES in order to track, report, and study chemical spills. The information in the HSEES system was used to plan for emergency events involving hazardous substances (including terrorist attacks). States also used the information to develop policies and programs to strengthen public health and reduce illnesses and deaths that can result from exposure to hazardous substances. For example, states used HSEES data to support legislation addressing the problem of hazardous chemicals at illegal methamphetamine labs. Other states used HSEES data to implement programs designed to minimize exposure to hazardous chemicals and mercury at schools. More than 50 published studies were conducted using HSEES data.
==== National Toxic Substance Incidents Program ====
As a successor to the HSEES program, ATSDR launched the National Toxic Substance Incidents Program (NTSIP) in 2009. One aspect of NTSIP is a national database of information related to chemical spills. NTSIP also has Assessment of Chemical Exposure teams to assist state and local health departments in the aftermath of toxic spills. These teams interview people who were exposed to the hazardous substances and collect samples to test the level of contamination in the environment and in people.
=== Emergency response ===
ATSDR represents the Department of Health and Human Services on the National Response Team and works with other agencies to provide technical assistance during emergencies involving hazardous substances, such as chemical spills. In July 2007, for example, ATSDR responded to the Verdigris River flood in Coffeyville, Kansas, after an oil refinery spilled crude oil into the floodwaters, contaminating many homes in the city. ATSDR worked with EPA and state and local authorities to provide health information to local residents and advised those agencies during the clean-up process. ATSDR also assists with responding to terrorism incidents, which have included the September 11 attacks and the 2001 anthrax attacks. ATSDR responded to 132 chemical emergency events in 2008.
In addition to working with communities and other agencies in the aftermath of chemical emergencies, ATSDR has developed the Managing Hazardous Materials Incidents series, which includes several tools to assist emergency medical services personnel and hospital emergency departments during chemical emergencies. This includes important information on emergency planning, emergency response, and rescuer protection. Another tool is the Medical Management Guidelines, which summarize important information on exposure to common chemicals and provide suggestions for safely treating and decontaminating patients.
=== Brownfield/land reuse initiative ===
ATSDR works closely with communities to evaluate the public health effects related to redevelopment of brownfields properties. These are sites that were formerly used for industrial purposes and may still be contaminated with hazardous substances. ATSDR has worked at more than 400 brownfield or land reuse sites to assess health effects of potential exposure to hazardous substances. The agency has created resources to provide guidance to communities when planning redevelopment projects, including tools to evaluate the potential threat of chemicals at development sites. In addition to evaluating the health effects of contamination at specific brownfield sites, ATSDR encourages communities to monitor community health. One of the agency's brownfields projects was the Menomonee Valley in Milwaukee, Wisconsin, where the agency evaluated potential health effects of contamination at the site and worked closely with developers and the city.
=== Community partnerships ===
A major focus of the work ATSDR does involves interacting with communities. ATSDR often establishes partnerships with state and local health departments to assist them with their public health duties. In 2008, ATSDR had cooperative agreements with 29 states and one tribal government, providing technical assistance to help those partners address local environmental health concerns. ATSDR also creates community assistance panels to solicit feedback and community health concerns from local residents when the agency works at sites to evaluate health effects resulting from exposure to toxic substances.
=== National Conversation on Public Health and Chemical Exposures ===
In June 2009, ATSDR and NCEH launched a joint project, the National Conversation on Public Health and Chemical Exposures. The goal of the National Conversation is to develop recommendations for ways ATSDR and other government agencies can improve their efforts to protect the public from harmful chemical exposures. To foster a productive dialogue, ATSDR encouraged broad public participation in the National Conversation and welcomed involvement from all interested stakeholders, including government agencies, public health professionals, environmental organizations, community leaders, business and industry representatives, tribal groups, and other interested citizens. The National Conversation is led by a 40-person Leadership Council that includes experts in various areas related to environmental public health. In addition, there are six work groups, which also have a diverse membership, to research and propose recommendations on certain key areas. To encourage involvement from community groups, interested citizens, and the general public, ATSDR developed a community toolkit to assist community leaders in holding discussions to solicit feedback and ideas for the National Conversation. ATSDR plans to release its final action agenda in early 2011.
== Quality of work ==
ATSDR prides itself on using "the best science." And in 2003, BBC News described ATSDR as "widely regarded as the world's leading agency on public health and the environment."
However, ATSDR has also been the focus of scrutiny from Congress and other groups. Much of the criticism is due to the fact that the agency has been overtasked yet understaffed and underfunded for much of its history.
In August 1991, the General Accounting Office (now the Government Accountability Office) published a report that faulted the quality of ATSDR's original public health assessments and questioned their usefulness. It also placed part of the blame on the deadlines and requirements that Congress imposed with SARA: "SARA’s requirement that ATSDR quickly assess 951 Superfund sites came at a time when the agency was still relatively new and ... not staffed or organized for the job." The report also noted that after meeting the SARA deadline, ATSDR was able to increase the rigor of its public health assessments.
In May 1992, the Environmental Health Network and the National Toxics Campaign Fund published "Inconclusive by Design," a report which noted structural limitations to the work of CDC and ATSDR.
In April 2008, the United States House of Representatives Committee on Science and Technology Subcommittee on Investigations and Oversight held a hearing on formaldehyde exposures in trailers that the Federal Emergency Management Agency (FEMA) provided as temporary housing to people displaced by Hurricane Katrina. A report based on the hearing, issued by the subcommittee's Democratic majority staff in September 2008, noted shortcomings in the agency’s original health consultation that examined the health risks of formaldehyde in the FEMA trailers.
In March 2009, the Democratic majority staff of the Subcommittee on Investigations and Oversight issued another report on ATSDR, which called for leadership changes within the agency. The report stated: "Time and time again ATSDR appears to avoid clearly and directly confronting the most obvious toxic culprits that harm the health of local communities throughout the nation. Instead, they deny, delay, minimize, trivialize or ignore legitimate concerns and health considerations of local communities and well respected scientists and medical professionals."
In the March 12, 2009, congressional hearing, the subcommittee chairman, Congressman Brad Miller, characterized ATSDR as keen to "please industries and government agencies" and referred to ATSDR's reports as "jackleg assessments saying 'not to worry.'" In defense of ATSDR's work, director Howard Frumkin noted that ATSDR's staff has declined from 500 to about 300, and that often communities expect "definitive answers about the links between exposures and illnesses," but expectations can be unmet due to scientific uncertainty. However, Frumkin also acknowledged the possibility that some assessments did not use the best data or monitoring techniques.
=== Vieques, Puerto Rico ===
In 2003, ATSDR released public health assessments that evaluated the potential health effects of pollution left behind by the United States Navy in Vieques, Puerto Rico. The public health assessments noted that residents of the island were exposed to environmental contamination at such low levels that no harmful health effects were expected, and the agency concluded that there was "no apparent public health hazard." In 2009, however, ATSDR announced that it had identified gaps in environmental data and planned to take a "fresh look" at Vieques by reviewing studies on the island.
=== West Lake Landfill, Missouri ===
In 2015, ATSDR released a report, based on EPA data, declaring no health risk to communities near West Lake Landfill. The agency's assessment contradicted findings from scientific investigations initiated by the Missouri attorney general and affected residents, who started organizing in 2012 when an underground fire in the landfill raised awareness of radioactive material and high rates of childhood cancer. Republic Services, one of the parties responsible for the landfill, has cited the report to argue against the removal of toxic waste.
== See also ==
Centers for Disease Control and Prevention
List of Superfund sites in the United States
National Priorities List
TOXMAP
United States Department of Health and Human Services
United States Navy in Vieques, Puerto Rico
== References ==
== External links ==
ATSDR website
Agency for Toxic Substances and Disease Registry in the Federal Register
World Trade Center Health Registry
National Priorities List
Why CDC Responded with 'Lack of Urgency' to Formaldehyde Warnings | Wikipedia/Agency_for_Toxic_Substances_and_Disease_Registry |
Risk Evaluation and Mitigation Strategies (REMS) is a program of the US Food and Drug Administration for the monitoring of medications with a high potential for serious adverse effects. REMS applies only to specific prescription drugs, but can apply to brand-name or generic drugs. The REMS program was formalized in 2007.
The FDA determines as part of the drug approval process that a REMS is necessary, and the drug company develops and maintains the individual program. REMS applies only to specific prescription drugs, but can apply to brand-name or generic drugs. REMS for generic drugs may be created in collaboration with the manufacturer of the brand-name drug. The FDA may remove the REMS requirement if it is found to not improve patient safety.
The REMS program developed out of previous systems dating back to the 1980s for monitoring the use of a small number of high-risk drugs such as isotretinoin, which causes serious birth defects; clozapine, which can cause agranulocytosis; and thalidomide, which is used to treat leprosy and certain cancers but causes serious birth defects. The 2007 Food and Drug Administration Amendments Act created section 505-1 of the Food, Drug, and Cosmetic Act, which allowed for the creation of the REMS program for applying individual monitoring restrictions to medications.
Some of the provisions required by the REMS program are training and certification of physicians allowed to prescribe the drug, requiring that the drug be administered in a hospital setting, requiring pharmacies to verify the status of patients receiving REMS drugs, requiring lab testing of patients to ensure that health status is satisfactory, or requiring that patients be entered into a registry.
== Usage ==
As of 2018, there are 74 medications subject to REMS monitoring.
62% of these include "elements to assure safe use". These typically require clinicians or healthcare institutions to become certified prior to prescribing. 12% include only a "communication plan" REMS element, which is informational in nature. These communication plans are typically composed of letters, websites, and fact sheets describing the specific safety risks identified in the REMS. 26% include only the "medication guide" REMS element.
== Communication aspect ==
In 2020, clinical settings enrolled in the REMS program asked the FDA to make their reviews of REMS compliance public so that they can more easily view the records and adjust to feedback.Between 2014 and 2017, the FDA stated they did not have enough data to determine whether the REMS program was sufficiently preventing opioid abuse.The Health and Human Services Office of the Inspector General recommended that parties in the REMS program provide the FDA more data.The FDA was habitually late in evaluating that data, reportedly leaving those parties with inadequate time to react to the review before their next assessment. In November 2020, the FDA planned to create a "Summary of the REMS Assessment" document that would publicize their assessments of clinical settings and manufacturers in the REMS program. The FDA made a public request for comment on the idea of publishing the Summary of the REMS Assessment. Without the publication of the summary, parties in the REMS program must request it using the Freedom of Information Act.
== References == | Wikipedia/Risk_Evaluation_and_Mitigation_Strategies |
Numerous governmental and non-governmental organizations have criticized the U. S. Food and Drug Administration for alleged excessive and/or insufficient regulation. The U.S. Food and Drug Administration (FDA) is an agency of the United States Department of Health and Human Services and is responsible for the safety regulation of most types of foods, dietary supplements, drugs, vaccines, biological medical products, blood products, medical devices, radiation-emitting devices, veterinary products, and cosmetics. The FDA also enforces section 361 of the Public Health Service Act and the associated regulations, including sanitation requirements on interstate travel as well as specific rules for control of disease on products ranging from animals sold as pets to donations of human blood and tissue.
A $1.8 million 2006 Institute of Medicine report on pharmaceutical regulation in the U.S. found major deficiencies in the FDA system for ensuring the safety of drugs on the American market. Overall, the authors called for an increase in the regulatory powers, funding, and independence of the FDA.
== Charges of over-regulation ==
A group of critics claim that the FDA possesses excessive regulatory authority.
=== Alleged problems in the drug approval process ===
The economist Milton Friedman has claimed that the regulatory process is inherently biased against approval of some worthy drugs, because the adverse effects of wrongfully banning a useful drug are undetectable, while the consequences of mistakenly approving a harmful drug are highly publicised and that therefore the FDA will take the action that will result in the least public condemnation of the FDA regardless of the health consequences.
Friedman and others have argued that delays in the approval process have cost lives. The thalidomide birth defects crisis led to passage of the 1962 Kefauver Harris Amendment, which required proof of efficacy in addition to safety for approval of new drugs — despite the fact that the thalidomide crisis was entirely a safety issue. Proving efficacy is much more expensive and time-consuming than proving safety. By requiring proof of efficacy in addition to safety, the Kefauver Harris Amendment added considerable cost and delay to the drug approval process — which critics say may well have cost many more lives than it was said to save. Prior to passage of the Kefauver Harris Amendment, the average time from the filing of an investigational new drug application (IND) to approval was 7 months. By 1998, it took an average of 7.3 years from the date of filing to approval. Prior to the 1990s, the mean time for new drug approvals was shorter in Europe than in the United States, although that difference has since disappeared.
Concerns about the length of the drug approval process were brought to the fore early in the AIDS epidemic. In the late 1980s, ACT-UP and other HIV activist organizations accused the FDA of unnecessarily delaying the approval of medications to fight HIV and opportunistic infections, and staged large protests, such as a confrontational October 11, 1988, action at the FDA campus which resulted in nearly 180 arrests. In August 1990, Louis Lasagna, then chairman of a presidential advisory panel on drug approval, estimated that thousands of lives were lost each year due to delays in approval and marketing of drugs for cancer and AIDS. Partly in response to these criticisms, the FDA introduced expedited approval of drugs for life-threatening diseases and expanded pre-approval access to drugs for patients with limited treatment options. All of the initial drugs approved for the treatment of HIV/AIDS were approved through accelerated approval mechanisms. For example, a "treatment IND" was issued for the first HIV drug, AZT, in 1985, and approval was granted 2 years later, in 1987. Three of the first 5 HIV medications were approved in the United States before they were approved in any other country.
=== Allegations that FDA regulation causes higher drug prices ===
Studies published in 2003 by Joseph DiMasi and colleagues estimated an average cost of approximately $800 million to bring a new drug to market, while a 2006 study estimated the cost to be anywhere from $500 million to $2 billion. The consumer advocacy group Public Citizen, using a different methodology, estimated the average cost for development to be under $200 million, about 29% of which is spent on FDA-required clinical trials. DiMasi rejects the claim that high R&D costs alone are responsible for high drug prices. Instead, in a published letter, DiMasi writes, "...longer development times increase R&D costs and shorten the period during which drug companies can earn the returns they need to make investment financially viable. Other things being equal, longer development times reduce innovation incentives. As a consequence, fewer new therapies might be developed."
Economist Gary S. Becker, who won the Nobel Memorial Prize in Economics, has argued that FDA-required clinical trials for new drugs do contribute to high drug prices for consumers, mainly because of patent protection that provides a temporary monopoly which disallows cheaper alternatives from entering the market. He advocates dropping many FDA requirements, many of which provide no additional safety or valuable information, as this would hasten the development of new drugs, because they would be faster to bring to market, thereby increasing supply, and as a consequence would lead to lower prices.
== Charges of under-regulation ==
In addition to those who see the FDA as a source of excessive regulation, other critics believe that the FDA does not regulate some products strictly enough. According to this view, the FDA allows unsafe drugs on the market because of pressure from pharmaceutical companies, fails to ensure safety in drug storage and labeling, and allows the use of dangerous agricultural chemicals, food additives, and food processing techniques.
A $1.8 million 2006 Institute of Medicine report on pharmaceutical regulation in the U.S. found major deficiencies in the current FDA system for ensuring the safety of drugs on the American market. Overall, the authors called for an increase in the regulatory powers, funding, and independence of the FDA.
=== Allegations that the FDA covered up exportation of unsafe products ===
In the 1980s, Cutter Laboratories introduced a heat-treated version of Factor VIII concentrate in the US, designed to eliminate the risk of HIV transmission. However, Cutter continued to market the untreated product overseas, potentially spreading HIV while the safer product was marketed in the US.
Cutter initially had a voluntary agreement with the FDA to stop marketing the untreated product. However, when it became clear that Cutter was not complying with the agreement, the FDA ordered the company to cease marketing untreated blood products, stating: "It was unacceptable for them to ship that material overseas." At the same time, the FDA, according to Cutter's internal documents, asked that the issue be "quietly solved without alerting the Congress, the medical community and the public", leading to charges that the FDA was complicit in covering up Cutter's actions.
=== Allegations that unsafe drugs are approved ===
Some critics believe that the FDA has been apt to overlook safety concerns in approving new drugs, and is slow to withdraw approved drugs once evidence shows them to be unsafe. Rezulin (troglitazone) and Vioxx (rofecoxib) are high-profile examples of drugs approved by the FDA which were later withdrawn from the market for posing unacceptable risks to patients.
Troglitazone is a diabetes drug that was also available abroad at the time the FDA approved it. Post-marketing safety data indicated that the drug had dangerous side-effects (in this case liver failure). The drug was pulled off that market in the UK in 1997, but was not withdrawn by the FDA until 2000, before which time it is claimed that thousands of Americans were injured or killed by the drug.
In the case of Vioxx, a pre-approval study indicated that a group taking the drug had four times the risk of heart attacks when compared to another group of patients taking another anti-inflammatory, naproxen. The FDA approval board accepted the manufacturer's argument that this was due to a previously unknown cardioprotective effect of naproxen, rather than a risk of Vioxx, and the drug was approved. In 2005, the results of a randomized, placebo-controlled study showed that Vioxx users suffered a higher rate of heart attacks and other cardiovascular disorders than patients taking no medication at all. The manufacturer, Merck, withdrew the drug after disclosures that it had withheld information about its risks from doctors and patients for over five years, resulting in between 88,000 and 140,000 cases of serious heart disease of which roughly half died. David Graham, a scientist in the Office of Drug Safety within the CDER, testified to Congress that he was pressured by his supervisors not to warn the public about dangers of drugs like Vioxx. He argued that an inherent conflict of interest exists when the office responsible for post-approval monitoring of drug safety is controlled by the same organization which initially approved those same drugs as safe and effective. He said that after testifying against Vioxx, he was "marginalized by FDA management and not asked to participate in the evaluation of any new drug safety issues. It's a type of ostracism." In a 2006 survey sponsored by the Union of Concerned Scientists, almost one-fifth of FDA scientists said they "have been asked, for non-scientific reasons, to inappropriately exclude or alter technical information or their conclusions in an FDA scientific document."
=== Allegations that unsafe food additives and processing technologies are approved ===
Food safety advocates have criticized the FDA for allowing meat manufacturers to use carbon monoxide gas mixtures during the packaging process to prevent discoloration of meat, a process that may hide signs of spoilage from the consumer.
The FDA has been criticised for allowing the use of recombinant bovine growth hormone (rBGH) in dairy cows. rBGH-treated cows secrete higher levels of insulin-like growth factor 1 (IGF-1) in their milk than do untreated cows. IGF-1 signalling is thought to play a role in sustaining the growth of some tumors, although there is little or no evidence that exogenously absorbed IGF could promote tumor growth. The FDA approved rBGH for use in dairy cows in 1993, after concluding that humans drinking such milk were unlikely to absorb biologically significant quantities of bovine IGF-1. A 1999 report of the European Commission Scientific Committee on Veterinary Measures relating to Public Health noted that scientific questions persist regarding the theoretical health risks of milk from rBGH-treated cows, particularly for feeding to infants. Since 1993, all EU countries have maintained a ban on rBGH use in dairy cattle.
The FDA has also been criticised for permitting the routine use of antibiotics in healthy domestic animals to promote their growth, a practice which allegedly contributes to the evolution of antibiotic-resistant strains of bacteria.
The FDA has taken recent steps to limit the use of antibiotics in farm animals. In September 2005, the FDA withdrew approval for the use of the fluoroquinolone antibiotic enrofloxacin (trade name Baytril) in poultry, out of concern that this practice could promote bacterial resistance to important human antibiotics such as ciprofloxacin.
The FDA has received criticism for its approval of certain coal tar derived food dyes such as FDC yellow 5 and 6, which are banned in most European countries. On September 6, 2007, the British Food Standards Agency revised advice on certain artificial food additives, including tartrazine.
Professor Jim Stevenson from Southampton University and author of the report said: "This has been a major study investigating an important area of research. The results suggest that consumption of certain mixtures of artificial food colours and sodium benzoate preservative are associated with increases in hyperactive behaviour in children.
The following additives were tested in the research:
Sunset yellow (FD&C Yellow #6) – Reddish-yellow coloring used in many foods and cosmetics
Carmoisine – Red coloring used in jellies
Tartrazine (FD&C Yellow #5) – Yellow coloring
Ponceau 4R – Red coloring
Sodium benzoate – Preservative
Quinoline yellow – Food coloring
Allura red AC (FD&C Red #40) – Orange / red food dye
On April 10, 2008, the Food Standards Agency called for a voluntary removal of the colors (but not sodium benzoate) by 2009. In addition, it recommended that there should be action to phase them out in food and drink in the European Union (EU) over a specified period.
UK ministers have agreed that the six colorings will be phased out by 2009. A Japanese group found in 1987 that tartrazine was not carcinogenic after being fed to mice for two years.
A German group found in 1989 that Sunset Yellow did not induce mutations that could lead to cancer in laboratory animals.
The FDA has also been criticized for giving permission for cloned animals to be sold as food without any special labeling, although "cloned products may not reach the U.S. market for years." and "Authorities lack the authority to require labeling of products from cloned animals."
In August 2013, a study released by The Pew Charitable Trusts found that of the 8105 additives that the FDA allows in food only 19% (1367) have toxicology information.
== Charges of FDA bias ==
=== Allegations of undue pharmaceutical industry influence ===
==== Pressure to allow pharmaceuticals ====
After his resignation, from his post as Commissioner of the Food and Drugs Administration in December 1969, Dr. Herbert L. Ley, Jr. In an interview to The New York Times, warned the public about the FDA's inability to safeguard consumers. People were being misled, he believed “The thing that bugs me is that the people think the FDA is protecting them - it isn't. What the FDA is doing and what the public thinks it's doing are as different as night and day,” he said. The agency, in his opinion, did not have the motivation to protect consumers, faced budget shortfalls, and lacked support from the Department of Health, Education, and Welfare. Dr. Ley was critical of Congress, the Administration and the drug industry, stating that he had "constant, tremendous, sometimes unmerciful pressure" from the drug industry, and that the drug company lobbyists, combined with the politicians who worked on behalf of their patrons, could bring “tremendous pressure” to bear on him and his staff, to try preventing FDA restrictions on their drugs. Ley stated that the entire issue was about money, “pure and simple”. On December 15, 1999, interviewed for the oral history program of the FDA History Office, Dr. Ley shared that from the first controversy in his tenure as FDA Commissioner he had a "gut feeling" that his life expectancy at the FDA was probably limited. He said he had done everything by the book, both in the FDA and the Department of Health, Education, and Welfare, and he thinks that what the Administration was really wishing, was that he would stonewall the whole Academy report because it was goring too many pharmaceutical companies.
==== Viewing the pharmaceutical industry as FDA clients ====
In a 2005 interview, Dr. David Graham, associate director of the FDA's Office of Drug Safety, stated that "FDA is inherently biased in favor of the pharmaceutical industry. It views industry as its client, whose interests it must represent and advance. It views its primary mission as approving as many drugs it can, regardless of whether the drugs are safe or needed"
The Prescription Drug User Fee Act allows the FDA to augment its budget by charging fees to pharmaceutical firms. Over $800 million was collected from 1993 to 2001 and rising each year. It also has been shown that oftentimes, the FDA expert advisory panels had direct financial interests in the drugs or products being evaluated. Former Editor of The New England Journal of Medicine, Marcia Angell, has stated that "It's time to take the Food and Drug Administration back from the drug companies.... In effect, the user fee act put the FDA on the payroll of the industry it regulates. Last year, the fees came to about $300 million, which the companies recoup many times over by getting their drugs to market faster." Critics have disputed the claim that the Prescription Drug User Fee Amendment has improved the speed of drug approvals.
On April 14, 2017, House and Senate leaders announced a bipartisan agreement to extend the FDA's ability to collect high user fees from drug companies and medical device manufacturers. This allows the FDA to charge huge licensing fees to drug manufacturers, which has led to enormous increases in generic drug pricing. In 2013 and 2014, generic drug pricing for over 200 drugs increased over 100%. Many of those drugs had price hikes over 1000%. It has been reported that 75% of the FDA generic drug oversight budget comes directly from private drug companies.
==== Bias toward more expensive drug ====
A historical example of how the FDA seemingly favors the pharmaceutical industry either from clandestine direct money payments to FDA directors and scientific advisers or other undisclosed or unknown means was seen with the generic drug droperidol. Droperidol was a widely used antiemetic used perioperatively safely for over 30 years. During that time there had never been a case reported in peer-reviewed medical literature of cardiac arrhythmias or cardiac issues when given at doses typically used for post-operative nausea and vomiting. Nonetheless, and without warning, in 2001 the FDA issued a black box warning regarding QTc prolongation (a dangerous finding on an ECG which can lead to cardiac arrest) with the use of droperidol. This effectively killed the common use of droperidol and made way for heavy usage of the much more expensive non-generic 5-HT3 serotonin receptor antagonists on the market even though these newer drugs had also been shown to prolong QTc as much, if not more than droperidol. In addition, each of the 5-HT3 antagonists available at that time had peer-reviewed reports of causing significant cardiac abnormalities, and in some cases, death. Despite an apparent discrepancy that deeply concerned the anesthesia and emergency room physician community, the FDA persisted in keeping the black box warning, while at the same time did not place any restrictions on the more expensive 5-HT3 antagonists. However, D2 antagonists like droperidol are occasionally prone to acute cognitive impairment and sedation at antiemetic doses. It can be said that 5-HT3 antagonists are superior to droperidol in this regard, which was one reason why droperidol fell out of favor after the advent of 5-HT3 antagonists.
=== Allegations of bias against gay men in blood donation process ===
Blood collecting organizations, such as the American Red Cross, have policies in accordance with FDA guidelines that prohibit accepting blood donations from any "male who has had sex with another male since 1977, even once". The inclusion of homo- and bisexual men on the prohibited list has created some controversy, but the FDA and Red Cross cite the need to protect blood recipients from HIV as justification for the continued ban. Even with PCR-based testing of blood products, a "window period" may still exist in which an HIV-positive unit of blood would test negative. All potential donors from HIV high-risk groups are deferred for this reason, including men who have sex with men. The issue has been periodically revisited by the Blood Products Advisory Committee within the FDA Center for Biologics Evaluation and Research and was last reconfirmed on May 24, 2007. Documentation from these meetings is available to the public.
However, in 2006, the AABB, America's Blood Centers and American Red Cross recommended to the FDA that the deferral period for men who had sex with other men should be changed to be equivalent with the deferral period for heterosexual's judged to be at risk. The FDA chose to uphold the blood ban. Female sexual partners of MSM (men who have sex with men) are deferred for one year since the last exposure. This is the same policy used for any sexual partner of someone in a high-risk group. The intent of these policies is to ensure that blood is collected from a population that is at low risk for disease, since the tests are not perfect and human error may lead to infected units not being properly discarded. The policy was first put in place in 1985.
In 2015, gay and bi men were allowed to donate blood after a one-year deferred period. In 2020 during the Covid-19 Pandemic, the deferred period was lowered to 3 months. In May 2023, gay and bi men can finally donate blood immediately “on the condition of being monogamous or just having one partner” regardless of sexual activity. Any non-monogamous individuals (regardless of sexual orientation) who have anal sex are automatically deferred to 3 months - Canada and the UK has implemented the same blood donation policy. It will take a while to be fully implemented, due to the American Red Cross donation centers and hospital computer systems and data needing to be upgraded with the new information.
=== Criticism of FDA's rejection of medical cannabis ===
In April 2005, the FDA issued a statement asserting that cannabis had no medical value and should not be accepted as a medicine, despite a great deal of research suggesting the opposite. The supporters of medical cannabis legalization criticized the FDA's statement as a politically motivated one instead of one based on solid science. A group of congressmen led by Maurice Hinchey wrote a letter to FDA's commissioner Andrew von Eschenbach, expressing their disapproval of the FDA's statement and pointed out the FDA's rejection of medical cannabis was inconsistent with the findings of the Institute of Medicine, which stated cannabis does have medical benefits. While the FDA has not approved marijuana it has approved THC (a compound found in cannabis) as an active ingredient for medicinal use. Critics argue that this approval is a politically motivated attempt to allow special interest groups to have patents over the substance, perhaps because the patents on previously patented competing substances have expired.
=== Allegations regarding management and FDA scientists ===
Nine FDA scientists appealed to President George W. Bush and at the time, President-elect Barack Obama over pressure from management to manipulate data, mainly in relation to the review process for medical devices. These concerns were highlighted in a 2006 report on the agency as well.
Monsanto-case: Mrs. Miller from Monsanto applies at FDA for product safety, changes her job to FDA and confirms her own safety application as FDA manager. 5th GcMAF Conference - 2017 Moscow - Speaker: Scott Tipps - National Health Federation
== Abolitionism ==
Libertarians such as American television personality John Stossel and editor-in-chief of Reason Katherine Mangu-Ward have advocated in favor of abolishing the FDA.
== See also ==
Criticism of the United States government#Criticism of agencies
Pharmaceutical industry
== References ==
== External links ==
Stockton, Nick. Infoporn: Proof That the FDA Isn’t Protecting Americans’ Health (2015), Wired | Wikipedia/Criticism_of_the_Food_and_Drug_Administration |
Neglected tropical diseases (NTDs) are a diverse group of tropical infections that are common in low-income populations in developing regions of Africa, Asia, and the Americas. They are caused by a variety of pathogens, such as viruses, bacteria, protozoa, and parasitic worms (helminths). These diseases are contrasted with the "big three" infectious diseases (HIV/AIDS, tuberculosis, and malaria), which generally receive greater treatment and research funding. In sub-Saharan Africa, the effect of neglected tropical diseases as a group is comparable to that of malaria and tuberculosis. NTD co-infection can also make HIV/AIDS and tuberculosis more deadly.
Some treatments for NTDs are relatively inexpensive. For example, praziquantel for schistosomiasis costs about US $0.20 per child per year. Nevertheless, in 2010 it was estimated that control of neglected diseases would require funding of between US$2 billion and $3 billion over the subsequent five to seven years. Some pharmaceutical companies have committed to donating all the drug therapies required, and mass drug administration efforts (for example, mass deworming) have been successful in several countries. While preventive measures are often more accessible in the developed world, they are not universally available in poorer areas.
Within developed countries, neglected tropical diseases affect the very poorest in society. In the United States, there are up to 1.46 million families, including 2.8 million children, living on less than two dollars per day. In developed countries, the burdens of neglected tropical diseases are often overshadowed by other public health issues. However, many of the same issues put populations at risk in developed as well as developing nations. For example, other problems stemming from poverty, such as lack of adequate housing, can expose individuals to the vectors of these diseases.
Twenty neglected tropical diseases are prioritized by the World Health Organization (WHO), though other organizations define NTDs differently. Chromoblastomycosis and other deep mycoses, scabies and other ectoparasites, and snakebite envenomation were added to the WHO list in 2017. These diseases are common in 149 countries, affecting more than 1.4 billion people (including more than 500 million children) and costing developing economies billions of dollars every year. They resulted in 142,000 deaths in 2013, down from 204,000 deaths in 1990.
== Reasons for neglect ==
The importance of neglected tropical diseases has been underestimated since many are asymptomatic and have long incubation periods. The connection between death and a neglected tropical disease that has been latent for a long period is often not realized. Areas of high endemicity are often geographically isolated, making treatment and prevention much more difficult.
There are three other major reasons that these diseases have been overlooked: they mainly affect the poorest countries of the developing world; in recent years public health efforts have focused heavily on decreasing the prevalence of HIV/AIDS, tuberculosis, and malaria (far more resources are given to those three diseases because of their higher mortality rates and higher public awareness of them); and neglected tropical diseases do not currently have a prominent cultural figure to champion their elimination.
=== Stigma ===
Neglected tropical diseases are often associated with social stigma, making their treatment more complex. Public health research has only recently begun to focus on stigma as a component of the issue. From the 1960s onward, approximately one citation a year related to social stigma. In 2006, there were 458.
Stigma greatly affects disease control by decreasing help-seeking and treatment adherence. Disease control programs since the 1980s have begun to integrate stigma mitigation into their offerings. In India, a leprosy program prioritized the message that "leprosy is curable, not hereditary" in order to inspire optimism in highly affected communities. The goal was to make leprosy a disease "like any other", so as to reduce stigma. At the same time, medical resources were optimized to fulfill the promise that the disease could be cured.
=== Economic incentives ===
Treatment and prevention of neglected tropical diseases are not seen as profitable, so patents and profit play a reduced role in stimulating innovation compared to other diseases. Like all non-commercial areas, communities affected by these diseases are reliant on governments and philanthropy. Currently, the pharmaceutical industry views research and development as highly risky. For this reason, resources are not often put into the field of NTDs, and new chemical products are often expensive. A review of public and private initiatives found that of the 1,393 new chemical products that were marketed between 1975 and 1999, only 16 were related to tropical diseases or tuberculosis. The same review found that there was a 13-fold greater chance of a newly marketed drug being for central nervous system disorders or cancer than for an NTD.
Because of a lack of economic incentives for the pharmaceutical industry, successful NTD treatment programs have often relied on donations. For instance, the Mectizan Donation Program has donated over 1.8 billion tablets of ivermectin. While developed countries often rely on government-run and private partnerships to fund such projects, developing nations frequently have significantly lower per-person spending on these diseases.
A 2006 report found that the Gates Foundation funded most extra activities to counter these diseases.
=== Neglected diseases in developed nations ===
Since 2008, the concept of "neglected diseases of poverty" has been developed and explored. This group of diseases, which overlaps with neglected tropical diseases, also pose a threat to human health in developed nations. In the United States alone, there are at least 12 million people with neglected parasitic infections. They make up a hidden disease burden among the poorest people in wealthy societies. In developed nations, lack of knowledge in the healthcare industry and lack of conclusive diagnostic tests perpetuate the neglect of this group of diseases.
In the United States, rates of parasitic infection can be distributed along geographic, racial, and socio-economic lines. Among African Americans, there may be up to 2.8 million cases of toxocariasis. Toxocariasis, trichomoniasis, and some other neglected infections occur in the United States at the same rate as in Nigeria. Within the Hispanic community, neglected infections are concentrated near the US–Mexico border. Vector-borne illnesses are especially high, with some rates approaching those of Latin America. Chagas disease was found in the US as early as the 1970s. However, in the developed world, diseases that are associated with poverty are often not addressed comprehensively. This may be due to a lack of economic incentives and public policy failings. A lack of awareness prevents effective policy generation and leaves healthcare services unequipped to address the issue. Additionally, little effort is put into creating and maintaining large data sets on neglected diseases in the United States and other developed nations. The first summit on the issue was held by the Adler Institute on Social Exclusion in the United States in 2009.
In Europe, a similar trend is seen. Neglected tropical diseases are concentrated in eastern and southern Europe, where poverty levels are highest. The most prevalent diseases in this region are ascariasis, trichuriasis, zoonotic helminth infections, and visceral leishmaniasis. Migration paths to Europe, most notably to Spain, have brought diseases to Europe as well. As many as 6,000 cases of Chagas disease have been introduced in this way. In response to a growing awareness of the burden on these populations, the European Centre for Disease Prevention and Control has laid out ten public health guidelines. They cover a variety of topics, from health education and promotion to community partnerships and the development of a minority healthcare workforce.
== List of diseases ==
There is some debate among the WHO, CDC, and infectious disease experts over which diseases are classified as neglected tropical diseases. Feasey, a researcher in neglected tropical diseases, notes 13 neglected tropical diseases: ascariasis, Buruli ulcer, Chagas disease, dracunculiasis, hookworm infection, human African trypanosomiasis, leishmaniasis, leprosy, lymphatic filariasis, onchocerciasis, schistosomiasis, trachoma, and trichuriasis. Fenwick recognizes 12 "core" neglected tropical diseases: the same as above, excluding hookworm.
These diseases result from four classes of causative pathogens: (i) protozoa (Chagas disease, human African trypanosomiasis, and leishmaniasis); (ii) bacteria (Buruli ulcer, leprosy, trachoma, and yaws), (iii) helminths or metazoan worms (cysticercosis/taeniasis, dracunculiasis, echinococcosis, foodborne trematodiases, lymphatic filariasis, onchocerciasis, schistosomiasis, and soil-transmitted helminthiasis); and (iv) viruses (dengue, chikungunya, and rabies).
The WHO recognizes the twenty diseases below as neglected tropical diseases.
The World Health Organization's 2010 report on neglected tropical diseases offers an expanded list including dengue, rabies, yaws, cysticercosis, echinococcosis, and foodborne trematode infections.
=== Buruli ulcer ===
Buruli ulcer is caused by the bacterium Mycobacterium ulcerans. It is related to the bacteria that cause tuberculosis and leprosy. Mycobacterium ulcerans produces a toxin, mycolactone, that destroys tissue. The prevalence of Buruli ulcer is unknown. The risk of mortality is low, although secondary infections can be lethal. Morbidity takes the form of deformity, disability, and skin lesions, which can be prevented through early treatment with antibiotics and surgery. It is found in Africa, Asia, Australia, and Latin America.
=== Chagas disease ===
Chagas disease is also known as American trypanosomiasis. There are approximately 15 million people infected with Chagas disease. Morbidity rates are higher for immunocompromised individuals, children, and the elderly, but can be very low if the disease is treated early. Chagas disease does not kill victims rapidly, instead causing years of debilitating chronic symptoms.
It is caused by the vector-borne protozoa Trypanosoma cruzi. It is spread by contact with Trypanosoma cruzi-infected feces of the triatomine (assassin bug). The protozoan can enter the body via the bug's bite, skin breaks, or mucous membranes. Infection can result from eating infected food or coming into contact with contaminated bodily fluids.
There are two phases of Chagas disease. The acute phase is usually asymptomatic. The first symptoms are usually skin chancres, unilateral purplish orbital oedema, local lymphadenopathy, and fever, accompanied by a variety of other symptoms depending on the infection site. The chronic phase occurs in 30 percent of all infections and can take three forms: asymptomatic (most prevalent), cardiac, and digestive lesions.
Chagas disease can be prevented by avoiding insect bites through insecticide spraying, home improvement, bed nets, hygienic food, medical care, laboratory practices, and testing. It can be diagnosed through a serological test, although the test is not very accurate. Treatment is with medication, which may have severe side effects.
=== Dengue and chikungunya ===
There are 50–100 million dengue virus infections annually. Dengue fever is usually not fatal, but infection with one of four serotypes can increase later susceptibility to other serotypes, resulting in a potentially fatal disease called severe dengue. Dengue fever is caused by a flavivirus which is spread mostly by the bite of the Aedes aegypti mosquito. No treatment for either dengue or severe dengue exists beyond palliative care. The symptoms are high fever and flu-like symptoms. It is found in Asia, Latin America, and Northern Australia.
Chikungunya is an arboviral disease transmitted by A. albopictus and A. aegypti mosquitoes. The virus was first isolated from an outbreak in Tanzania in 1952. Chikungunya virus is a member of the genus Alphavirus and family Togaviridae. The word "chikungunya" is from the Makonde language and means "that which bends up", referring to the effect of debilitating joint pain on the patient. Symptoms, generally appearing 5–7 days after exposure, can be confused with dengue and include fever, rash, headache, joint pain, and swelling. The disease mainly occurs in Africa and Asia.
=== Dracunculiasis ===
Dracunculiasis is also known as Guinea-worm disease. In 2019, 53 cases were reported across four countries, a substantial decrease from 3,500,000 cases in 1986. It is not fatal, but can cause months of inactivity. It is caused by drinking water contaminated by water fleas infected with guinea-worm larvae. Approximately one year after infection, a painful blister forms and one or more worms emerge. Worms can be up to 1 metre long.
It is usually treated by World Health Organization volunteers who clean and bandage wounds caused by worms and return daily to pull the worm out a few more inches. Dracunculiasis is preventable by water filtration, immediate case identification to prevent spread, health education, and treating ponds with larvicide. An eradication program has been able to reduce prevalence. As of 2014, the four endemic countries are Chad, Ethiopia, Mali, and South Sudan.
=== Echinococcosis ===
The rate of echinococcosis is higher in rural areas, and there are more than one million people infected currently. It is caused by ingesting parasites in animal feces.
There are two versions of the disease: cystic and alveolar. Both versions involve an asymptomatic incubation period of several years. In the cystic version, liver cysts cause abdominal pain, nausea, and vomiting, while cysts in the lungs cause chronic cough, chest pain, and shortness of breath. In alveolar echinococcosis, a primary cyst develops, usually in the liver, in addition to weight loss, abdominal pain, malaise, and signs of liver failure. Untreated alveolar echinococcosis is fatal.
Surgery and drugs can be used to treat echinococcosis. It can be prevented by deworming dogs, sanitation, proper disposal of animal feces, health education, and livestock vaccination. Cystic echinococcosis is found in the eastern portion of the Mediterranean region, northern Africa, southern and eastern Europe, the southern portion of South America, and Central Asia. Alveolar echinococcosis is found in western and northern China, Russia, Europe, and northern North America. It can be diagnosed through imaging techniques and serological tests.
=== Yaws ===
There are limited data available on the prevalence of yaws, although it primarily affects children. The mortality risk is very low, but the disease causes disfigurement and disability if untreated. The most common symptom is skin lesions. It is a chronic bacterial infection, transmitted by skin contact, and caused by the spirochete bacterium Treponema pallidum pertenue. It is treated with antibiotics and can be prevented through hygiene and sanitation. Yaws is most prevalent in warm, moist tropical regions of the Americas, Africa, Asia, and the Pacific.
=== Foodborne trematodiases ===
Foodborne trematode infections include clonorchiasis, opisthorchiasis, fascioliasis, and paragonimiasis. These infections are all zoonotic, primarily affecting domestic or wild animals, but can also be transmitted to humans. They are acquired by eating food, such as raw fish, contaminated with the larval stages of the parasites. At least 40 million people are thought to be infected.
=== Human African trypanosomiasis ===
African trypanosomiasis (African sleeping sickness) is a somewhat rare protozoal disease, with fewer than 10,000 cases currently. Human African trypanosomiasis is vector-borne and spreads through the bite of the tsetse fly. The most common symptoms are fever, headache, lymphadenopathy, sleeping disturbances, personality changes, cognitive decline, and coma. The disease is always fatal if untreated. The current forms of treatment are highly toxic and ineffective, as resistance is spreading. It is diagnosed through an inexpensive serological test.
=== Leishmaniasis ===
The three forms of leishmaniasis, a protozoal disease, are visceral (Kala-azar), cutaneous, and mucocutaneous. There are an estimated 12 million people infected. It is fatal if untreated, and 20,000 deaths from visceral leishmaniasis occur annually. It is a vector-borne disease caused by the bite of sandflies. At least 90 percent of visceral leishmaniasis occurs in Bangladesh, Brazil, Ethiopia, India, South Sudan, and Sudan. Cutaneous leishmaniasis occurs in Afghanistan, Algeria, Brazil, Colombia, Iran, Pakistan, Peru, Saudi Arabia, and Syria. Around 90 percent of mucocutaneous leishmaniasis occurs in Bolivia, Brazil, and Peru.
A vaccine is under development to prevent leishmaniasis. The only other method of prevention is avoidance of sandfly bites. Diagnosis can be made by clinical signs, serological tests, or parasitological tests. Leishmaniasis can be treated with expensive medications.
=== Leprosy ===
According to recent figures from the WHO, 208,619 new cases of leprosy were reported in 2018 from 127 countries. It is most prevalent in India (69% of cases), Brazil, Indonesia, Nigeria, the Democratic Republic of the Congo, Madagascar, and East Africa from Mozambique to Ethiopia, with the highest relative incidence in India, Brazil, and Nepal. There are one to two million individuals currently disabled or disfigured due to past or present leprosy. It is caused by bacteria and transmitted through droplets from the mouth and nose of infected individuals.
Leprosy causes disfigurement and physical disabilities if untreated. It is curable if treated early. Treatment requires multidrug therapy. The BCG vaccine has some preventative effect against leprosy. Leprosy has a 5–20 year incubation period, and the symptoms are damage to the skin, nerves, eyes, and limbs.
=== Lymphatic filariasis ===
Lymphatic filariasis is also known as elephantiasis. There are approximately 120 million individuals infected and 40 million with deformities. Approximately two-thirds of cases are in Southwest Asia, and one-third are in Africa. Lymphatic filariasis is rarely fatal but has lifelong implications, such as lymphoedema of the limbs, genital disease, and painful recurrent attacks. Most people are asymptomatic but have lymphatic damage. Up to 40 percent of infected individuals have kidney damage. It is a vector-borne disease, caused by nematode worms that are transmitted by mosquitoes.
It can be treated with cost-effective antihelminthic treatments, and washing skin can slow or even reverse damage. It is diagnosed with a finger-prick blood test.
=== Noma ===
Noma, an opportunistic bacterial infection causing gangrenous necrosis of the mouth, was added to the World Health Organization's list of neglected tropical diseases in December 2023.
=== Onchocerciasis ===
Onchocerciasis is also known as river blindness. There are 20.9 million people infected, and prevalence is higher in rural areas. Over 99 percent of cases are in sub-Saharan Africa. It causes blindness, skin rashes, lesions, intense itching, and skin depigmentation. It is a vector-borne disease, caused by blackflies infected with filarial worms.
It can be treated with ivermectin and prevented by insecticide spraying or preventative dosing with ivermectin.
=== Rabies ===
There are two forms of rabies: furious and paralytic. It is mostly found in Asia and Africa. There is a higher prevalence in rural areas, and it disproportionately affects children. Rabies is fatal after symptoms develop. It is caused by a lyssavirus transmitted through wounds or bites from infected animals.
The first symptoms are fever and pain near the infection site, which occur after a one- to three-month incubation period. Furious rabies (the more common type) causes hyperactivity, hydrophobia, and aerophobia; death by cardio-respiratory arrest occurs within days. Paralytic rabies causes a slow progression from paralysis to coma to death. There are 60,000 deaths from rabies annually.
It can be prevented in dogs by vaccination and by cleaning and disinfecting bite wounds and post-exposure prophylaxis. Rabies is undiagnosable before symptoms develop. It can be detected through tissue testing after symptoms develop.
=== Schistosomiasis ===
There are over 200 million cases of schistosomiasis. Approximately 85 percent of cases are in sub-Saharan Africa. The disease can be fatal by causing bladder cancer and hematemesis. Schistosoma species have a complex life cycle that alternates between humans and freshwater snails. Infection occurs when the skin comes into contact with contaminated fresh water in which snails that carry the parasite are living. Symptoms for schistosomiasis are not caused by the worms but by the body's reaction to the eggs. The eggs that do not pass out of the body can become lodged in the intestine or bladder, causing inflammation or scarring. Children who are repeatedly infected can develop anemia, malnutrition, and learning difficulties. The symptoms are usually haematuria, bladder obstruction, renal failure, bladder cancer, periportal fibrosis, bladder fibrosis, liver fibrosis, portal hypertension, cervical lesions, ascites, and esophageal varices.
Inexpensive praziquantel can be used to treat individuals with schistosomiasis, but it cannot prevent reinfection. The cost of prevention is US$0.32 per child per year. Mass deworming treatment with praziquantel, better access to safe water, sanitation, and health education can all be used to prevent schistosomiasis. Vaccines are under development. It can be diagnosed through a serological test, but the test often produces false negatives.
=== Soil-transmitted helminthiasis ===
Soil-transmitted helminthiasis is the most prevalent neglected tropical disease. The four major worm species responsible for soil-transmitted helminthiasis are Ascaris (roundworms), Trichuris (whipworm), the hookworms Necator americanus and Ancylostoma duodenale, and Strongyloides stercoralis. There are 1.5 billion people currently infected. Soil-transmitted helminthiasis occurs in sub-Saharan Africa, the Americas, China, and East Asia. The mortality risk is very low. The most common symptoms are anemia, stunted growth, intestinal problems, lack of energy, and compromised physical and cognitive development. Infected children often fall behind in schooling. The severity of symptoms depends on the number of worms in the body.
Parasitic worms are generally transmitted via exposure to infected human feces and soil that are spread in the environment, for example, due to open defecation. The most common treatment is medicine. It can be prevented through hygienically prepared food and clean water, improved sanitation, periodic deworming, and health education. The World Health Organization recommends mass deworming without prior diagnosis.
=== Taeniasis/cysticercosis ===
Cysticercosis is a tapeworm larvae infection, while taeniasis is infection with adult tapeworms. Both are found in Asia, Africa, and Latin America, particularly on farms in which pigs are exposed to human excrement.
Cysticercosis is the most common preventable cause of epilepsy in the developing world. Cysticercosis occurs after ingestion of contaminated food, water, or soil. Cysts and lesions can cause headaches, blindness, seizures, hydrocephalus, meningitis, and dementia. Neurocysticercosis, or the parasitic infection of the nervous system, can be fatal. Taeniasis is not fatal. It is usually contracted after eating undercooked contaminated pork. Taeniasis has mild symptoms, including abdominal pain, nausea, diarrhea, or constipation.
Drugs are used to treat both diseases. Infection can be prevented through stricter meat-inspection standards, livestock confinement, improved hygiene and sanitation, health education, safe meat preparation, and identifying and treating human and pig carriers.
=== Trachoma ===
There are 21.4 million people infected with trachoma, of whom 2.2 million are partially blind and 1.2 million are blind. It is found in Africa, Asia, Central and South America, the Middle East, and Australia. The disease disproportionately affects women and children. The mortality risk is very low, although multiple re-infections eventually lead to blindness. The symptoms are internally scarred eyelids, followed by eyelids turning inward. Trachoma is caused by a micro-organism that spreads through eye discharges (on hands, cloth, etc.) and by "eye-seeking flies".
It is treated with antibiotics. The only known prevention method is interpersonal hygiene.
=== Chromoblastomycosis and other deep mycoses ===
Other important endemic mycoses with common systemic involvement are histoplasmosis, paracoccidioidomycosis, coccidioidomycosis, blastomycosis and talaromycosis. These infections are also seldomly seen in returning travelers in western countries
=== Scabies ===
=== Snakebite envenoming ===
Snakebite was added to the list in 2017, after years of criticism of the WHO by activists for not making it a priority. The greatest burden of snakebite morbidity is in India and Southeast Asia. Snakebite envenoming (SBE) affects as many as 2.7 million people every year, most of whom live in some of the world’s most remote, poorly developed, and politically marginalised tropical communities. With annual mortality of 81,000 to 138,000 and 400,000 surviving victims suffering permanent physical and psychological disabilities, SBE is a disease in urgent need of attention. <Gutierrez JM, Calvete JJ, Habib AG, Harrison RA, Williams DJ, Warrell DA. Snakebite envenoming. Nat Rev Dis Primers. 2017;3:17063. Epub 2017/09/15. pmid:28905944.> but snakebites often go unreported. A policy analysis however found that the placement of snakebite in the global health agenda of WHO is fragile due to reluctance acceptance of the disease in the neglected tropical disease community and the perceived colonial nature of the network driving the agenda.
== Effects for patients ==
=== Social effects ===
==== Social stigma ====
Several NTDs, such as leprosy, cause severe deformities that result in social stigma. Stigma is considered to be the "hidden burden" of NTDs and is not accounted for in measures such as disability-adjusted life years (DALYs). Other NTDs that carry heavy social stigma include onchocerciasis, lymphatic filariasis, plague, Buruli ulcer, leishmaniasis, and Chagas disease. Lymphatic filariasis, for example, causes severe deformities that can result in denial of marriage and inability to work. Studies in Ghana and Sri Lanka have demonstrated that support groups for patients with lymphatic filariasis can increase participants' self-esteem, quality of life, and social relations through social support and providing practical advice on how to manage their illness. The social effects of neglected tropical diseases have been shown to affect men and women in different ways. Men are socially stigmatized in a way that detrimentally affects their economic prospects. Women are more likely to be affected in the areas of marriage and family.
==== Mental health ====
A 2012 review found that infection with a neglected tropical disease predisposes individuals to poor mental health. This is partially due to the social stigma that surrounds NTDs, but is also likely caused by the subsequent lack of access to health and social services. Overall, being a member of the infected community was found to cut individuals off from multiple aspects of society via civic rights, educational opportunities, and employment. A high prevalence of post-traumatic stress disorder (PTSD) and depression was found among people who had survived snakebites. More research needs to be directed to understanding psychological aspects of NTDs to understand their effects more fully and to direct strategies to manage them better in healthcare systems where mental health professionals are scarce.
==== Gender ====
NTDs disproportionately affect women and children. There is also added risk of hookworm infection during pregnancy and potential to transfer diseases such as Chagas during pregnancy. A study in Uganda found that women were able to obtain treatment more easily than men because they had fewer occupational responsibilities and were more trusting of treatments, but ignorance of the effects of medicines during pregnancy prevented adequate care. The paper concludes that gender should be considered when designing treatment programs in Uganda. Additionally, women often bear a heavier social stigma in relation to the pressure to marry.
=== Economic effects ===
The cost of treatment of some of these diseases, such as Buruli ulcer, can be almost the average household income for families in the highest quarter of incomes, while for those in the lowest quarter it can be over twice the yearly income. These enormous financial costs often cause deferral of treatment and financial ruin. These diseases also cost the government in terms of healthcare provision and lost worker productivity through morbidity and shortened life spans. In Kenya, for example, deworming is estimated to increase average adult income by 40 percent, which is a benefit-to-cost ratio of 100. Each untreated case of trachoma is estimated to cost US$118 in lost productivity. Each case of schistosomiasis causes a loss of 45.4 days of work per year. Most of the diseases cost the economies of developing countries millions of dollars. Large-scale prevention campaigns are predicted to increase agricultural output and education levels.
The low cost of treatment for NTDs can be attributed to the large scale of the programs, free provision of drugs by pharmaceutical companies, delivery modes of drugs, and unpaid volunteers who distribute the drugs. The economic burden of NTDs is undervalued and therefore the corresponding economic effect and cost-effectiveness of decreasing prevalence of NTDs is underestimated. The investment return on measures to control NTDs is estimated to be between 14 and 30 percent, depending on the disease and region.
=== Health effects ===
==== Coinfection ====
Coinfection is a major concern with NTDs, making them more damaging than their mortality rates might suggest. Because factors such as poverty, inadequate healthcare and inadequate sanitation practices contribute to all NTDs, they are often found in overlapping distributions. Helminth infections, as the most common infection of humans, are often found to be in multi-infection systems. For example, in Brazil, low socioeconomic status contributes to overcrowded housing. In these same areas, coinfection by Necator americanus and Schistosoma mansoni is common. The effect of each worm weakens the immune system, making infection from the other more likely and more severe. For this reason, coinfection carries a higher risk of mortality. NTDs may also play a role in infection with other diseases, such as malaria, HIV/AIDS, and tuberculosis. The ability of helminths to manipulate the immune system may create a physiological environment that could exacerbate the progression of HIV/AIDS. Some evidence from Senegal, Malawi, and Thailand has shown that helminth infections raise the risk of malarial infection.
== Prevention, treatment and eradication ==
Prevention and eradication are important because "of the appalling stigma, disfigurement, blindness and disabilities caused by NTDs." The principal aim of the London Declaration on Neglected Tropical Diseases was the elimination or eradication of dracunculiasis, leprosy, lymphatic filariasis, onchocerciasis, trachoma, sleeping sickness, visceral leishmaniasis, and canine rabies within ten years of its launch in January 2012. The declaration is a collaborative effort involving the WHO, the World Bank, the Bill & Melinda Gates Foundation, the world's 13 leading pharmaceutical companies, and government representatives from the US, UK, United Arab Emirates, Bangladesh, Brazil, Mozambique, and Tanzania.
While there has been a noticeable uptick in biological research into NTDs, prevention may be supplemented by social and development outreach. Spiegel and coauthors advocated for "social offset", which reallocates some funding for biotechnological research to social programs. This attempts to alleviate some of the factors (such as poverty, poor sanitation, overcrowding and poor healthcare) that greatly exacerbate conditions brought on by NTDs. Projects such as these also strengthen the goal of sustained eliminations rather than quickly addressing symptoms.
=== Policy initiatives ===
There are many prevention and eradication campaigns funded by organizations such as the World Health Organization, US Agency for International Development, Bill & Melinda Gates Foundation, and UK Department for International Development.
Sustainable Development Goal 3 has the target: "By 2030, [to] end the epidemics of AIDS, tuberculosis, malaria and neglected tropical diseases and combat hepatitis, water-borne diseases and other communicable diseases."
==== WHO Roadmap of 2012 ====
In 2012, WHO published an NTD "roadmap", which contained milestones for 2015 and 2020, and specified targets for eradication, elimination and intensified control of the different NTDs. For example:
NTDs planned to be eradicated: dracunculiasis by the year 2015, endemic treponematoses (yaws) by 2020
NTDs planned to be eliminated globally by 2020: blinding trachoma, leprosy, human African trypanosomiasis, and lymphatic filariasis
NTDs planned to be eliminated in certain regions: rabies (by 2015 in Latin America, by 2020 in Southeast Asia and the western Pacific), Chagas disease (transmission through blood transfusion by 2015, intra-domiciliary transmission by 2020 in the Americas), visceral leishmaniasis (by 2020 in the Indian subcontinent), onchocerciasis (by 2015 in Latin America), and schistosomiasis (by 2015 in the eastern Mediterranean region, the Caribbean, Indonesia, and the Mekong River basin, and by 2020 in the Americas and western Pacific)
NTDs planned to be eliminated in certain countries: human African trypanosomiasis (by 2015 in 80 percent of areas in which it occurs), onchocerciasis (by 2015 in Yemen, by 2020 in selected countries in Africa), and schistosomiasis (by 2020 in selected countries in Africa)
Intensified control with specific targets for 2015 and 2020 are provided for these NTDs: dengue, Buruli ulcer, cutaneous leishmaniasis, taeniasis/cysticercosis and echinococcosis/hydatidosis, foodborne trematode infections, and soil-transmitted helminthiases.
In 2021, WHO updated their NTD roadmap "Together towards 2030", outlining their approach for 2021–2030.: v–vi
==== Others ====
The U.S. Food and Drug Administration priority review voucher is an incentive for companies to invest in new drugs and vaccines for tropical diseases. A provision of the Food and Drug Administration Amendments Act of 2007 awards a transferable "priority review voucher" to any company that obtains approval for a treatment for one of the listed diseases. The voucher can later be used to accelerate the review of an unrelated drug. This program is for all tropical diseases and includes medicines for malaria and tuberculosis. The first voucher given was for Coartem, a malaria treatment.
The prize was proposed by Duke University faculty Henry Grabowski, Jeffrey Moe, and David Ridley in their 2006 Health Affairs paper "Developing Drugs for Developing Countries". In 2007, United States Senators Sam Brownback (R-KS) and Sherrod Brown (D-OH) sponsored an amendment to the Food and Drug Administration Amendments Act of 2007. President George W. Bush signed the bill in September 2007.
=== Deworming treatment ===
Deworming treatments in infected children may have some nutritional benefit, as worms are often partially responsible for malnutrition. However, in areas where these infections are common, there is strong evidence that mass deworming campaigns do not have a positive effect on children's average nutritional status, levels of blood haemoglobin, cognitive abilities, performance at school, or survival. To achieve health gains in the longer term, improvements in sanitation and hygiene behaviours are also required, together with deworming treatments.
The effect of mass deworming on school attendance is disputed. It has been argued that mass deworming has a positive effect on school attendance. The long-term benefits of deworming include a decrease in school absenteeism by 25 percent and an increase in adult earnings by 20 percent. A systematic review, however, found that there is little or no difference in attendance in children who receive mass deworming compared to children who did not. One study found that boys were enrolled in primary school for more years than boys who were in schools that did not offer such programs. Girls in the same study were about a quarter more likely to attend secondary school if they received treatment. Both groups went on to participate in more skilled sectors of the labor market. The economic growth generated from school programs such as this may balance out the actual expenses of the program. However, the results of this study are disputed (due to a high risk of bias in the study), and the positive long-term outcomes of mass deworming remain unclear.
=== Integration of treatment ===
Inclusion of NTDs into initiatives for malaria, HIV/AIDS, and tuberculosis, as well as integration of NTD treatment programs, may have advantages given the strong link between these diseases and NTDs. Some neglected tropical diseases share common vectors (sandflies, black flies, and mosquitos). Both medicinal and vector control efforts may be combined.
A four-drug rapid-impact package has been proposed that targets multiple diseases together. This package is estimated to cost US$0.40 per patient, with estimated saving of 26–47% compared to treating the diseases separately. While more research must be done in order to understand how NTDs and other diseases interact in both the vector and the human stages, safety assessments have so far produced positive results.
Many neglected tropical diseases and other prevalent diseases share common vectors, creating another opportunity for treatment and control integration. One such example of this is malaria and lymphatic filariasis, which are both transmitted by the same or related mosquito vectors. Vector control, through the distribution of insecticide-treated nets, reduces human contact with a wide variety of disease vectors. Integrated vector control may also alleviate pressure on mass drug administration, especially with respect to rapidly evolving drug resistance. Combining vector control and mass drug administration deemphasizes both, making each less susceptible to resistance evolution.
=== Integration with water, sanitation and hygiene (WASH) programs ===
Water, sanitation, and hygiene (WASH) interventions are essential in preventing many NTDs, such as soil-transmitted helminthiasis. Mass drug administration alone will not protect people from re-infection. A more holistic and integrated approach to NTDs and WASH efforts will benefit both sectors along with the communities they are aiming to serve. This is especially true in areas where more than one NTD is endemic.
In August 2015, the World Health Organization unveiled a global strategy and action plan to integrate WASH with other public health interventions to accelerate the elimination of NTDs. The plan aimed to intensify control or eliminate certain NTDs in specific regions by 2020, and referred to the NTD "roadmap" milestones from 2012 that included eradication of dracunculiasis by 2015 and of yaws by 2020, elimination of trachoma and lymphatic filariasis as public health problems by 2020, and intensified control of dengue, schistosomiasis, and soil-transmitted helminthiases.
Closer collaboration between WASH and NTD programmes can lead to synergies. They can be achieved through collaborative planning, delivery and evaluation of programmes, strengthening and sharing of evidence, and using monitoring tools to improve the equity of health services.
Reasons why WASH plays an important role in NTD prevention and patient care include:
NTDs affect more than one billion people in 149 countries. They occur mainly in regions with a lack of basic sanitation. About 2.4 billion people worldwide do not have adequate sanitation facilities. 663 million do not have access to improved drinking water sources.
A leading cause of preventable blindness is trachoma. The bacterial infection is transmitted through contact with eye-seeking flies, fingers, and fomites. Prevention components are facial cleanliness, which requires water for face washing, and environmental improvement, which includes safe disposal of excreta to reduce fly populations.
Improved sanitation prevents soil-transmitted helminthiases. It impedes fecal pathogens such as intestinal worm eggs from contaminating the environment and infecting people through contaminated food, water, dirty hands, and direct skin contact with the soil.
Improved sanitation and water management can contribute to reduced proliferation of mosquitoes that transmit diseases, such as lymphatic filariasis, dengue, and chikungunya. Breeding of the Culex mosquito, which transmits filarial parasites, is facilitated through poorly constructed latrines. Breeding of the Aedes aegypti and Aedes albopictus mosquitoes, which transmit dengue and chikungunya, can be prevented through safe storage of water.
Feces and urine that contain worm eggs can contaminate surface water and lead to transmission of schistosomiasis. This can be prevented through improved sanitation. Not only human but also animal (cow, buffalo) urine or feces can transmit some schistosome species. Therefore, it is important to protect freshwater from animals and animal waste.
Treatment of many NTDs requires clean water and hygienic conditions for healthcare facilities and households. For Guinea-worm disease, Buruli ulcer, and cutaneous leishmaniasis, wound management is needed to speed up healing and reduce disability. Lymphatic filariasis causes chronic disabilities. People who have this disease need to maintain rigorous personal hygiene with water and soap to prevent secondary infections.
NTDs that lead to permanent disabilities make tasks such as carrying water long distances or accessing toilets difficult. However, people affected by these diseases often face stigma and can be excluded from accessing water and sanitation facilities. This increases their risk of poverty and severe illness. Clean water and soap are essential for these groups to maintain personal hygiene and dignity. Therefore, additional efforts to reduce stigma and exclusion are needed. In this manner, WASH can improve the quality of life of people affected by NTDs.
In a meta-analysis, safe water was associated with significantly reduced odds of Schistosoma infection, and adequate sanitation was associated with significantly lower odds of infection with both S. mansoni and S. haematobium.
A systematic review and meta-analysis showed that better hygiene in children is associated with lower odds of trachoma. Access to sanitation was associated with 15 percent lower odds of active trachoma and 33 percent lower odds of C. trachomatis infection of the eyes.
Another systematic review and meta-analysis found a correlation between WASH access and practices, and lower odds of soil-transmitted helminthiasis infections by 33 to 77 percent. Persons who washed their hands after defecating were less than half as likely to be infected as those who did not. Traditionally, preventive chemotherapy is used as a measure of control, although this measure does not stop the transmission cycle and cannot prevent reinfection. In contrast, improved sanitation can.
=== Pharmaceutical market ===
Biotechnology companies in the developing world have targeted neglected tropical diseases due to a need to improve global health.
Mass drug administration is considered a possible method for eradication, especially for lymphatic filariasis, onchocerciasis, and trachoma, although drug resistance is a potential problem. According to Fenwick, Pfizer donated 70 million doses of drugs in 2011 to eliminate trachoma through the International Trachoma Initiative. Merck has helped The African Programme for the Control of Onchocerciasis (APOC) and Oncho Elimination Programme for the Americas to greatly diminish the effect of onchocerciasis by donating ivermectin. Merck KGaA pledged to give 200 million tablets of praziquantel, the only cure for schistosomiasis, over 10 years. GlaxoSmithKline has donated two billion tablets of medicine for lymphatic filariasis and pledged 400 million deworming tablets per year for five years in 2010. Johnson & Johnson has pledged 200 million deworming tablets per year. Novartis has pledged leprosy treatment, and EISAI pledged two billion tablets to help treat lymphatic filariasis.
=== NGO initiatives ===
Non-governmental organizations that focus exclusively on NTDs include the Schistosomiasis Control Initiative, Deworm the World, and the END Fund. Despite under-funding, treatment and prevention of many neglected diseases is cost-effective. The cost of treating a child for infection of soil-transmitted helminths and schistosomes (some of the main causes of neglected diseases) is less than US$0.50 per year when administered as part of school-based mass deworming by Deworm the World. This programme is recommended by Giving What We Can and the Copenhagen Consensus Centre as one of the most efficient and cost-effective solutions. The efforts of the Schistosomiasis Control Initiative to combat neglected diseases include the use of rapid-impact packages: supplying schools with packages including four or five drugs, and training teachers in how to administer them.
Health Action International based in Amsterdam worked with the WHO to get snakebite envenoming on the list of neglected tropical diseases.
=== Public-private initiatives ===
An alternative to the profit-driven drug development model emerged in 2000 to address the needs of these neglected patients. Product development partnerships (PDPs) aim at implementing and accelerating the research and development (R&D) of safe and effective health tools (diagnostics, vaccines, drugs) to combat neglected diseases. Drugs for Neglected Disease initiative (DNDi) is one of these PDPs that has already developed new treatments for NTDs.
The Sabin Vaccine Institute, founded in 1993, works to address the issues of vaccine-preventable diseases as well as NTDs. They run three main programs: Sabin Vaccine Development, Global Network for Neglected Tropical Diseases, and Vaccine Advocacy and Education. Their product development partnership affiliates them with the Texas Children's Hospital as well as the Baylor College of Medicine. Their major campaign, End7, aims to end seven of the most common NTDs (elephantiasis, river blindness, snail fever, trachoma, roundworm, whipworm, and hookworm) by 2020. Through End7, college campuses undertake fundraising and educational initiatives for the broader goals of the campaign.
WIPO Re:Search was established in 2011 by the World Intellectual Property Organization in collaboration with BIO Ventures for Global Health (BVGH) and with the active participation of leading pharmaceutical companies and other private and public sector research organizations. It allows organizations to share their intellectual property, compounds, expertise, facilities, and know-how royalty-free with qualified researchers worldwide working on new solutions for NTDs, malaria, and tuberculosis.
In 2013, the Government of Japan, five Japanese pharmaceutical companies, the Bill and Melinda Gates Foundation, and the UNDP established a new public–private partnership, the Global Health Innovative Technology Fund. They pledged over US$100 million to the fund over five years, to be awarded as grants to R&D partnerships across sectors in Japan and elsewhere, working to develop new drugs and vaccines for 17 neglected diseases, in addition to HIV, malaria, and tuberculosis. Affordability of the resulting drugs and vaccines is one of the key criteria for grant awards.
==== London Declaration on Neglected Tropical Diseases ====
The London Declaration on Neglected Tropical Diseases, initiated by the Bill and Melinda Gates Foundation launched on 30 January 2012 in London. Inspired by the WHO roadmap to eradicate or prevent transmission for neglected tropical diseases, it aimed to eradicate or reduce NTDs by the year 2020. It was endorsed by governments and organisations around the world, as well as major pharmaceutical companies including Abbott, AstraZeneca, Bayer HealthCare Pharmaceuticals, Becton Dickinson, Bristol-Myers Squibb, Eisai, Gilead Sciences, GlaxoSmithKline, Johnson & Johnson, Merck KGaA, Merck Sharp & Dohme, MSD, Novartis, Pfizer, and Sanofi. It was not a complete success, but millions of lives were saved, the burden of the infections was reduced, and 42 countries eliminated at least one disease. To commemorate the programme, WHO adopted 30 January as the World NTD Day.
==== Kigali Declaration on Neglected Tropical Diseases ====
The Kigali Declaration on Neglected Tropical Diseases was launched at the Kigali Summit on Malaria and Neglected Tropical Diseases (NTDs) hosted by the Government of Rwanda at its capital city Kigali on 23 June 2022. It was signed as a support for the World Health Organization's 2021–30 road map for NTDs and the target of Sustainable Development Goal 3 to end NTD epidemics; and as a follow-up project of the London Declaration . Supported by WHO, governments of the Commonwealth of Nations pledged the endorsement, along with commitments from GSK plc, Novartis, and Pfizer.
=== Others ===
An open-access journal dedicated to neglected tropical diseases called PLoS Neglected Tropical Diseases first began publication in 2007.
One of the first large-scale initiatives to address NTDs came from a collaboration between Kenneth Warren and the Rockefeller Foundation. Ken Warren is regarded as a pioneer in neglected tropical disease research. The Great Neglected Tropical Diseases Network was a consortium of scientists from all over the world, hand-picked by Warren, working to expand the research base in neglected diseases. Many of the scientists that he recruited had not been involved in NTD research before. The network ran from 1978 to 1988. Warren's vision was to establish units within biological labs across the world, dedicated to R&D. By forming a critical mass of scientists in NTD research, he hoped to attract new students into the field. The interdisciplinary group met annually to update the community on research progress. Much of the work done by this group focused on understanding the mechanisms behind infection. At these informally structured meetings, research partnerships were formed. Warren himself encouraged these partnerships, especially if they bridged the divide between developed and developing nations. Through the Great Neglected Tropical Disease Network, a great number of scientists were brought into the field of parasitology.
== Epidemiology ==
The distribution of neglected tropical disease disproportionally affects about one billion of the world's poorest populations, causing mortality, disability, and morbidity. Lack of funding, resources, and attention can result in treatable and preventable diseases causing death. Factors like political dynamics, poverty, and geographical conditions can make the delivery of NTD control programs difficult. Intersectional collaboration of poverty reduction policies and neglected tropical diseases creates cross-sector approaches to simultaneously address these issues.
The six most common NTDs include soil-transmitted helminths (STHs)—specifically roundworms (Ascaris lumbricoides), whipworm (Trichuris trichiura), and hookworms (Necator americanus and Ancylostoma duodenale)—schistosomiasis, trachoma, and lymphatic filariasis (LF). These diseases affect one-sixth of the world's population, with 90 percent of the disease burden occurring in sub-Saharan Africa.
Information on the frequency of neglected tropical diseases is of low quality. It is currently difficult to summarize all of the information on this family of diseases. One effort to do so is the Global Burden of Disease framework. It aims to create a standardized method of measurement. The principle components of the approach involve 1) the measuring of premature mortality as well as disability, 2) the standardized usage of DALYs (disability-adjusted life years), and 3) widespread inclusion of diseases and injury causes with the estimation of missing data. However, the DALY has been criticized as a "systematic undervaluation" of disease burden. King asserts that DALY emphasizes the individual too much while ignoring the effects of the ecology of the disease. In order for the measure to become more valid, it may have to take the context of poverty more into account. King also emphasizes that DALYs may not capture the non-linear effects of poverty on the cost-utility analysis of disease control. The Socio-Demographic Index (SDI) and Healthy Life Expectancy (HALE) are other summary measures that can be used to take into account other factors. HALE is a metric that weights years lived and health loss before death to provide a summary of population health. SDI is a measurement that includes lag-distributed income per capita, average education, and fertility rate. Socioeconomic factors greatly influence the distribution of neglected tropical diseases, and not addressing these factors in models and measurements can lead to ineffective public health policy.
== Research and development ==
NTD interventions include programs to address environmental and social determinants of health (e.g., vector control, water quality, sanitation) as well as programs offering mass drug administration for disease prevention and treatment. Drug treatments exist to confront many of the NTDs and represent some of the world's essential medicines. Despite significant health and economic improvements using available medicines, the low number of new compounds being researched and developed for NTDs is an ongoing and significant challenge. The dearth of candidates in pharmaceutical company drug pipelines is primarily attributed to the high costs of drug development and the fact that NTDs are concentrated among the world's poor. Other disincentives to investment include weak existing infrastructure for distribution and sales as well as concerns regarding intellectual property protection. However, the major stakeholders in NTD drug development—governments, foundations, pharmaceutical companies, academia, and NGOs—are involved in activities to help address the research and development shortfall and meet the many challenges presented by neglected tropical diseases. Initiatives include public-private partnerships, global R&D capacity building, priority vouchers to speed drug approval processes, open source scientific collaborations, and harmonization of global governance structures concerning NTDs.
The diseases considered neglected tropical diseases vary. Some researchers no longer consider malaria, HIV, and tuberculosis to be neglected due to the amount of public attention and increased funding they have received. Outside "The Big Three", the seven most prevalent neglected tropical diseases in order of their global prevalence are ascariasis, trichuriasis, hookworm infection, schistosomiasis, lymphatic filariasis, and trachoma. These seven are among a larger list of thirteen major NTDs: onchocerciasis, leishmaniasis, Chagas disease, leprosy, human African trypanosomiasis (sleeping sickness), dracunculiasis, and Buruli ulcer.
=== Deficient market ===
In their 2002 review of the U.S. Food and Drug Administration (FDA) databases and the European Agency for the Evaluation of Medicinal Products, Troullier et al. found that 16 out of 1393 new chemical entities were approved for NTDs between 1975 and 1999 (~1%). Cohen et al. revisited the data and using the same methodology found 32 new chemical entities during the time period. In a second analysis using an expanded list of NTDs based on the G-FINDER survey, the number was slightly higher, with 46 new drugs and vaccines approved (~3% of the total including HIV drugs). Between 2000 and 2009, there has been some increase with an additional 26 newly approved drugs and vaccines for NTDs.
A number of factors are recognized as contributing to the low number. The barrier most reported is the high cost of drug development. Estimates are that pharmaceutical companies' development costs to approval fall between $500 million and $2 billion. DiMasi, Hansen, and Grabowski calculated an average of $802 million in year 2000 dollars. Furthermore, the time that drugs are approved for use averages seven years out of the twenty years on patent, meaning a tendency for the market to focus on diseases of developed nations where high prices can be used to recoup research and development costs, and subsidize failed R&D efforts. In short, NTD research and development is considered a high investment risk, given that NTDs predominantly affect the poor in low- and middle-income countries. Additional barriers include drug safety regulatory requirements, intellectual property protection problems, and poor infrastructure for distribution and sales.
Although drug companies have not invested heavily in NTDs, in several cases, rather than focus on profits, some have decided to donate key drugs to address NTDs. For example, Merck has had a program since the mid-1980s to donate ivermectin (Mectizan) indefinitely to support the global fight against onchocerciasis. GlaxoSmithKline and several other large pharmaceutical companies have donation programs as well. Drug donation, however, does not ameliorate the deficiency of new chemical entities being researched and developed. This is especially of concern with reports of emerging resistance among existing drugs.
=== Policy initiatives ===
==== Public–private partnerships ====
Governments, foundations, the non-profit sector, and the private sector have found new connections to help address market deficiencies by providing funding support and spreading both the costs and risks of NTD research and development. The proliferation of public–private partnerships (PPPs) has been recognized as a key innovation in the past decade, helping to unlock existing and new resources.
Major PPPs for NTDs include: the Sabin Vaccine Institute, Norvartis Vaccines Institute for Global Health, MSD Wellcome Trust Hilleman Laboratories, Infectious Diseases Research Institute, Institut Pasteur and INSERM, WIPO Re:Search, and the International Vaccine Institute. Likewise, a number of new academic drug development centers have been created in recent years drawing in industry partners. Support for these centers is frequently traced to the Bill & Melinda Gates Foundation, the Sandler Foundation, and the Wellcome Trust.
==== R&D capacity building in middle-income countries ====
Growing NTD research and development capacity in middle-income countries is an area of policy interest. A 2009 study of biotechnology companies in India, China, Brazil, and South Africa revealed 62 NTD products in development and on the market out of approximately 500 products offered (~14%). When products to fight HIV, malaria, and TB were included in the analysis, the number increased to 123 products, approximately 25% of the total products offered.
Researchers have argued that, unlike most multinationals, small and mid-sized "Global South" companies see significant business opportunities in the development of NTD-related diagnostics, biologics, pharmaceuticals, and services. Potential actions to improve and expand this R&D capacity have been recommended, including expansion of human capital, increased private investment, knowledge and patent sharing, infrastructure building for business incubation, and innovation support.
==== Innovation prizes and grants ====
Competitive innovation prizes have been used to spur development in a range of fields such as aerospace engineering, clean technology, and genomics. The X-Prize Foundation is launching a competition for high-speed, point-of-care diagnostics for tuberculosis. A more widely defined annual "Global Health EnterPrize" for neglected tropical diseases has been proposed to reward health innovators, particularly those based in countries where NTDs represent a serious health burden.
The Bill & Melinda Gates Foundation offers the Grand Challenges Explorations Opportunities on a rolling basis. This grant program allows individuals from any organization or background to apply to address priority global health issues. Each project award is $100,000 and is drawn from a Foundation funding pool of $100 million. Awardees have tended to offer research projects on topics that are highly speculative but offer potentially game-changing breakthroughs in global health.
==== FDA priority review vouchers (PRV) ====
In 2006, Ridley et al. recommended the development of a priority review voucher (PRV) in the journal Health Affairs. It gained interest from Senator Sam Brownback of Kansas, who championed its introduction in the FDA Amendments Act of 2007. Under the enacted law, FDA approval of a non-NTD drug can be accelerated through the drug review process if paired with a drug that addresses an NTD. The potential economic benefit to a pharmaceutical company is estimated to be potentially as high as $300 million per drug. Three drugs have earned NTD PRVs to date (December 2014): Coartem (by Novartis, for malaria); bedaquiline (by Janssen, for TB); and miltefosine (by Knight, for leishmaniasis). However, the success of the PRV system is now under much scrutiny, given that Knight benefitted by $125 million from the sale of a PRV earned from a drug (miltefosine) that was largely researched and developed by the WHO. Médecins Sans Frontières are now pressuring Knight to guarantee to supply miltefosine at cost price, thus far without success.
The PRV isn't limited to the pairing of drugs within a single company as it can be transferred between companies. Companies with NTD drug candidates in their pipelines but without a blockbuster drug are able to sell their vouchers, producing financial returns. In the EU, similar priority review incentives are now under consideration to increase the speed of regulatory pricing and reimbursement decisions.
However, PRVs have been criticized as being open to manipulation and possibly encouraging errors through too rapid regulatory decision-making.
==== Open source collaboration initiatives ====
Several companies and scientific organizations are participating in open-source initiatives to share drug data and patent information over the web, and facilitate virtual collaboration on NTD research.
One rich area to explore is the wealth of genomic data resulting from the sequencing of parasite genomes. These data offer opportunities for the exploration of new therapeutic products using computational and open-source collaboration methods for drug discovery. The Tropical Disease Initiative, for example, has used large amounts of computing power to generate the protein structures for ten parasite genomes. An open-source drug bank was matched algorithmically to determine compounds with protein interaction activity, and two candidates were identified. In general, such methods may hold important opportunities for off-label use of existing approved drugs.
== History ==
In 1977, Kenneth S. Warren, an American researcher, invented the concept of what is now "neglected tropical diseases".
In 2005 Lorenzo Savioli, a senior United Nations civil servant, was appointed director of the "Department of Control of Neglected Tropical Diseases".
The World Health Organization definition of neglected tropical disease has been criticised to be restrictive and described as a form of epistemic injustice.
== See also ==
Contagious disease
Fecal–oral route transmission
Neglected Tropical Disease Research and Development
Drugs for Neglected Diseases Initiative
Eradication of infectious diseases
Global Network for Neglected Tropical Diseases
Orphan diseases
== References ==
== External links ==
WHO – Control of neglected tropical disease
PLOS Neglected Tropical Diseases
United Nations World Health Organization
U.S. Food and Drug Administration
India's neglected tropical diseases
Neglected tropical disease targets must include morbidity
Global health policy and neglected tropical diseases: Then, now, and in the years to come
UK's One Health Vector-Borne Diseases Hub | Wikipedia/Neglected_tropical_diseases |
The Family Smoking Prevention and Tobacco Control Act, (Pub. L. 111–31 (text) (PDF), H.R. 1256) is a federal statute in the United States that was signed into law by President Barack Obama on June 22, 2009. The Act gives the Food and Drug Administration the power to regulate the tobacco industry. A signature element of the law imposes new warnings and labels on tobacco packaging and their advertisements, with the goal of discouraging minors and young adults from smoking. The Act also bans flavored cigarettes, places limits on the advertising of tobacco products to minors and requires tobacco companies to seek FDA approval for new tobacco products.
== Origins and proposal ==
On March 21, 2000, the Supreme Court in FDA v. Brown & Williamson Tobacco Corp., in a 5–4 decision, held that the Federal Food, Drug, and Cosmetic Act, particularly when considering "Congress’ subsequent tobacco-specific legislation," that Congress had not given the FDA the authority to regulate tobacco products as customarily marketed. Thus the Family Smoking Prevention and Tobacco Control Act was introduced to respond to the decision, which had held that the Clinton administration's FDA had "overreached" its congressionally delegated authority, thus giving the FDA the authority the Court determined it had lacked.
== Legislative history ==
The bill passed the United States House of Representatives on April 2, 2009, by a vote of 298 to 112. The House bill had 178 cosponsors and the companion legislation in the Senate, S. 982 had 57 cosponsors. On May 20, 2009, the Senate Committee on Health, Education, Labor, and Pensions ordered the Senate bill to be reported favorably with amendments on a 15-8 vote.
The Capitol Hill newspaper The Hill reported on May 25, 2009, that Senate Majority Leader Reid planned to move on the bill during the month of June 2009. Senators Burr and Hagan of North Carolina were proposing alternative legislation.
On June 2, the Senate voted 84-11 to proceed to consideration of the House bill. On June 8, the Senate voted 61-30 on cloture on amendments to the Senate bill. The "Senate bill requires that cigarette health warning labels be large enough to make up 50 percent of the front and rear panels of the package and that the word “warning” appear in capital letters."
On June 11, the Senate passed H.R. 1256 by a vote of 79-17, with 3 Senators not voting. Passage of the legislation came a week later than was originally scheduled. The Senate's version of the bill was approved by the House on June 12, by a bipartisan vote of 307-97.
Media accounts stated that the opposition in the Senate was largely from tobacco-farming states, particularly Kentucky, North Carolina, South Carolina and Georgia, with the only Democrat in opposition being Kay Hagan, from North Carolina. Notable exceptions were Virginia Senators Jim Webb and Mark Warner who supported the measure, despite the state's connection to the tobacco industry.
The Family Smoking Prevention and Tobacco Control Act was signed into law on June 22, 2009, by President Barack Obama.
== Provisions ==
Creates the Center for Tobacco Products, a tobacco control center within the FDA and gives the FDA authority to regulate the content, marketing and sale of tobacco products.
Requires tobacco companies and importers to reveal all product ingredients and seek FDA approval for any new tobacco products (see premarket tobacco application).
Allows the FDA to change tobacco product content.
The ban on flavoring applies to any product meeting the definition of a "cigarette" according to section 3(1) of the Federal Cigarette Labeling and Advertising Act. This includes any tobacco that comes rolled in paper or a non-tobacco substance, and added to this definition in the Family Smoking Prevention and Tobacco Control Act is any tobacco with the purpose to be rolled such as rolling tobacco.
Calls for new rules to prevent sales except through direct, face-to-face exchanges between a retailer and a consumer.
Limits advertising that could attract young smokers.
Requires cigarette warning labels to cover 50 percent of the front and rear of each pack, with the word warning in capital letters.
Requires FDA approval for the use of expressions such as "light, "mild" or "low" that give the impression that a particular tobacco product poses less of a health risk (see modified risk tobacco product).
The bill makes no provisions that ban the import of the banned items for personal consumption, only for "sale or distribution." (Division A Title II Section 201)
== Reception and impact ==
Passing of the law was supported by the American Cancer Society, whose CEO said in a press release that "[t]his bill forces Big Tobacco to disclose the poisons in its products and has the power to finally break the dangerous chain of addiction for generations to come." The ACS press release also noted that the legislation would "require cigarette companies to disclose all ingredients used in cigarettes and to stop using words like 'light' and 'ultra-light' to give the impression that some tobacco products have a lower health risk." The legislation also garnered support from the American Heart Association, whose CEO said that the bill "provides a tremendous opportunity to finally hold tobacco companies accountable and restrict efforts to addict more children and adults."
The law was criticized by some as ineffectual, with community health sciences professor Michael Siegel stating that it "creates the appearance of regulation without allowing actual regulation." Critics argue that without the authority to eliminate nicotine completely, the reduction of nicotine levels in cigarettes may result in compensation by existing smokers, increasing their cigarette smoke inhalation to consume a level of nicotine which will satisfy their cravings. The Tobacco Control Act has been called "the Marlboro Protection Act" because it grandfathered in tobacco products marketed before 2007, while erecting nearly impassable financial and regulatory barriers for the introduction of competing products to the US market. These marketing restrictions enacted by the law make it more difficult to promote safer smokeless alternatives to cigarettes. The restrictions have been disputed on the grounds of free speech, with some stating that the legislation violates the First Amendment to the United States Constitution.
The bill bans flavored cigarettes, including cloves, cinnamon, candy, and fruit flavors, with a special exception for menthol cigarettes. Because Philip Morris is the largest producer of cigarettes in the United States and the law would have the effect of eliminating potential competition, the law has been nicknamed the Marlboro Monopoly Act of 2009. Philip Morris strongly supports FDA regulation. The exemption was reportedly influenced by the Congressional Black Caucus. The Tobacco Products Scientific Advisory Committee provisioned under the bill is to submit a recommendation on menthol cigarettes to the United States Secretary of Health and Human Services no later than one year after its establishment.
=== Lawsuits and constitutionality ===
On August 31, 2009, Commonwealth Brands filed suit (Commonwealth Brands, Inc. v. United States) against the United States and the Food and Drug Administration. Alleging that the advertising restrictions embodied in the FSPTCA unconstitutionally infringe on the First Amendment. These provisions include: restricting advertising to black-and-white text; restricting tobacco companies from advertising "light" cigarettes; prohibiting advertising within 1,000 feet of areas where children congregate; banning event sponsorship by tobacco companies; and prohibiting free sample distribution of cigarettes.
In June 2011, the FDA released nine new warning signs containing both graphic text and images that should be included on all cigarette packaging and advertisement by September 2012.
The textual warnings state:
Each warning is to be paired with one of the following colored images: man exhaling cigarette smoke through a tracheotomy hole in his throat; plume of cigarette smoke enveloping an infant receiving a kiss from his or her mother; pair of diseased lungs next to a pair of healthy lungs; diseased mouth afflicted with what appears to be cancerous lesions; man breathing into an oxygen mask; bare-chested male cadaver lying on a table, and featuring what appears to be post-autopsy chest staples down the middle of his torso; woman weeping uncontrollably; man wearing a T-shirt that features a "no smoking" symbol and the words "I Quit."
Four tobacco companies responded to the mandate by filing a legal challenge in August:
BBK Tobacco & Foods, LLP v. U.S. Food and Drug Admin., the plaintiffs argued that flavored rolling papers, as utilized in the process of roll-your-own-tobacco cigarettes, did not qualify as tobacco products under the FSPTCA
Lorillard Inc. filed lawsuit in the U.S. District Court for the District of Columbia and was joined by R.J. Reynolds Tobacco Co., Commonwealth Brands Inc. and Liggett Group LLC, challenging the constitutionality of the FSPTCA, regarding free speech in advertising claims
The constitutionality of the provision requiring graphic warnings on cigarette packs has been questioned with tobacco companies and others saying that the new warnings violated the first amendment by going beyond being informational and require manufactures of a legal product to "engage in anti-smoking advocacy" on the government's behalf. R.J. Reynolds, Lorillard, Liggett Group and Commonwealth Brands, filed a lawsuit against the FDA in August 2011. Altria did not take any legal action. On November 7, 2011, US district judge Richard Leon granted a temporary injunction postponing the implementation of the new warnings, ruling that "It is abundantly clear from viewing these images that the emotional response they were crafted to induce is calculated to provoke the viewer to quit, or never to start smoking - an objective wholly apart from disseminating purely factual and uncontroversial information." The Court of Appeals for the D.C. Circuit upheld the District Court's opinion that the labels were unconstitutional, analyzing the labels under the Central Hudson standard. Before the D.C. Circuit issued its ruling, a divided panel for the Sixth Circuit Court of Appeals upheld the constitutionality of the Act in the case of Discount Tobacco City & Lottery v. FDA. On April 22, 2013, the Supreme Court declined review of the 6th Circuit's decision.
=== International litigation ===
On 12 April 2010, Indonesia filed a formal complaint with the World Trade Organization stating the ban on kreteks (clove cigarettes) in America amounts to discrimination because menthol cigarettes are exempt from the new regulation. Trade Ministry Director General of International Trade Gusmardi Bustami has stated that the Indonesian government has asked the WTO panel to review US violations on trade regulations, including the General Agreement on Tariff and Trade (GATT) 1994, Technical Barriers to Trade (TBT) and Sanitary and Phytosanitary (SPS) Agreement. The TBT Agreement is of special importance as it defines clove cigarettes and menthol cigarettes as "like products." Claims of discrimination are enhanced when noting that 99% of kreteks were imported from countries other than the United States (chiefly Indonesia), while menthol cigarettes are produced almost entirely by American tobacco manufacturers. Indonesia's case is further strengthened by comparing the number of young kretek smokers in America with the number of young menthol cigarette smokers. According to US health reports, 43% of young smokers smoke menthol cigarettes, which accounts for nearly 25% of the total cigarette consumption in the United States. Young smokers habituated to kreteks, however, account for less than 1% of cigarette consumption in the US, and <1% of the total cigarettes sold in the US. On 4 April 2012, the WTO ruled in favor of Indonesia's claim, though it is unclear how this will affect U.S. law.
The WTO was asked to bring this to the Dispute Settlement Body (DSB) for resolution in 2013 after the US failed to adhere to the findings scheduled to be implemented by the end of July 2012. They sought damages of reportedly $55 million claiming the US had not taken measures to meet compliance. The matter was moved to arbitration in line with Article 22.6 of the Dispute Settlement Understanding, the WTO agreement governing trade disputes. In June 2013 the two parties jointly asked the arbitrators to suspend circulation of this decision to the public and asked to keep the award confidential. Diplomatic meetings followed and in exchange for ending the controversy created by the ban of clove cigarettes the US agreed to refrain from submitting any WTO challenges to Indonesia's controversial mineral export restrictions. A Generalized System of Preferendes (GSP) scheme was pledged by the US which granted additional "facilities" that exceeded certain value limitations for the following five years.
== See also ==
Tobacco Products Scientific Advisory Committee
Tobacco Products Directive
WHO Framework Convention on Tobacco Control
== Notes ==
== References ==
== External links ==
Tobacco Bill to Drag Into Next Week - Roll Call
Senate vote a sea change for tobacco - David Rogers - POLITICO.com
Up in Smoke: How the Tobacco Industry Shaped the New Smoking Bill - video report by Democracy Now! | Wikipedia/Family_Smoking_Prevention_and_Tobacco_Control_Act |
The Center for Drug Evaluation and Research (CDER, pronounced "see'-der") is a division of the U.S. Food and Drug Administration (FDA) that monitors most drugs as defined in the Food, Drug, and Cosmetic Act. Some biological products are also legally considered drugs, but they are covered by the Center for Biologics Evaluation and Research. The center reviews applications for brand name, generic, and over the counter pharmaceuticals, manages US current Good Manufacturing Practice (cGMP) regulations for pharmaceutical manufacturing, determines which medications require a medical prescription, monitors advertising of approved medications, and collects and analyzes safety data about pharmaceuticals that are already on the market.
CDER receives considerable public scrutiny, and thus implements processes that tend toward objectivity and tend to isolate decisions from being attributed to specific individuals. The decisions on approval will often make or break a small company's stock price (e.g., Martha Stewart and Imclone), so the markets closely watch CDER's decisions.
The center has around 1,300 employees in "review teams" that evaluate and approve new drugs. Additionally, the CDER employs a "safety team" with 72 employees to determine whether new drugs are unsafe or present risks not disclosed in the product's labeling.
The FDA's budget for approving, labeling, and monitoring drugs is roughly $290 million per year. The safety team monitors the effects of more than 3,000 prescription drugs on 200 million people with a budget of about $15 million a year.
Patrizia Cavazzoni is the current director of CDER.
== Responsibilities ==
CDER reviews New Drug Applications to ensure that the drugs are safe and effective. Its primary objective is to ensure that all prescription and over-the-counter (OTC) medications are safe and effective when used as directed.
The FDA requires a four-phased series of clinical trials for testing drugs. Phase I involves testing new drugs on healthy volunteers in small groups to determine the maximum safe dosage. Phase II trials involve patients with the condition the drug is intended to treat to test for safety and minimal efficacy in a somewhat larger group of people. Phase III trials involve one to five thousand patients to determine whether the drug is effective in treating the condition it is intended to be used for. After this stage, a new drug application is submitted. If the drug is approved, stage IV trials are conducted after marketing to ensure there are no adverse effects or long-term effects of the drug that were not previously discovered.
With the rapid advancement of biologically-derived treatments, the FDA has stated that it is working to modernize the process of approval for new drugs. In 2017, Commissioner Scott Gottlieb estimated that they have more than 600 active applications for gene and cell-based therapies.
== Divisions ==
CDER is divided into 8 sections with different responsibilities:
Office of New Drugs
This office is responsible for oversight of clinical trials and other studies during drug development, and for the evaluation of new drug applications
The Office of New Drugs is divided into several departments based on the indication of the drug (the medical need for which it is being proposed)
Office of Generic Drugs
This office reviews generic drug applications to ensure generic drugs are equivalent to their branded forms
Office of Strategic Programs
This office is responsible for business programs, represents CDER in the FDA Bioinformatics Board, and communicates with other agencies
Office of Pharmaceutical Quality
This office is responsible for integrating assessment, inspection, surveillance, policy, and research activities to strengthen pharmaceutical quality on a global scale.
Office of Surveillance and Epidemiology
This office is responsible for post-marketing surveillance to identify adverse effects that may not have been apparent during clinical trials, using the MedWatch program
Office of Translational Sciences
This office promotes collaboration across offices in CDER by maintaining databases and biostatistical tools for evaluating drugs
Office of Medical and Regulatory Policy
This office develops and reviews guidelines pertinent to CDER's mission of ensuring the safety of drugs
Office of Compliance
This office ensures compliance with regulations relating to drug development and marketing
== History ==
The FDA has had the responsibility of reviewing drugs since the passage of the 1906 Pure Food and Drugs Act. The 1938 Federal Food, Drug and Cosmetic Act required all new drugs to be tested before marketing by submitting the original form of the new drug application. Within the first year, the FDA's Drug Division, the predecessor to CDER, received over 1200 applications. The Drug Amendments of 1962 required manufacturers to prove to the FDA that the drug in question was both safe and effective. In 1966, the division was reorganized to create the Office of New Drugs, which was responsible for reviewing new drug applications and clinical testing of drugs.
In 1982, when the beginning of the biotechnology revolution blurred the line between a drug and a biologic, the Bureau of Drugs was merged with the FDA's Bureau of Biologics to form the National Center for Drugs and Biologics during an agency-wide reorganization under Commissioner Arthur Hayes. This reorganization similarly merged the bureaus responsible for medical devices and radiation control into the Center for Devices and Radiological Health.
In 1987, under Commissioner Frank Young, CDER and the Center for Biologics Evaluation and Research (CBER) were split into their present form. The two groups were charged with enforcing different laws and had significantly different philosophical and cultural differences. At that time, CDER was more cautious about approving therapeutics and had a more adversarial relationship with the industry. The growing crisis around HIV testing and treatment and an inter-agency dispute between officials from the former Bureau of Drugs and officials from the former Bureau of Biologics over whether to approve Genentech's Activase (tissue plasminogen activator) led to the split.
In its original form, CDER was composed of six offices: Management, Compliance, Drug Standards, Drug Evaluation I, Drug Evaluation II, Epidemiology and Biostatistics, and Research Resources. The Division of Antiviral Products was added in 1989 under Drug Evaluation II due to the large amount of drugs proposed for treating AIDS. The Office of Generic Drugs was also formed.
In 2002, the FDA transferred a number of biologically produced therapeutics to CDER. These include therapeutic monoclonal antibodies, proteins intended for therapeutic use, immunomodulators, and growth factors and other products designed to alter production of blood cells.
== References ==
== External links ==
[1] | Wikipedia/Center_for_Drug_Evaluation_and_Research |
The United States Food and Drug Administration Modernization Acts (FDAMA) are amendments to the Federal Food, Drug, and Cosmetic Act, which regulated products by the FDA. The first bill, the FDA Modernization Act of 1997, reduced the timeline for approving new pharmaceutical drugs. It also loosened rules around broadcast pharmaceutical advertising.
In 2022, the Act was updated with the FDA Modernization Act 2.0, which cancelled a 1938 mandate to require animal testing for every drug development protocol.
== History ==
Congressman Richard Burr and Senator James M. Jeffords were the chairperson sponsors of the Food and Drug Administration Regulatory Modernization Act of 1997 or FDA Modernization Act of 1997. The U.S. legislation was signed by Bill Clinton on 21 November 1997, and fully enacted by 1 April 1999, putting into law reforms begun under the National Partnership for Reinventing Government. One result of the passing of the act was a reduction in the time for the approval of new pharmaceutical drugs. Critics questioned whether the shortened time frame for the approval of prescription drugs would do more harm than good.
In 2022, the Act was updated with the FDA Modernization Act 2.0. Signed into law by President Joe Biden, the act cancelled an earlier mandate (set by the Federal Food, Drug, and Cosmetics Act of 1938) to require animal testing in drug development.
== FDA Modernization Act of 1997 ==
The following are the most significant provisions of the 1997 act:
=== Prescription drug user fees ===
The act reauthorized, for five more years, the Prescription Drug User Fee Act of 1992 (PDUFA). This enabled the FDA to reduce the average time required for a drug review from 30 months to 15 months.
=== FDA initiatives and programs ===
The law enacted FDA initiatives undertaken under Vice President Al Gore's Reinventing Government program. The initiatives include measures to modernize the regulation of biological products by bringing them in harmony with the regulations for drugs and eliminating the need for establishment license application; eliminate the batch certification and monograph requirements for insulin and antibiotics; streamline the approval processes for drug and biological manufacturing changes; and reduce the need for environmental assessment as part of a product application.
The act also codified FDA regulations and practice to increase patient access to experimental drugs and medical devices and to accelerate review of important new medications. In addition, the law provided for an expanded database on clinical trials, ClinicalTrials.gov.
=== Information on off-label use and drug economics ===
The law abolishes the long-standing prohibition of broadcasting by manufacturers of information about unapproved uses of drugs and medical devices. The act allows a firm to circulate peer-reviewed journal articles about an off-label indication of its product, providing the company is also committing itself to file proof of research within a certain amount of time.
The act also allows drug companies to provide economic information about their products to formulary committees, managed care organizations, and similar large-scale buyers of health-care products. The law, however, does not permit the spreading of economic information that could affect prescribing choices to individual medical practitioners.
=== Pharmacy compounding ===
The act creates a special exemption to ensure continued availability of compounded drug products prepared by pharmacists to provide patients with individualized therapies not available commercially. The law, however, seeks to prevent manufacturing under the guise of compounding by establishing parameters within which the practice is appropriate and lawful.
=== Risk-based regulation of medical devices ===
The act complements and builds on the FDA's measures to focus its resources on medical devices that present the greatest risks to patients. The law also directs the FDA to focus its post market surveillance on higher risk devices, and allows the agency to implement a reporting system that concentrates on a representative sample of user facilities—such as hospitals and nursing homes—that experience deaths and serious illnesses or injuries linked with the use of devices.
Finally, the law expands an ongoing pilot program under which the FDA accredits outside—so-called "third party"—experts to conduct the initial review of all low-to-intermediate risk class I and II devices. The act, however, specifies that an accredited person may not review devices that are permanently implantable, life-supporting, life sustaining, or for which clinical data are required.
=== Food safety and labeling ===
The act eliminates the requirement of the FDA's premarket approval for most packaging and other substances that come in contact with food and may migrate into it. Instead, the law establishes a process whereby the manufacturer can notify the agency of its intent to use certain food contact substances and, unless the FDA objects within 120 days, the manufacturer may proceed with the marketing of the new product. Implementation of the notification process is contingent on additional appropriations to cover its cost to the agency. The act also expands procedures under which the FDA can authorize health claims and nutrient content claims without reducing the statutory standard.
=== Standards for medical products ===
In the area of drugs, the law codifies the agency's current practice of allowing in certain circumstances one clinical investigation as the basis for product approval. The act, however, does preserve the presumption that, as a general rule, two adequate and well-controlled studies are needed to prove the product's safety and effectiveness.
In the area of medical devices, the act specifies that the FDA may keep out of the market products whose manufacturing processes are so deficient that they could present a serious health hazard. The law also gives the agency authority to take appropriate action if the technology of a device suggests that it is likely to be used for a potentially harmful unlabeled use.
== FDA Modernation Act 2.0 ==
In 2022, the FDA Modernization Act 2.0 was approved and signed into law by President Joe Biden. The FDA Modernization Act of 2.0 removed the requirement for animal testing in drug development, making it optional. This enabled further development of new alternative technologies such as cell assays, computer modeling, and bioprinting.
== See also ==
Food and Drug Administration Amendments Act of 2007
== References ==
== External links ==
FDA page on the FDAMA
FDAMA Implementation Chart of Completed Items | Wikipedia/Food_and_Drug_Administration_Modernization_Act_of_1997 |
A myograph is any device used to measure the force produced by a muscle when under contraction. Such a device is commonly used in myography, the study of the velocity and intensity of muscular contraction.
A myograph can take several forms: for tubular structures such as blood vessels these include the pressure myograph (where a segment of a blood vessel is cannulated at either or both ends) and the wire myograph (where the blood vessel segment is threaded onto a pair of pins or wires); for skeletal muscle other devices such as the acceleromyograph can be used.
In pharmacology, myography is used to record muscle contraction in organ bath preparations. The related technique of electromyography (EMG) is used to measure the electrical activity of the muscle instead of force. In addition, there is an optomyography (OMG) technique that uses active near-infra-red optical sensors.
== Wire Myograph ==
A wire myograph is a type of laboratory apparatus that can measure the contractility of luminal tissue segments smaller than 2 mm in diameter. It is used by pharmacologists to measure the effect of test articles on blood pressure or on airway contractility.
=== History of the wire myograph ===
Diagrams of the first ever wire myograph were revealed by Mulvany and Halpern in their 1976 paper "Contractile properties of small arterial resistance vessels in [...] rats". The group based the design of this apparatus on a technique developed by Bevan and Osher to measure arterial contractility ex vivo. Development of the wire myograph was significant because it allowed researchers to estimate the effect of novel drugs on blood pressure for the first time.
=== Structure of the wire myograph ===
The structure of the wire myograph has not changed much since its invention in 1977. Tissues are mounted in the myograph bath via two wires threaded through their lumen. These wires are attached to two opposing stainless steel jaws which secure tissue in place throughout the culture period. Multi-myograph units can contain up to four separate tissue baths, allowing four different tissue segments to be cultured simultaneously.
== References ==
== External links ==
Information on microvessel studies (wire myograph)
Various types of blood vessel myographs
Blood vessel myographs | Wikipedia/Myography |
An acceleromyograph is a piezoelectric myograph, used to measure the force produced by a muscle after it has undergone nerve stimulation. Acceleromyographs may be used, during anaesthesia when muscle relaxants are administered, to measure the depth of neuromuscular blockade and to assess adequacy of recovery from these agents at the end of surgery. Acceleromyography is classified as quantitative neuromuscular monitoring.
== Rationale ==
Patients who undergo anesthesia may receive a drug that paralyzes muscles, facilitating endotracheal intubation and improving operating conditions for the surgeon. Longer-acting drugs have higher prevalence of residual blockade in the PACU or ICU than shorter acting drugs. Different clinical tests to measure or exclude evidence of residual muscle weakness have been described but cannot exclude postoperative residual curarization. Small degrees of muscle blockade can only accurately be measured by the use of quantitative neuromuscular monitoring. Specifically, the observer cannot reliably measure muscular fade when train-of-four ratios are between 0.4 and 0.9.
== Acceleromyograph design ==
Acceleromyographs measure muscle activity using a miniature piezoelectric transducer that is attached to the stimulated muscle. A voltage is created when the muscle accelerates and that acceleration is proportion to force of contraction. The mass of the piezoelectric transducer is known and the acceleration is measured therefore the force can be calculated, (Force = mass × acceleration). Acceleromyographs are more costly than the more common twitch monitors, but have been shown to better alleviate residual blockade and associated symptoms of muscle weakness, and to improve overall quality of recovery.
== See also ==
Muscle relaxant
Myograph
Neuromuscular-blocking drug
Neuromuscular monitoring
== References ==
== External links ==
Comparison of mechanomyography and acceleromyography in myotonic dystrophy type 1 at Respond2Articles.com | Wikipedia/Acceleromyography |
In medicine and food law, a test article is a prototype product specifically manufactured to test the product. Since medical and food test products involve human safety, they are subject to legal regulation.
== United States ==
In the United States, medical and food test products are regulated by the Food and Drug Administration (FDA).
Title 21 "Food and Drugs" , Part 50 "Protection of Human Subjects" defines test article as "drug (including a biological product for human use), medical device for human use, human food additive, color additive, electronic product, or any other article subject to regulation under the act or under sections 351 and 354-360F of the Public Health Service Act (42 U.S.C. 262 and 263b-263n)." Title 21 "Food and Drugs" , Part 58 "Good Laboratory Practice for Nonclinical Laboratory Studies" defines test article similarly: as "any food additive, color additive, drug, biological product, electronic product, medical device for human use, or any other article subject to regulation under the act or under sections 351 and 354-360F of the Public Health Service Act".
Generally, prior to the usage of test articles in research involving human subjects, and approval from the institutional review board (IRB), however emergency life-threatening situations are exempt form this requirement. IRB must be notified about an emergency usage of test articles within 5 business days.
== References == | Wikipedia/Test_article_(food_and_drugs) |
Optomyography (OMG) was proposed in 2015 as a technique that could be used to monitor muscular activity. It is possible to use OMG for the same applications where Electromyography (EMG) and Mechanomyography (MMG) are used. However, OMG offers superior signal-to-noise ratio and improved robustness against the disturbing factors and limitations of EMG and MMG.
The basic principle of OMG is to use active near-infra-red optical sensors to measure the variations in the measured signals that are reflected from the surface of the skin while activating the muscles below and around the skin spot where the photoelectric sensor is focusing to measure the signals reflected from this spot.
== Applications ==
A glasses based optomyography device was patented for measuring facial expressions and emotional responses particularly for mental health monitoring [1]. Generating proper control signals is the most important task to be able to control any kind of a prosthesis, computer game or any other system which contains a human-computer interaction unit or module. For this purpose, surface-Electromyographic (s-EMG) and Mechanomyographic (MMG) signals are measured during muscular activities and used, not only for monitoring and assessing these activities, but also to help in providing efficient rehabilitation treatment for patients with disabilities as well as in constructing and controlling sophisticated prostheses for various types of amputees and disabilities. However, while the existing s-EMG and MMG based systems have compelling benefits, many engineering challenges still remain unsolved, especially with regard to the sensory control system.
== References == | Wikipedia/Optomyography |
In the fields of computational chemistry and molecular modelling, scoring functions are mathematical functions used to approximately predict the binding affinity between two molecules after they have been docked. Most commonly one of the molecules is a small organic compound such as a drug and the second is the drug's biological target such as a protein receptor. Scoring functions have also been developed to predict the strength of intermolecular interactions between two proteins or between protein and DNA.
== Utility ==
Scoring functions are widely used in drug discovery and other molecular modelling applications. These include:
Virtual screening of small molecule databases of candidate ligands to identify novel small molecules that bind to a protein target of interest and therefore are useful starting points for drug discovery
De novo design (design "from scratch") of novel small molecules that bind to a protein target
Lead optimization of screening hits to optimize their affinity and selectivity
A potentially more reliable but much more computationally demanding alternative to scoring functions are free energy perturbation calculations.
== Prerequisites ==
Scoring functions are normally parameterized (or trained) against a data set consisting of experimentally determined binding affinities between molecular species similar to the species that one wishes to predict.
For currently used methods aiming to predict affinities of ligands for proteins the following must first be known or predicted:
Protein tertiary structure – arrangement of the protein atoms in three-dimensional space. Protein structures may be determined by experimental techniques such as X-ray crystallography or solution phase NMR methods or predicted by homology modelling.
Ligand active conformation – three-dimensional shape of the ligand when bound to the protein
Binding-mode – orientation of the two binding partners relative to each other in the complex
The above information yields the three-dimensional structure of the complex. Based on this structure, the scoring function can then estimate the strength of the association between the two molecules in the complex using one of the methods outlined below. Finally the scoring function itself may be used to help predict both the binding mode and the active conformation of the small molecule in the complex, or alternatively a simpler and computationally faster function may be utilized within the docking run.
== Classes ==
There are four general classes of scoring functions:
Force field – affinities are estimated by summing the strength of intermolecular van der Waals and electrostatic interactions between all atoms of the two molecules in the complex using a force field. The intramolecular energies (also referred to as strain energy) of the two binding partners are also frequently included. Finally since the binding normally takes place in the presence of water, the desolvation energies of the ligand and of the protein are sometimes taken into account using implicit solvation methods such as GBSA or PBSA.
Empirical – based on counting the number of various types of interactions between the two binding partners. Counting may be based on the number of ligand and receptor atoms in contact with each other or by calculating the change in solvent accessible surface area (ΔSASA) in the complex compared to the uncomplexed ligand and protein. The coefficients of the scoring function are usually fit using multiple linear regression methods. These interactions terms of the function may include for example:
hydrophobic — hydrophobic contacts (favorable),
hydrophobic — hydrophilic contacts (unfavorable) (Accounts for unmet hydrogen bonds, which are an important enthalpic contribution to binding. One lost hydrogen bond can account for 1–2 orders of magnitude in binding affinity.),
number of hydrogen bonds (favorable contribution to affinity, especially if shielded from solvent, if solvent exposed no contribution),
number of rotatable bonds immobilized in complex formation (unfavorable conformational entropy contribution).
Knowledge-based – based on statistical observations of intermolecular close contacts in large 3D databases (such as the Cambridge Structural Database or Protein Data Bank) which are used to derive statistical "potentials of mean force". This method is founded on the assumption that close intermolecular interactions between certain types of atoms or functional groups that occur more frequently than one would expect by a random distribution are likely to be energetically favorable and therefore contribute favorably to binding affinity.
Machine-learning – Unlike these classical scoring functions, machine-learning scoring functions are characterized by not assuming a predetermined functional form for the relationship between binding affinity and the structural features describing the protein-ligand complex. In this way, the functional form is inferred directly from the data. Machine-learning scoring functions have consistently been found to outperform classical scoring functions at binding affinity prediction of diverse protein-ligand complexes. This has also been the case for target-specific complexes, although the advantage is target-dependent and mainly depends on the volume of relevant data available. When appropriate care is taken, machine-learning scoring functions tend to strongly outperform classical scoring functions at the related problem of structure-based virtual screening. Furthermore, if data specific for the target is available, this performance gap widens These reviews provide a broader overview on machine-learning scoring functions for structure-based drug design. The choice of decoys for a given target is one of the most important factors for training and testing any scoring function.
The first three types, force-field, empirical and knowledge-based, are commonly referred to as classical scoring functions and are characterized by assuming their contributions to binding are linearly combined. Due to this constraint, classical scoring functions are unable to take advantage of large amounts of training data.
== Refinement ==
Since different scoring functions are relatively co-linear, consensus scoring functions may not improve accuracy significantly. This claim went somewhat against the prevailing view in the field, since previous studies had suggested that consensus scoring was beneficial.
A perfect scoring function would be able to predict the binding free energy between the ligand and its target. But in reality both the computational methods and the computational resources put restraints to this goal. So most often methods are selected that minimize the number of false positive and false negative ligands. In cases where an experimental training set of data of binding constants and structures are available a simple method has been developed to refine the scoring function used in molecular docking.
== References == | Wikipedia/Scoring_functions_for_docking |
A protein superfamily is the largest grouping (clade) of proteins for which common ancestry can be inferred (see homology). Usually this common ancestry is inferred from structural alignment and mechanistic similarity, even if no sequence similarity is evident. Sequence homology can then be deduced even if not apparent (due to low sequence similarity). Superfamilies typically contain several protein families which show sequence similarity within each family. The term protein clan is commonly used for protease and glycosyl hydrolases superfamilies based on the MEROPS and CAZy classification systems.
== Identification ==
Superfamilies of proteins are identified using a number of methods. Closely related members can be identified by different methods to those needed to group the most evolutionarily divergent members.
=== Sequence similarity ===
Historically, the similarity of different amino acid sequences has been the most common method of inferring homology. Sequence similarity is considered a good predictor of relatedness, since similar sequences are more likely the result of gene duplication and divergent evolution, rather than the result of convergent evolution. Amino acid sequence is typically more conserved than DNA sequence (due to the degenerate genetic code), so it is a more sensitive detection method. Since some of the amino acids have similar properties (e.g., charge, hydrophobicity, size), conservative mutations that interchange them are often neutral to function. The most conserved sequence regions of a protein often correspond to functionally important regions like catalytic sites and binding sites, since these regions are less tolerant to sequence changes.
Using sequence similarity to infer homology has several limitations. There is no minimum level of sequence similarity guaranteed to produce identical structures. Over long periods of evolution, related proteins may show no detectable sequence similarity to one another. Sequences with many insertions and deletions can also sometimes be difficult to align and so identify the homologous sequence regions. In the PA clan of proteases, for example, not a single residue is conserved through the superfamily, not even those in the catalytic triad. Conversely, the individual families that make up a superfamily are defined on the basis of their sequence alignment, for example the C04 protease family within the PA clan.
Nevertheless, sequence similarity is the most commonly used form of evidence to infer relatedness, since the number of known sequences vastly outnumbers the number of known tertiary structures. In the absence of structural information, sequence similarity constrains the limits of which proteins can be assigned to a superfamily.
=== Structural similarity ===
Structure is much more evolutionarily conserved than sequence, such that proteins with highly similar structures can have entirely different sequences. Over very long evolutionary timescales, very few residues show detectable amino acid sequence conservation, however secondary structural elements and tertiary structural motifs are highly conserved. Some protein dynamics and conformational changes of the protein structure may also be conserved, as is seen in the serpin superfamily. Consequently, protein tertiary structure can be used to detect homology between proteins even when no evidence of relatedness remains in their sequences. Structural alignment programs, such as DALI, use the 3D structure of a protein of interest to find proteins with similar folds. However, on rare occasions, related proteins may evolve to be structurally dissimilar and relatedness can only be inferred by other methods.
=== Mechanistic similarity ===
The catalytic mechanism of enzymes within a superfamily is commonly conserved, although substrate specificity may be significantly different. Catalytic residues also tend to occur in the same order in the protein sequence. For the families within the PA clan of proteases, although there has been divergent evolution of the catalytic triad residues used to perform catalysis, all members use a similar mechanism to perform covalent, nucleophilic catalysis on proteins, peptides or amino acids. However, mechanism alone is not sufficient to infer relatedness. Some catalytic mechanisms have been convergently evolved multiple times independently, and so form separate superfamilies, and in some superfamilies display a range of different (though often chemically similar) mechanisms.
== Evolutionary significance ==
Protein superfamilies represent the current limits of our ability to identify common ancestry. They are the largest evolutionary grouping based on direct evidence that is currently possible. They are therefore amongst the most ancient evolutionary events currently studied. Some superfamilies have members present in all kingdoms of life, indicating that the last common ancestor of that superfamily was in the last universal common ancestor of all life (LUCA).
Superfamily members may be in different species, with the ancestral protein being the form of the protein that existed in the ancestral species (orthology). Conversely, the proteins may be in the same species, but evolved from a single protein whose gene was duplicated in the genome (paralogy).
=== Diversification ===
A majority of proteins contain multiple domains. Between 66-80% of eukaryotic proteins have multiple domains while about 40-60% of prokaryotic proteins have multiple domains. Over time, many of the superfamilies of domains have mixed together. In fact, it is very rare to find “consistently isolated superfamilies”. When domains do combine, the N- to C-terminal domain order (the "domain architecture") is typically well conserved. Additionally, the number of domain combinations seen in nature is small compared to the number of possibilities, suggesting that selection acts on all combinations.
== Examples ==
α/β hydrolase superfamily
Members share an α/β sheet, containing 8 strands connected by helices, with catalytic triad residues in the same order, activities include proteases, lipases, peroxidases, esterases, epoxide hydrolases and dehalogenases.
Alkaline phosphatase superfamily
Members share an αβα sandwich structure as well as performing common promiscuous reactions by a common mechanism.
Globin superfamily
Members share an 8-alpha helix globular globin fold.
Immunoglobulin superfamily
Members share a sandwich-like structure of two sheets of antiparallel β strands (Ig-fold), and are involved in recognition, binding, and adhesion.
PA clan
Members share a chymotrypsin-like double β-barrel fold and similar proteolysis mechanisms but sequence identity of <10%. The clan contains both cysteine and serine proteases (different nucleophiles).
Ras superfamily
Members share a common catalytic G domain of a 6-strand β sheet surrounded by 5 α-helices.
RSH superfamily
Members share capability to hydrolyze and/or synthesize ppGpp alarmones in the stringent response.
Serpin superfamily
Members share a high-energy, stressed fold which can undergo a large conformational change, which is typically used to inhibit serine and cysteine proteases by disrupting their structure.
TIM barrel superfamily
Members share a large α8β8 barrel structure. It is one of the most common protein folds and the monophylicity of this superfamily is still contested.
== Protein superfamily resources ==
Several biological databases document protein superfamilies and protein folds, for example:
Pfam - Protein families database of alignments and HMMs
PROSITE - Database of protein domains, families and functional sites
PIRSF - SuperFamily Classification System
PASS2 - Protein Alignment as Structural Superfamilies v2
SUPERFAMILY - Library of HMMs representing superfamilies and database of (superfamily and family) annotations for all completely sequenced organisms
SCOP and CATH - Classifications of protein structures into superfamilies, families and domains
Similarly there are algorithms that search the PDB for proteins with structural homology to a target structure, for example:
DALI - Structural alignment based on a distance alignment matrix method
== See also ==
== References ==
== External links ==
Media related to Protein superfamilies at Wikimedia Commons | Wikipedia/Protein_homology |
Behçet's disease (BD) is a type of inflammatory disorder which affects multiple parts of the body. The most common symptoms include painful sores on the mucous membranes of the mouth and other parts of the body, inflammation of parts of the eye, and arthritis. The sores can last from a few days, up to a week or more. Less commonly there may be inflammation of the brain or spinal cord, blood clots, aneurysms, or blindness. Often, the symptoms come and go.
The cause is unknown. It is believed to be partly genetic. Behçet's is not contagious. Diagnosis is based on at least three episodes of mouth sores in a year, together with at least two of the following: genital sores, eye inflammation, skin sores, a positive skin prick test.
There is no cure. Treatments may include immunosuppressive medication such as corticosteroids and anti-TNFs as well as lifestyle changes. Lidocaine mouthwash may help with the pain. Colchicine may decrease the frequency of attacks.
While rare in the United States and Europe, it is more common in the Middle East and Asia. In Turkey, for example, about 2 per 1,000 are affected. Onset is usually in a person's twenties or forties. The disease was initially described by Turkish dermatologist Hulusi Behçet in 1937.
== Signs and symptoms ==
=== Skin and mucosa ===
Nearly all people with Behçet's disease present with some form of painful ulcerations inside the mouth. They are a form of aphthous ulcers or non-scarring oral lesions. The oral lesions are similar to those found in inflammatory bowel disease and can be relapsing. Painful genital ulcerations usually develop around the anus, vulva, or scrotum and cause scarring in 75 percent of the patients. Additionally, patients may present with erythema nodosum, cutaneous pustular vasculitis, and lesions similar to pyoderma gangrenosum.
=== Eyes ===
Inflammatory eye disease can develop early in the disease course and lead to permanent vision loss in 20 percent of cases. Ocular involvement can be in the form of posterior uveitis, anterior uveitis, or retinal vasculitis. Anterior uveitis presents with painful eyes, conjuctival redness, hypopyon, and decreased visual acuity, while posterior uveitis presents with painless decreased visual acuity and visual field floaters. A rare form of ocular (eye) involvement in this syndrome is retinal vasculitis which presents with painless decrease of vision with the possibility of floaters or visual field defects.
Optic nerve involvement in Behçet's disease is rare, typically presenting as progressive optic atrophy and visual loss. However, cases of acute optic neuropathy (specifically anterior ischemic optic neuropathy) have also been reported to occur. Optic nerve atrophy has been identified as the most common cause of visual impairment. Behçet's disease may result in primary or secondary optic nerve involvement. Papilledema as a result of dural sinus thrombosis and atrophy resulting from retinal disease, have been characterized as secondary causes of optic nerve atrophy in Behçet's disease.
Signs and symptoms of acute optic neuropathy include painless loss of vision which may affect either one or both eyes, reduced visual acuity, reduced color vision, relative afferent pupillary defect, central scotoma, swollen optic disc, macular edema, or retrobulbar pain. When these symptoms occur with concurrent mucocutaneous ulcerations, they raise suspicion of acute optic neuropathy in Behçet's Disease. Progressive optic atrophy may result in decreased visual acuity or color vision. Intracranial hypertension with papilledema may be present.
Episcleritis may occur, which causes eye redness and mild pain, without a significant impact on vision.
=== Bowels ===
Gastrointestinal (GI) manifestations include abdominal pain, nausea, and diarrhea with or without blood, and they often involve the terminal ileum and ileocecal valve. Some patients with BD experience abdominal tenderness, bloating, and general abdominal discomfort. When mild this can resemble irritable bowel syndrome; more severe cases bear similarities to inflammatory bowel diseases such as ulcerative colitis or Crohn's. Behçet's disease causes ulcers in the terminal ileum and ileocecal valve. The ulcers may be aphthous or have a classic punched out appearance with undermining. Linear and fissuring ulcers up to 5 cm may be present. Biopsies show vasculitis (phlebitis or venulitis) with a neutrophilic inflammatory infiltrate. Involvement of the oesophagus, stomach and large intestine is rare.
=== Lungs ===
Lung involvement is typically in the form of hemoptysis, pleuritis, cough, or fever, and in severe cases can be life-threatening if the outlet pulmonary artery develops an aneurysm which ruptures causing severe vascular collapse and death from bleeding in the lungs. Pulmonary artery thrombosis may occur.
=== Joints ===
Arthritis is seen in up to half of people, and is usually a non-erosive poly or oligoarthritis primarily of the large joints of the lower extremities.
=== Kidneys ===
Behçet's disease can rarely result in renal involvement. This can manifest in the following:
Glomerulonephritis
Renal amyloidosis
IgA nephropathy
Vascular disease
Drug side effects, such as NSAIDs (non-steroidal anti-inflammatories), cyclophosphamide, cyclosporine and tacrolimus.
Small vessel vascular disease results in renal vasculitis, whereas large vessel involvement causes aneurysms (bulging) and thrombosis (blockages). Serious kidney problems are more common in men typically with a history of large vessel involvement in other parts of the body. Bladder and urethral involvement is rare in Behçet's disease.
=== Brain ===
Central nervous system (CNS) involvement most often occurs as a chronic meningoencephalitis. Lesions tend to occur in the brainstem, the basal ganglia and deep hemispheric white matter and may resemble those of multiple sclerosis (MS). Brainstem atrophy is seen in chronic cases.
Neurological involvements range from aseptic meningitis to vascular thrombosis such as dural sinus thrombosis and organic brain syndrome manifesting with confusion, seizures, and memory loss. Sudden hearing loss (sensorineural) is often associated with it. They often appear late in the progression of the disease but are associated with a poor prognosis.
=== Heart ===
Chronic aortic regurgitation due to aortic root disease may also be seen. Although infrequent, myocardial infarction (heart attack) with angiographically identified acute coronary artery thrombosis has been reported, including one case with a pathologically demonstrable lesion due to arteritis found at autopsy.
=== Blood vessels ===
Blood vessel problems are observed in 7–29% of people with arterial lesions representing 15% of vascular lesions. Arterial lesions pose a greater risk. Most common arterial lesions are occlusions or stenosis and aneurysms or pseudoaneurysms.
== Cause ==
The cause is not well-defined, but it is primarily characterized by auto-inflammation of the blood vessels. Although sometimes erroneously referred to as a diagnosis of exclusion, the diagnosis can sometimes be reached by pathologic examination of the affected areas.
The primary mechanism of the damage is autoimmune, which by definition is an overactive immune system that targets the patient's own body. The involvement of a subset of T cells (Th17) seems to be important. The primary cause is not well known. In fact, no one knows yet why the immune system starts to behave this way in Behçet's disease. There does however seem to be a genetic component involved, as first degree relatives of the affected patients are often affected in more than the expected proportion for the general population.
Research suggests that previous infections may provoke the autoimmune responses present in Behçet's disease. Heat shock proteins (HSPs) are present in some bacteria and serve as a "danger signal" to the immune system. However, some HSPs share a similarity in bacteria and humans. The anti-HSP60 and anti-HSP65 antibodies that target HSPs produced by Streptococci (including S. sanguinis and S. pyogenes) and Mycobacterium tuberculosis can also target human HSPs, leading to immune responses linked to uveitis and various symptoms shown in parenchymal neuro-Behçet's disease.
An association with the GIMAP ("GTPase of the immunity-associated protein") family of genes on the long arm of chromosome 7 (7q36.1) has been reported. Gene locations of single-nucleotide polymorphisms associated with Behçet's disease included GIMAP1, GIMAP2 and GIMAP4.
== Pathophysiology ==
Behçet's disease is considered more prevalent in the areas surrounding the old silk trading routes in the Middle East and in Central Asia. Thus, it is sometimes known as Silk Road disease. However, this disease is not restricted to people from these regions. A large number of serological studies show a linkage between the disease and HLA-B51. HLA-B51 is more frequently found from the Middle East to South Eastern Siberia, but the incidence of B51 in some studies was 3 fold higher than the normal population. However, B51 tends not to be found in disease when a certain SUMO4 gene variant is involved, and symptoms appear to be milder when HLA-B27 is present. At the current time, a similar infectious origin has not yet been confirmed that leads to Behçet's disease, but certain strains of S. sanguinis has been found to have a homologous antigenicity.
Vasculitis resulting in occlusion of the vessels supplying the optic nerve may be the cause of acute optic neuropathy and progressive optic atrophy in Behçet's disease. Histological evaluation in a reported case of acute optic neuropathy demonstrated substitution of the axonal portion of the optic nerve with fibrous astrocytes without retinal changes. CNS involvement in Behçet's disease may lead to intracranial hypertension most commonly due to dural venous sinus thrombosis and subsequent secondary optic atrophy.
== Diagnosis ==
There is no specific pathological testing or technique available for the diagnosis of the disease, although the International Study Group criteria for the disease are highly sensitive and specific, involving clinical criteria and a pathergy test. Behçet's disease has a high degree of resemblance to diseases that cause mucocutaneous lesions such as Herpes simplex labialis, and therefore clinical suspicion should be maintained until all the common causes of oral lesions are ruled out from the differential diagnosis.
Visual acuity, or color vision loss with concurrent mucocutaneous lesions or systemic Behçet's disease symptoms should raise suspicion of optic nerve involvement in Behçet's disease and prompt a work-up for Behçet's disease if not previously diagnosed in addition to an ocular work-up. Diagnosis of Behçet's disease is based on clinical findings including oral and genital ulcers, skin lesions such as erythema nodosum, acne, or folliculitis, ocular inflammatory findings and a pathergy reaction. Inflammatory markers such ESR, and CRP may be elevated. A complete ophthalmic examination may include a slit lamp examination, optical coherence tomography to detect nerve loss, visual field examinations, fundoscopic examination to assess optic disc atrophy and retinal disease, fundoscopic angiography, and visual evoked potentials, which may demonstrate increased latency. Optic nerve enhancement may be identified on Magnetic Resonance Imaging (MRI) in some patients with acute optic neuropathy. However, a normal study does not rule out optic neuropathy. Cerebrospinal fluid (CSF) analysis may demonstrate elevated protein level with or without pleocytosis. Imaging including angiography may be indicated to identify dural venous sinus thrombosis as a cause of intracranial hypertension and optic atrophy.
=== Diagnostic guidelines ===
According to the International Study Group guidelines, for a patient to be diagnosed with Behçet's disease, the patient must have oral (aphthous) ulcers (any shape, size, or number at least three times in any twelve-month period) along with two of the following four hallmark symptoms:
eye inflammation (iritis, uveitis, retinal vasculitis, cells in the vitreous)
genital ulcers (including anal ulcers and spots in the genital region and swollen testicles or epididymitis in men)
pathergy reaction (papule >2 mm dia. 24–48 hrs or more after needle-prick). The pathergy test has a specificity of 95 percent to 100 percent, but the results are often negative in American and European patients
skin lesions (papulo-pustules, folliculitis, erythema nodosum, acne in post-adolescents not on corticosteroids)
Despite the inclusive criteria set forth by the International Study Group, there are cases where not all the criteria can be met and therefore a diagnosis cannot readily be made. There is, however, a set of clinical findings that a physician can rely upon in making a tentative diagnosis of the disease; essentially, Behçet's disease does not always follow the International Study Group guidelines and so a high degree of suspicion for a patient who presents having any number of the following findings is necessary:
arthritis/arthralgia
cardio-vascular problems of an inflammatory origin
changes of personality, psychoses
deep vein thrombosis
epididymitis
extreme exhaustion – chronic fatigue
inflammatory problems in chest and lungs
mouth ulcers
nervous system symptoms
problems with hearing or balance
stomach or bowel inflammation
superficial thrombophlebitis
any other members of the family with a diagnosis of Behçet's disease.
== Treatment ==
Current treatment is aimed at easing the symptoms, reducing inflammation, and controlling the immune system. The quality of the evidence for treating the oral ulcers associated with Behçet's disease, however, is poor.
High-dose corticosteroid therapy is often used for severe disease manifestations. Anti-TNF therapy such as infliximab has shown promise in treating the uveitis associated with the disease. Infliximab as well as other anti-TNF therapies including etanercept and adalimumab may be useful in treating mucocutaneous disease according to several case reports and prospective studies, as well as one randomized trial for etanercept. Apremilast may also be used to treat oral ulcers associated with Behçet's disease.
Interferon alpha-2a may also be an effective alternative treatment, particularly for the genital and oral ulcers as well as ocular lesions. Azathioprine, when used in combination with interferon alpha-2b also shows promise, and colchicine can be useful for treating some genital ulcers, erythema nodosum, and arthritis. Benzathine-penicillin may also reduce new arthritic attacks.
Thalidomide has also been used due to its immune-modifying effect. Dapsone and rebamipide have been shown, in small studies, to have beneficial results for mucocutaneous lesions.
Given its rarity, the optimal treatment for acute optic neuropathy in Behçet's disease has not been established. Early identification and treatment are essential. Response to ciclosporin, periocular triamcinolone, and IV methylprednisolone followed by oral prednisone has been reported although relapses leading to irreversible visual loss may occur even with treatment. Immunosuppressants such as interferon-alpha and tumour necrosis factor antagonists may improve though not completely reverse symptoms of ocular Behçet's disease, which may progress over time despite treatment. When symptoms are limited to the anterior chamber of the eye prognosis is improved. Posterior involvement, particularly optic nerve involvement, is a poor prognostic indicator. Secondary optic nerve atrophy is frequently irreversible. Lumbar puncture or surgical treatment may be required to prevent optic atrophy in cases of intracranial hypertension refractory to treatment with immunomodulators and steroids.
Intravenous immunoglobulin therapy (IVIg) could be a treatment for severe or complicated cases.
A recent 2024 reports that infliximab improved the likelihood of achieving a complete response at 22 weeks for patients with severe Behçet’s syndrome compared to cyclophosphamide, according to head-to-head trial data. Mild to moderate adverse events, primarily infections, were reported in 29.6% of patients on infliximab and 64% on cyclophosphamide. Serious adverse events occurred in 15% and 12% of patients, respectively.
=== Surgery ===
Surgical treatment of arterial manifestations of BD bears many pitfalls since the obliterative endarteritis of vasa vasorum causes thickening of the medial layer and splitting of elastin fibers. Therefore, anastomotic pseudoaneurysms are likely to form, as well as pseudoaneurysms at the site of the puncture in case of angiography or endovascular treatment; furthermore, early graft occlusion may occur.
For these reasons, invasive treatment should not be performed in the acute and active phases of the disease when inflammation is at its peak. The evaluation of disease's activity is usually based on relapsing symptoms, ESR (erythrocyte sedimentation rate), and serum levels of CRP (C-reactive protein).
Endovascular treatment can be an effective and safe alternative to open surgery, with less postoperative complications, faster recovery time, and reduced need for intensive care, while offering patency rates and procedural success rates comparable with those of surgery. This notwithstanding, long-term results of endovascular treatment in BD are still to be determined.
== Epidemiology ==
The syndrome is rare in the United States, Africa and South America, but is common in Asia, suggesting a possible cause endemic to those areas. A theory suggested that past exposure to lethal infectious agents might have fixed the genetic susceptibility factors to Behçet's disease in those area. An estimated 15,000 to 20,000 Americans have been diagnosed with this disease. In the UK, it is estimated to have about 1 case for every 100,000 people. Globally, males are affected more frequently than females.
In an epidemiologic study, 56 percent of patients with Behçet's disease developed ocular involvement at a mean age of 30. Ocular involvement was the first manifestation of Behçet's disease in 8.6 percent of patients. Ocular Behçet's disease with involvement of the optic nerve is rarely reported. Among patients with ocular Behçet's disease funduscopic findings of optic atrophy, and optic disc paleness have been identified with a frequency of 17.9 percent and 7.4 percent, respectively. Other fundoscopic findings include vascular sheathing (23.7%), retinal hemorrhage (9%), macular edema (11.3%), branch retinal vein occlusion (5.8%), and retinal edema (6.6%). However, optic atrophy was the most significant cause of visual impairment identified in 54 percent of patients with ocular Behçet's disease and permanent visual impairment.
== Pregnancy ==
With Behçet's disease as a pre-existing disease in pregnancy or acquired, the pregnancy does not have an adverse effect on the course of Behçet's disease and may possibly ameliorate its course. Still, there is a substantial variability in clinical course between patients and even for different pregnancies in the same patient. Also, the other way around, Behçet's disease confers an increased risk of pregnancy complications, miscarriage and Cesarean section.
Behçet's can cause male infertility, either as a result of the condition itself or of a side effect of concomitant medication such as colchicine, which is known to lower sperm count.
== History ==
The first modern formal description of the symptoms was made by H. Planner and F. Remenovsky and published in 1922 in the Archiv für Dermatologie und Syphilis. Behçet's disease is named after Hulusi Behçet (1889–1948), the Turkish dermatologist and scientist who first recognized the three main symptoms of the syndrome in one of his patients in 1924 and reported his research on the disease in Journal of Skin and Venereal Diseases in 1936. The name (Morbus Behçet) was formally adopted at the International Congress of Dermatology in Geneva in September 1947. Symptoms of this disease may have been described by Hippocrates in the 5th century BC, in his Epidemion (book 3, case 7).
Some sources use the term "Adamantiades's syndrome" or "Adamantiades–Behçet syndrome", for the work done by Benediktos Adamantiades. However, the current World Health Organization/ICD-10 standard is "Behçet's disease". In 1991, Saudi Arabian medical researchers described neuro-Behçet's disease, a neurological involvement in Behçet's disease, considered one of the most devastating manifestations of the disease. The mechanism can be immune-mediated or thrombotic. The term dates back to at least 1990.
== References ==
== Further reading ==
== External links ==
Questions and answers about Behçet's disease – US National Institute of Arthritis and Musculoskeletal and Skin Diseases | Wikipedia/Behcet's_Disease |
A drug-eluting stent (DES) is a tube made of a mesh-like material used to treat narrowed arteries in medical procedures both mechanically (by providing a supporting scaffold inside the artery) and pharmacologically (by slowly releasing a pharmaceutical compound). A DES is inserted into a narrowed artery using a delivery catheter usually inserted through a larger artery in the groin or wrist. The stent assembly has the DES mechanism attached towards the front of the stent, and usually is composed of the collapsed stent over a collapsed polymeric balloon mechanism, the balloon mechanism is inflated and used to expand the meshed stent once in position. The stent expands, embedding into the occluded artery wall, keeping the artery open, thereby improving blood flow. The mesh design allows for stent expansion and also for new healthy vessel endothelial cells to grow through and around it, securing it in place.
A DES is different from other types of stents in that it has a coating that delivers medication directly into the blood vessel wall. The stent slowly releases a drug to prevent the growth of scar tissue and new obstructive plaque material which caused the original blood vessel stenosis, this clogging of a stent is termed restenosis. A DES is fully integrated with a catheter delivery system and is viewed as one integrated medical device.
DESs are commonly used in the treatment of narrowed arteries in the heart (coronary artery disease), but also elsewhere in the body, especially the legs (peripheral artery disease). Over the last three decades, coronary stenting has matured into a primary minimally invasive treatment tool in managing CAD. Coronary artery stenting is inherently tied to percutaneous coronary intervention (PCI) procedures. PCI is a minimally invasive procedure performed via a catheter (not by open-chest surgery), it is the medical procedure used to place a DES in narrowed coronary arteries. PCI procedures are performed by an interventional cardiologist using fluoroscopic imaging techniques to see the location of the required DES placement. PCI uses larger peripheral arteries in the arms or the legs to thread a catheter/DES device through the arterial system and place the DES in the narrowed coronary artery or arteries. Multiple stents are often used depending on the degree of blockage and the number of diseased coronary arteries that are being treated.
== Design ==
A drug-eluting stent (DES) is a small mesh tube that is placed in the arteries to keep them open in the treatment of vascular disease. The stent slowly releases a drug to block cell proliferation (a biological process of cell growth and division), thus preventing the arterial narrowing (stenosis) that can occur after stent implantation. While such stents can be used in various arteries throughout the body, they are commonly placed in the coronary arteries to treat coronary heart disease. DES products are integrated medical devices and are part of a percutaneous coronary intervention (PCI) delivery system.
DES is a medical device with several key properties: it functions as a structural scaffold, physically keeping an artery open to ensure blood flow; the device has specific drug delivery features, and the chosen drug is critical for its effectiveness. The drug, the hallmark compenent of the device, is selected for its suitability in inhibiting restenosis and its pharmacokinetics. Apart from the drug, the materials used in the fabrication of the device are also essential and are carefully chosen for their biocompatibility and durability in a biological environment, such as human blood; these materials must also withstand the constant motion of the heart's beat and be suitable for future patient imaging using magnetic resonance imaging (MRI) technologies, which employ high magnetic fields.
Other components, such as the catheter design, also play significant roles in the device's overall functionality and effectiveness.
DES are typically composed of metal alloys, most commonly stainless steel or cobalt-chromium, but can also be made of other materials such as platinum-chromium or nickel-titanium. The stent is often coated with a polymer to control the release of drugs. The role of polymers in drug delivery is significant as they regulate the rate at which the drug is released into the surrounding tissue. There are also polymer-free stents where the drug is directly coated on the stent or contained in reservoirs within the stent.
The design of the stent includes struts, which are thin wire structures that make up the stent frame. The strut thickness can influence the stent's performance, with thinner struts generally being associated with lower restenosis rates and reduced thrombosis risk.
Most DES are balloon-expandable, meaning they are mounted on a balloon catheter and expand when the balloon is inflated. There are also self-expanding stents, which automatically expand when deployed. The very first stent, introduced in 1986, was of this type.
The stent tube mesh is initially collapsed onto the catheter—in this collapsed state, it is small enough to be passed though relatively narrow arteries and then expanded in its destination place, pushing firmly to the diseased artery wall.
The pharmaceutical compounds that DES emit are antiproliferative agents such as sirolimus, everolimus, zotarolimus, paclitaxel and biolimus. These drugs help prevent the arterial narrowing that can occur after stent implantation. These drugs are also used for other purposes, that involve moderating the immune system or treating cancer. They work by inhibiting cell growth. In DES, they are used in very small amounts and for a short time, and only in the area where the stent is placed.
There is a distinction between coronary stents and peripheral stents. While both are used to prevent the narrowing of arteries, coronary stents are specifically for the coronary arteries, while peripheral stents are for any other arteries in the body. Peripheral stents are mostly bare metal ones; some peripheral DES, of the self-expanding type, are used in arteries of the legs.
Bioresorbable DES are made of materials that can be absorbed by the body over time, potentially reducing potential long-term complications associated with permanent stents.
== Uses ==
=== Atherosclerosis: a general background ===
Atherosclerosis is a chronic disease that affects the large and medium-sized arteries. It is characterized by the accumulation of calcium, fats (such as cholesterol) and other substances in the innermost layer of the endothelium, a layer of cells that line the interior surface of blood vessels. Atherosclerosis is considered to be the most common form of arteriosclerosis, which refers to the loss of arterial elasticity caused by thickening and stiffening of blood vessels.
Atherosclerosis can begin as early as childhood with the development of small "fatty streaks" within arteries. These streaks are essentially deposits of fat. Over time, these initial lesions grow larger and become thicker, forming atheromas (atherosclerotic plaques).
Drug-eluting stents (DESs) are used in the treatment of atherosclerosis in both coronary interventions and peripheral arterial interventions:
In coronary interventions, DESs are used to treat coronary artery disease, which is primarily caused by atherosclerosis. The stents are inserted into narrowed coronary arteries and then expanded to open up the narrowed artery. The drug compound released by the stents suppresses cellular growth in the newly stented area, reducing the potential for blockage within the stent area itself.
In peripheral arterial interventions, DESs have established themselves as the go-to choice for addressing symptomatic peripheral arterial disease (PAD). These highly effective stents are deployed in the treatment of peripheral arterial occlusive disease (PAOD), a condition that shares resemblances with coronary artery disease but specifically affects the peripheral arteries. By employing DESs, healthcare professionals can provide optimal care and intervention to manage PAOD, ultimately improving patient outcomes and mitigating associated complications.
DESs are used in the management of atherosclerosis in both coronary and peripheral arterial interventions. They help improve blood flow and reduce the risk of restenosis, thereby improving patient outcomes. The use of DESs is accompanied by appropriate medical therapy and lifestyle modifications to manage atherosclerosis effectively.
=== Stenosis and restenosis of blood vessels ===
Stenosis of blood vessels refers to the narrowing of the blood vessels, which can restrict blood flow to the organs and tissues. This condition is often caused by the buildup of fatty deposits in the arteries, a process also called atherosclerosis.
In the context of stents, stenosis is a significant concern. Stents are inserted into a narrowed artery during a procedure known as angioplasty. The stents help to open up the narrowed artery and improve blood flow. However, over time, the treated artery can close up again, a condition known as restenosis.
Restenosis, or in-stent restenosis, is a blockage or narrowing that comes back in the portion of the artery previously treated with a stent. Restenosis tends to happen three to six months after the procedure. Restenosis is even more likely to occur if a stent would not have been used.
When restenosis occurs, another procedure may be needed to correct the problem, such as the placement of a DES that gradually release a drug compound that suppresses cellular growth, thereby reducing the potential for blockage within the stent area itself. This therapy significantly reduces the occurrence of adverse events post-stenting.
Technically, a DES in a mesh tube implant devices that is used in angioplasty procedures to treat stenosis of blood vessels and prevent restinosis: the stent, which elutes drugs, is implanted into the blood vessel to help keep the vessel open and improve blood flow. Specifically, drug-eluting stents are used in the treatment of various medical conditions usually at the site of stenotic or occlusive arterial lesions, but one of the primary medical uses is in the treatment of coronary artery disease. Stents are inserted into narrowed coronary arteries, where the narrowing is primarily caused by atherosclerosis. Stents are then expanded to open up the narrowed artery. Such stents gradually release a drug compound that suppresses cellular growth, into the newly stented area, thereby reducing the potential for blockage within the stent area itself. Such blockage is termed in-stent restenosis (ISR). This in-stent blockage is most often caused by excessive cell proliferation or thrombi (blood clots). Anticoagulation therapy (blood thinners), has become a standard treatment following the placement of DES. This therapy significantly reduces the occurrence of adverse events post-stenting.
=== Coronary interventions ===
DESs have played a transformative role in the management of coronary artery disease. These stents are tiny, flexible mesh tubes employed during percutaneous coronary intervention (PCI) to address narrowed coronary arteries. What sets them apart is their special coating, which incorporates a drug delivery system that enables controlled release of medication over a specific period, typically within the first 30 to 45 days following implantation. This medication aids in inhibiting the formation of scar tissue within the stent and subsequent re-narrowing of the blood vessel.
PCI is a minimally invasive procedure. It involves the placement of a drug-eluting stent (DES) in a coronary artery. This procedure, previously known as angioplasty with a stent, is considered non-surgical as it is performed through a small puncture in a peripheral artery, avoiding the need to open the chest wall. While bleeding from the puncture site was once a concern, advancements in PCI practices have mitigated this issue through the use of pressure bands and arterial closure systems. Modern DES/PCI procedures are generally painless, although some mild discomfort may be experienced. In PCI, multiple DES are sometimes implanted within a single patient; the decision to use multiple stents is typically contingent on the extent of the coronary artery disease present and the number of diseased coronary arteries that require treatment.
=== Peripheral arterial interventions ===
DESs have emerged as the primary therapeutic approach for managing symptomatic peripheral arterial disease (PAD). These specialized stents are now widely utilized in the treatment of peripheral arterial occlusive disease (PAOD), a condition that shares similarities with coronary artery disease but affects the peripheral arteries. By deploying DESs, healthcare professionals can effectively address and alleviate the complications associated with PAOD, enhancing patient outcomes and quality of life. The use of DESs in peripheral arterial interventions has shown encouraging results in terms of primary patency (PP) and target lesion revascularization (TLR) compared with bare-metal stents (BMSs).
Different types of DESs are available on the market, each with different concentrations of drugs and showing varying efficacy. Among the different DESs, sirolimus-eluting stents and everolimus-eluting stents were found to be more effective than paclitaxel-eluting stents.
=== Clinical indications ===
PCI and stent placement are considered when someone shows signs of reduced blood flow in the arteries that supply the heart or when tests, such as different types of coronary artery imaging, show a blockage in those arteries.
Symptoms can include:
severe, pressure-like chest pain unrelieved by rest;
shortness of breath, fatigue, lightheadedness;
palpitations;
atypical symptoms: nausea, vomiting, indigestion, confusion, back pain.
In a medical setting, it's not very useful for doctors to rely solely on what people say about where their pain comes from or how it feels, because the way people describe chest pain caused by reduced blood flow to the heart can vary greatly and may not match what is typically taught in medical education or described in books and articles.
=== Contraindications ===
DES is not recommended in some cases as it may do more harm than good. DES is not suitable:
when individuals have a bleeding tendency;
when a coronary artery has no clear and identifiable narrowing;
when only one diseased coronary artery supplies oxygenated blood to the heart muscle. During stent placement, there is a short period of blood flow blockage by the balloon inflation. This blockage time is often longer than twenty seconds to allow the DES to expand and embed into the arterial wall. In this case, this time may be too long and cause serious events due to lack of blood to the heart muscle.
Bleeding disorders make DES unsuitable because of the need for anticoagulation drugs (blood thinners) during the procedure and in post-stenting aftercare. Other factors that could rule out the use of stents include a history of in-stent blockage, bleeding problems, complex or unsuitable coronary anatomy, or a short life expectancy due to other serious medical conditions.
=== Risks and complications ===
==== Risks from the procedure ====
Stent placement risks include bleeding, allergic reactions to the contrast agents used to visualize the coronary arteries, and myocardial infarction. With percutaneous coronary intervention (PCI), the requirement for emergency coronary artery bypass graft (CABG) surgery has decreased as better practices have been introduced. In some situations, coronary stenting is permitted in hospitals without cardiac surgery facilities, but such permission remains controversial because of the rare but unpredictable risk of coronary artery perforation.
==== Stent thrombosis risks ====
A complication of coronary stenting is stent thrombosis (blood clots). This occurs when a new clot forms within the stent and occludes blood flow, causing a heart attack.
==== In-stent restenosis risks (ISR) ====
DES were designed to specifically combat issues of restenosis that occurred with older bare-metal stents (BMS). Though less frequent with drug-eluting stents, restenosis can still occur.
Since the advent of DES technology, the incidence of ISR has significantly decreased.
=== Usage outside the scope of typical regulatory approval ===
DES have been shown to be superior to BMS in reducing short-term complications of stenting in saphenous vein grafts. However, the use of DESs in bypass grafts was not their originally intended use nor within the scope of originally regulatory approval (US FDA, European Medicines Agency, etc.). The practice of using a medical device or drug in a way not specified in the original or current approved labeling is often referred to as "off-label" use.
In regions were cardiac stenting has become commonplace, think tanks and advocacy groups express concern about the overzealous use of stents, because patients who received stents for unapproved reasons often have worse outcomes compared to patients who received stents for approved uses.
== Clinical procedure ==
=== DES placement ===
People who receive a coronary stent have different needs depending on their medical condition. Some patients are actually having a heart attack and need immediate life-saving emergency care. Other patients are at high risk of having a heart attack in the very near future. For people from each of these groups, PCI procedures may vary slightly, with particular modifications as to how they are sedated, pain management, and broader intensive care issues such as breathing support.
Many people who are not in critical care situations are usually fully awake during the PCI procedure and DES placement, but they receive local anesthetic at the site of catheter entry, to ensure there is no pain. Different sedation and pain management practices are used by different medical institutions and practitioners, but patient comfort is always a primary consideration.
The catheter/stent system is inserted into the body by piercing a peripheral artery (an artery in the arm or leg) and moved through the arterial system to deliver the DES into the blocked coronary artery. The stent is then expanded to widen (open) blocked or narrowed coronary arteries (narrowed by plaque buildup), caused by a condition called atherosclerosis. Peripheral arterial access is usually through the femoral (upper leg) or the radial artery (arm/wrist) and less often done through the brachial or ulnar artery (wrist/arm). In the past, controlling bleeding at the point of arterial access after the procedure was a problem. Modern arterial pressure bands and arterial closure systems now exist, which have helped control bleeding after the procedure, but it is still a concern.
Modern catheter/stent systems are integrated medical devices, made of a guidewire, catheter, balloon, and stent. The stent tube mesh is initially collapsed onto the balloon of the device, and it is small enough to be passed through relatively narrow peripheral arteries. When in position, the balloon is inflated by introducing physiological saline, and this pushes the overlaying stent firmly into the diseased artery wall, inflation time and pressure are recorded during this placement procedure. After placement, the balloon is deflated, and the device is removed from the body, leaving the expanded stent in place and opening up the artery.
The interventional cardiologist decides how to treat the blockage in the best way during the PCI/DES placement, based on real-time data. The cardiologist uses imaging data provided by both intravascular ultrasound (IVUS), and fluoroscopic imaging (combined with a radiopaque dye). During the procedure, the information obtained from these two sources enables the cardiologist to track the path of the catheter-DES device as it moves through the arterial blood vessels. This information also helps determine both the location and characteristics of any plaque causing narrowing in the arteries. Data from these two techniques is used to correctly position the stent and to obtain detailed information relating to the coronary arterial anatomy. Given that this anatomy varies greatly among individuals, having this information becomes a prerequisite for effective treatment. The obtained data is recorded on video and may be used in cases when further treatment is needed.
=== Post-stenting recovery and rehabilitation ===
For many people the stenting procedure does not require staying in the hospital for any extended time period, most people leave the hospital the same day. Much of the time immediately after the stenting is spent in a recovery area to make sure the access site is not bleeding and to ensure vital signs are stable.
In most hospital settings, the interventional cardiologist who performed the procedure will speak directly with the patient/family and give them information about how things went, and follow-up instructions. The nursing staff will keep an eye on the person's condition and use tools like ECG to monitor their heart. To prevent a blood clot from forming in the stent, medications are given right after the procedure. One common medication is plavix, which is a potent blood thinner that comes as a pill. Other medicines that thin the blood are also used, and it's typical to combine aspirin with plavix. For people who have had a heart attack, the length of hospitalization is dependent on the degree of heart muscle damage caused by the event.
A catheter with DES is a medical device, so people who receive it are given a medical device card. This card has information on the implanted DES and a medical device serial number. This information is important for future medical procedures, because it helps the doctors to know what type of device is in the person's body. Some arterial closure systems, which are devices that help to seal the access site after the procedure, are also medical devices and have their own informational cards.
The access site is the place where the catheter enters the artery in the arm or leg. There is usually soreness and bruising at this site. This bruising and soreness usually get better after a week or so. People are advised to rest for a week or two and not to lift heavy things. This is mainly to make sure the access site heals well. It is normal to have follow-up appointments with a cardiologist or a primary care provider/general practitioner within a week or two of the procedure.
People who get a coronary stent usually have more check-ups every three to six months for the first year, but this can vary. They usually do not need to have another coronary angiography, which is a test that uses a special dye and X-rays to see the arteries of the heart. If the doctors suspect that the heart disease is getting worse, they can prescribe a stress test, which is a test that measures how the heart works during physical activity. People who have symptoms or show signs of reduced blood flow to the heart in a stress test may need to have a diagnostic cardiac re-catheterization.
After PCI-stenting procedures, physical examinations are important. People who have a high risk of complications or more complex coronary problems may need to have angiography. This may be the case even if the results of non-invasive stress tests, which are tests that measure how the heart works during physical activity, appear normal.
Cardiac rehabilitation activities depend on many factors, but mainly on how much the heart muscle was damaged before the PCI/DES procedure. Many people who have this procedure have not had a heart attack, and their hearts may be fine. Others may have had a heart attack and their hearts may have trouble pumping oxygen-rich blood to the body. Rehabilitation activities are tailored to each person's needs.
== Efficacy ==
=== Benefits ===
DES are an improvement over older BMS devices as they reduce the chances of in-stent blockages. This reduces the incidence of serious post-stenting events such as, angina occurrence or recurrence, heart attacks, and death. They also reduce the likelihood of requiring another PCI procedure to open a blockage caused by the actual stent.
The major benefit of drug-eluting stents (DES) when compared to bare-metal stents (BMS) is the prevention of in-stent restenosis (ISR). Restenosis is a gradual re-narrowing of the stented segment that occurs most commonly between 3–12 months after stent placement. High rates of restenosis associated with BMS prompted the development of DES, which resulted in a reduction of ISR incidence to around 5-10%. Continued development of newer generation DES have resulted in the near-elimination of BMS from clinical practice.
=== Procedure outcomes ===
A key benefit of DES usage compared to BMS is a lower incidence of repeat revascularization procedures (re-stenting, invasive bypass surgeries etc.). Revascularization procedures are treatments that restore blood flow to parts of the heart that are not getting enough blood, a problem called ischemia. This can happen because of plaque buildup in the arteries of the heart, which can narrow or block them. Rates of repeat revascularizations and stent thrombosis (blood clots) are significantly lower in those who received DES compared to BMS.
Newer generations of DES devices have substantially improved safety outcomes, specifically regarding stent thrombosis, recurrent myocardial infarctions, and death.
== Considerations for regulatory submission, assessment and approval ==
There are a number of very detailed medical device design considerations for DES products, these considerations are included in submissions for approval to regulatory authorities such as the US FDA:
Aspects of the design that relate to a DES as structural devices that keep an artery open by purely physical means.
Choice of the construction materials, with a particular focus on biocompatibility, longevity in the human body, mechanical stress resistance and the suitability of the chosen material for future patient imaging using MRI technologies, due to the high magnetic fields used in such imaging.
Choice of a mechanism of the drug release: how long the drug lasts, and how to make the stent release the drug in a manner that inhibits in-stent restenosis.
Choice of chemical agent the stent will deliver.
Choice of the stent delivery technology as an integrated system: catheter design, placement visualization and assessment of the success of artery reperfusion (is the treated artery actually supplying cardiac muscle with sufficient oxygenated blood).
Quality assurance considerations such as those defined in ISO 13485.
Quality control considerations: what testing can be performed on each manufactured unit prior to release for sale to demonstrate its usage suitability.
Traceability issues, can a single stent be traced from the manufacturer to the patient it was implanted in. In the case of a recall of a product it is critical to be able to trace the stent from design, manufacture, and distribution to the patient.
The drug choice is a critical design element and determining its true effectiveness in inhibiting neointimal growth due to the proliferation of smooth muscle cells that would cause restenosis can be a design challenge. Much of the neointimal hyperplasia seems to be caused by inflammation.
Vascular stents are classified by the US as class III medical devices, meaning that they pose the highest risk to patients and are subject to both general and premarket approval, which requires clinical trials and scientific evidence of safety and effectiveness, as well as rigorous mechanical testing. During the mechanical testing process, universal testing machines induce bending, stretching, twisting, and putting pressure on vascular stents from various angles.
The specific properties of each type of stent and its intended use depend on the results of testing, and vice versa: different types of stents may need different or additional tests based on where they will be placed in the body and what they will be used for. Some of these additional tests might include checking how well the stent can withstand being crushed or bent out of shape, its resistance to getting kinks in it, whether it resists corrosion or damage over time, as well as making sure any coatings on the device remain intact.
== Alternatives to stenting procedures ==
Pharmacological therapy for coronary artery disease may be indicated instead of or in addition to invasive treatment. For those requiring percutaneous coronary intervention or surgery, medical therapy should be viewed as complementary to revascularization procedures, rather than an opposing strategy. Coronary artery bypass graft (CABG) surgery is an alternative to percutaneous coronary intervention (PCI) with drug-eluting stents (DES) for patients with ischemic left ventricular systolic dysfunction (LVSD). CABG is associated with lower risks of all-cause mortality, repeat revascularization, and myocardial infarction compared to PCI.
== History ==
The first procedure to treat blocked coronary arteries was coronary artery bypass graft surgery (CABG), wherein a section of vein or artery from elsewhere in the body is used to bypass the diseased segment of the coronary artery. In 1977, Andreas Grüntzig introduced percutaneous transluminal coronary angioplasty (PTCA), also called balloon angioplasty, in which a catheter was introduced through a peripheral artery and a balloon expanded to dilate the narrowed segment of the artery.
As equipment and techniques improved, the use of PTCA rapidly increased, and by the mid-1980s, PTCA and CABG were being performed at equivalent rates. Balloon angioplasty was generally effective and safe, but restenosis was frequent, occurring in about 30–40% of cases, usually within the first year after dilation. In about 3% of balloon angioplasty cases, failure of the dilation and acute or threatened closure of the coronary artery (often because of dissection) prompted emergency CABGs.
Charles Theodore Dotter and Melvin Judkins had proposed using prosthetic devices inside arteries in the leg to maintain blood flow after dilation as early as 1964. In 1986, Puel and Sigwart implanted the first coronary stent in a human patient. Several trials in the 1990s showed the superiority of stent placement over balloon angioplasty. Restenosis was reduced because the stent acted as a scaffold to hold open the dilated segment of the artery. Acute closure of the coronary artery (and the requirement for emergency CABG) was reduced, because the stent repaired dissections of the arterial wall. By 1999, stents were used in 84% of percutaneous coronary interventions (i.e., those done via a catheter, and not by open-chest surgery).
Early difficulties with coronary stents included a risk of early thrombosis (clotting) resulting in occlusion of the stent. Coating stainless steel stents with other substances such as platinum or gold did not eliminate this problem. High-pressure balloon expansion of the stent to ensure its full apposition to the arterial wall, combined with drug therapy using aspirin and another inhibitor of platelet aggregation (usually ticlopidine or clopidogrel) nearly eliminated this risk of early stent thrombosis.
Though it occurred less frequently than with balloon angioplasty or other techniques, stents nonetheless remained vulnerable to restenosis, caused almost exclusively by neointimal tissue growth (tissue formation in the inner 'tube' structure of the artery). To address this issue, developers of drug-eluting stents used the devices themselves as a tool for delivering medication directly to the arterial wall. While initial efforts were unsuccessful, the release (elution) of drugs with certain specific physicochemical properties from the stent was shown in 2001 to achieve high concentrations of the drug locally, directly at the target lesion, with minimal systemic side effects. As currently used in clinical practice, "drug-eluting" stents refers to metal stents that elute a drug designed to limit the growth of neointimal scar tissue, thus reducing the likelihood of stent restenosis.
The first type of DES to be approved by the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA) were sirolimus-eluting stents (SES), which release a natural product called sirolimus, an immunosuppressant drug. SES were shown to reduce the need for repeat procedures and improve the outcomes of patients with coronary artery disease. The sirolimus-eluting Cypher stent received CE mark approval in Europe in 2002, and then underwent a larger trial to demonstrate its safety and effectiveness for the US market. The trial, published in 2003, enrolled 1058 patients with more complex lesions and confirmed the superiority of SES over bare metal stents in terms of angiographic and clinical outcomes. Based on these results, the Cypher stent received FDA approval and was released in the US in 2003. The FDA approval process for DES involves submitting an investigational device exemption (IDE) application to conduct clinical trials under 21 CFR Part 812, and then a premarket approval (PMA) application to obtain marketing authorization under 21 CFR Part 8144. The FDA assigns the primary review responsibility to the Center for Devices and Radiological Health (CDRH), but also consults with the Center for Drug Evaluation and Research (CDER) for the drug component of the combination product.
The second type of DES to be approved by the EMA and the FDA were paclitaxel-eluting stents (PES), which release another natural product called paclitaxel. PES also reduced the need for repeat procedures and improved the outcomes of patients with different types of lesions and risk factors. The paclitaxel-eluting Taxus stent received FDA approval and was launched in the US in 2004, after a series of trials that compared it with a bare metal stent in various settings. The trials showed a significant reduction in target lesion revascularization and major adverse cardiac events with the Taxus stent at 9 and 12 months. Both SES and PES use natural products as the active agents to prevent the recurrence of blockages in the arteries. These DES have changed the practice of interventional cardiology and have become the preferred treatment for many patients with coronary artery disease.
The initial rapid acceptance of DES led to their peak usage in 2005, accounting for 90% of all stent implantations, but concerns about late stent thrombosis led to a decrease in DES usage in late 2006. Subsequent studies reassured the medical community about their safety, showing that while DES may have a slightly higher risk for very late stent thrombosis, they significantly reduce target vessel revascularization without increasing the incidence of death or myocardial infarction; these reassurances led to a resurgence in DES utilization, although it did not reach the peak usage rates seen in early 2006.
The concept of using absorbable (also called biodegradable, bioabsorbable or bioresorbable) materials in stents was first reported in 1878 by Huse who used magnesium wires as ligatures to halt the bleeding in vessels of three patients. Despite extensive search, the full name of this pioneer in the field remains elusive. In 20th century, a resorbable stent tested in humans was developed by the Igaki Medical Planning Company in Japan and was constructed from poly-L-lactic acid (a form of polylactic acid); they published their initial results in 2000. The German company Biotronik developed a magnesium absorbable (bioresorbable) stent and published clinical results in 2007.
The first company to bring a bioresorbable stent to market was Abbott Vascular which received European marketing approval in September 2012; the second was Elixir which received its CE mark in May 2013.
Despite the initial promise, the first-generation bioresorbable stents, such as the Absorb bioresorbable stent by Abbott, faced significant challenges in their performance. In comparison to current-generation drug-eluting stents, numerous trials revealed that these first-generation bioresorbsble stents exhibited poor outcomes. Specifically, they showed high rates of stent thrombosis (cases where an implanted coronary stent caused a thrombotic occlusion), target-lesion myocardial infarction (heart attack occurring at the site of the treated lesion), and target vessel revascularization (the need for further procedures to restore blood flow in the treated artery). In 2017, Abbott pulled its bioabsorbable stent, Absorb, from the European market after negative press regarding the device. Boston Scientific also announced termination of its Renuvia bioresorbable coronary stent program as studies showed higher risk of serious adverse events.
Currently, fully bioresorbable stents do not play a significant role in coronary interventions. While various manufacturers are proposing new stents and continuing their development, it remains uncertain whether they will have a substantial impact, unless there will be more data from their clinical trials. As of now, these stents are not widely utilized in practice.
Due to challenges in developing resorbable stents, many manufacturers have focused efforts on targeting or reducing drug release through bioabsorbable-polymer coatings. Boston Scientific's Synergy bioabsorbable polymer stent has been shown potential to reduce the length of dual antiplatelet therapy post-implantation. MicroPort's Firehawk target eluting stent has been shown to be non-inferior to traditional drug-eluting stents while using one-third of the amount of equivalent drug.
As for the materials used to make a DES, the first DES products available for treating patients were stainless steel alloys composed of iron, nickel, and chromium and were based on existing bare metal stents. These stents were hard to visualize with medical imaging, posed a risk of causing allergic responses, and were difficult to deliver. Subsequent new alloys were used, namely cobalt-chrome and platinum chrome, with improved performance. Bioresorbable stents have been developed in which the stent itself dissolves over time. Materials explored for use include magnesium, polylactic acid, polycarbonate polymers, and salicylic acid polymers. Resorbable stents have held the promise of providing an acute treatment that would eventually allow the vessel to function normally, without leaving a permanent device behind.
For the coating of DES, one to three or more layers of polymer can be used: a base layer for adhesion, a main layer that holds and elutes (releases) the drug into the arterial wall by contact transfer, and sometimes a top coat to slow down the release of the drug and extend its effect. The first few drug-eluting stents to be licensed used durable coatings. The first generation of coatings appears to have caused immunological reactions at times, and some possibly led to thrombosis. This has driven experimentation and the development of new coating approaches.
== Research directions ==
A research direction for a DES is to improve the material from which a device is made. The first-generation DES were made of stainless steel, while contemporary DES mainly consist of different kinds of alloys such as cobalt chromium and platinum chromium. In the current generation DES, thinner struts are employed than in the first-generation DES with preserved radial strength and radio-opacity. The lower strut thickness is believed to be associated with better stent-related outcomes including target lesion revascularization, myocardial infarction, and stent thrombosis.
Another area of research for DES focuses on polymers. The current generation DES includes both durable polymer-coated stents and biodegradable polymer-coated stents. It has been reported that the presence of a durable polymer in the body over a long period can lead to chronic inflammation and neoatherosclerosis. To address this potential limitation, researchers have developed biodegradable polymer DES as an alternative solution.
Scientists are also studying different drugs that could be used in DES to prevent restenosis. These drugs, which have immunosuppressive and anti-cancer properties, aim to inhibit the growth of smooth muscle cells. Additionally, there is a specific type of stent that features an extra layer of anti-CD4 antibodies on its struts. This additional layer is positioned on top of the polymer coating and aims to capture circulating endothelial progenitor cells. The goal behind this design is to promote improved healing of the blood vessel lining, known as the endothelium.
A potential research focus for DES is the application of a polymer-free DES in clinical practice: moving away from polymer-based DES and instead using either a polymer-free DES or a drug-coated coronary stent. In the case of the polymer-free DES, it utilizes an abluminal coating of probucol to control the release of sirolimus. On the other hand, the drug-coated coronary stent has a micro-structured abluminal surface that allows for direct application of an anti-restenotic drug.
== Society and culture ==
=== Brand names and manufacturers ===
As of 2023 there are over 20 different types of drug-eluting stents available, with differences in features and characteristics.
=== Economics ===
The economic evaluation of DES has been a topic of extensive research. In 2007, the overall incremental cost-effectiveness ratio in Europe was €98,827 per quality-adjusted life-years gained. Avoiding one revascularization with DES would cost €4,794, when revascularization with BMS costs €3,2606.
=== Controversies ===
There were controversies related to the use of DES. In 2012, a meta-analysis of clinical trial data showed no benefit of the use of DES for people with stable coronary artery compared to treatment with drugs, yet, The New York Times interviewed David Brown, an author of the analysis, who said that more than half of patients with stable coronary artery disease were implanted with stents without even trying drug treatment and that he believed this happened because hospitals and doctors wanted to make more money.
The interview sparked a debate among cardiologists, researchers, and patients about the appropriateness and effectiveness of DES for stable coronary artery disease: some agreed with the study's findings and questioned the overuse of stents, while others criticized the study's methods and limitations and defended the benefits of stents, arguing that the interviewee's statement was "outrageous and defamatory" and that he was "insulting the integrity of the entire profession.
In 2013 the Times of India reported that DES were widely overused and that Indian distributors used profits from high markups on DES to bribe doctors to use them.
In 2014 an investigation by the Maharashtra Food and Drug Administration found that high markups and bribery related to DES was still widespread.
=== Intellectual property disputes ===
There have been several patent disputes related to drug-eluting stents. In one of them, Boston Scientific Corporation (BSC) has been found guilty of infringing upon a patent awarded to the University of Texas at Arlington in 2003 and licensed to TissueGen. This patent involves technology developed by TissueGen founder Kevin Nelson, during his time as a faculty member at the university. The technology is designed to deliver drugs through an extruded fiber within an implanted vascular stent. As a result, BSC has been ordered to pay $42 million in lost royalties to both TissueGen and the university
=== Class action lawsuits ===
Drug-eluting stents have been associated with legal and ethical controversies, and there have been related class action lawsuits. In 2014, the former owners of St. Joseph Medical Center in Maryland settled a class action lawsuit for $37 million with hundreds of patients who received unnecessary DES implantation. The lawsuit alleged that Dr. Mark Midei, a cardiologist at the center, falsified the degree of coronary artery stenosis to justify the use of DES, exposing the patients to increased risks of thrombosis, bleeding, and infection. Another DES manufacturer, Cordis Corporation, a subsidiary of Johnson & Johnson, was involved in lawsuits from people who suffered adverse events from the Cypher Stent, a stainless-steel DES coated with sirolimus, an immunosuppressant drug. The Cypher Stent was approved by the FDA in 2003, but soon after, the FDA issued a Safety Warning following 290 reports of subacute thrombosis and at least 60 deaths related to the device.
== See also ==
bioresorbable stent – medical stent that dissolves or is absorbed by the body;
coronary stent – medical stent implanted into coronary arteries;
drug-eluting implant – implant for delivering a drug.
== References == | Wikipedia/Drug-eluting_stents |
The United Network for Organ Sharing (UNOS) is a non-profit scientific and educational organization that administers the only Organ Procurement and Transplantation Network (OPTN) in the United States, established (42 U.S.C. § 274) by the U.S. Congress in 1984 by Gene A. Pierce, founder of United Network for Organ Sharing. Located in Richmond, Virginia, the organization's headquarters are situated near the intersection of Interstate 95 and Interstate 64 in the Virginia BioTechnology Research Park.
== Activities ==
United Network for Organ Sharing is involved in many aspects of the organ transplant and donation process:
Managing the national transplant waiting list, matching donors to recipients.
Maintaining the database that contains all organ transplant data for every transplant event that occurs in the U.S.
Bringing together members to develop policies that make the best use of the limited supply of organs and give all patients a fair chance at receiving the organ they need, regardless of age, sex, ethnicity, religion, lifestyle, or financial/social status.
Monitoring every organ match to ensure organ allocation policies are followed.
Providing assistance to patients, family members and friends.
Educating transplant professionals about their important role in the donation and transplant processes.
Educating the public about the importance of organ donation.
== History ==
United Network for Organ Sharing was awarded the initial Organ Procurement and Transplantation Network contract on September 30, 1986, and it is the only organization to ever manage the Organ Procurement and Transplantation Network.
United Network for Organ Sharing provides the Organ Procurement and Transplantation Network with a functional, effective management system incorporating the Board of Directors, committees and regional membership to operate OPTN elements and activities.
In late December 2013, it was announced that United Network for Organ Sharing had developed new policies and regulations governing the new field of hand and face transplants like it does standard organ transplants, giving more Americans who are disfigured by injury or illness a chance at reconstruction. In July 2014, government regulations went into effect making hand and face transplants subject to the same oversight by United Network for Organ Sharing as heart or kidney transplants. The rules mean potential transplant recipients will be added to the United Network for Organ Sharing network, for matching of donated hands and face tissue to ensure correct tissue type and compatibility for skin color, size, gender and age. Transplants and their outcomes will be tracked.
In 2020, the Senate Finance Committee launched a bipartisan investigation into UNOS, seeking information into various abuses and patient harms. In 2022, the committee published a bipartisan report concluding that "From the top down, the U.S. transplant network is not working, putting Americans’ lives at risk.". UNOS has also come under intense scrutiny for issues related to outdated and insecure technology, as well as failing to address fatal patient safety risks and anti-patient misinformation.
An investigation by the United States Senate Committee on Finance published in August 2022 catalogs over a thousand complaints from the previous decade, including patient deaths and injuries caused by failures to check for disease and match blood type.
At an oversight hearing, Senator Elizabeth Warren pointed out that "UNOS is 15 times more likely to lose or damage an organ in transit as an airline is to lose or damage your luggage." Temperature regulation during transport can also be problematic.
== Regions ==
United Network for Organ Sharing and Organ Procurement and Transplantation Network operate by grouping states into several different regions throughout the country.
Connecticut, Maine, Massachusetts, New Hampshire, Rhode Island, and Eastern Vermont
Delaware, District of Columbia, Maryland, New Jersey, Pennsylvania, West Virginia, and the part of Northern Virginia in the Donation Service Area served by the Washington Regional Transplant Community (DCTC) Organ procurement organization
Alabama, Arkansas, Florida, Georgia, Louisiana, Mississippi, and Puerto Rico
Oklahoma and Texas
Arizona, California, Nevada, New Mexico, and Utah
Alaska, Hawaii, Idaho, Montana, Oregon, and Washington
Illinois, Minnesota, North Dakota, South Dakota, and Wisconsin
Colorado, Iowa, Kansas, Missouri, Nebraska, and Wyoming
New York and Western Vermont
Indiana, Michigan, and Ohio
Kentucky, North Carolina, South Carolina, Tennessee, and most of Virginia
== Allocation ==
United Network for Organ Sharing uses a set policy to remove as much subjectivity as possible from the process of matching organs with recipients (referred to as a "match run"). There are several factors that are involved, including, but not limited to:
Age
Ability of the patient to recover
ABO (though very young recipients are often considered for ABO-incompatible listing)
Distance
Height and weight
Life support status
Listing status
Time on the waiting list
The individual criteria varies from one organ type to another. For example, with heart and lung transplantation, candidate recipients are given one of four status levels (1A - the highest level, 1B, 2, and 7). A matching born (i.e. not in utero) candidate of Status 1A within the donor region, of matching ABO type, and within 500 miles will be given the highest priority, with multiple matches being ranked by time on the waiting list. Each of those criteria will be progressively relaxed until a match is found.
Some healthy organs that are donated go to waste despite about 20 people dying per day while on waiting lists. Critics state that this is because once a given set of organs are turned down once or twice, other potential recipients begin to be concerned about the condition of the organs, and eventually the organs are destroyed after thousands of refusals. Excessive conservatism may be the result of evaluating transplant surgeons based on success rate, giving them an incentive only to attempt procedures with the highest probability of success, rather than maximizing the number of lives saved. New rules announced by the Department of Health and Human Services in 2020 aimed to better balance waiting lists in different regions caused by demographic differences in causes of death.
== Membership ==
United Network for Organ Sharing has five classes of members, with varying levels of rights and obligations.
Institutional members: Regional organ procurement organizations (such as Gift of Hope), hospitals that perform transplantation, or histocompatibility laboratories that serve the aforementioned hospitals.
Medical/scientific members: Professional organizations whose membership serve the field of transplantation, such as the American Society of Transplant Surgeons or the American Academy of Pediatrics.
Public organization members: Organizations that serve to support transplant donors, recipients, and their families, such as National Kidney Foundation or the American Diabetes Association, or hospitals that refer donors but do not themselves perform transplants.
Business members: Companies that do business with two or more institutional members.
Individual members: Current or former members of the UNOS Board of Directors; Members or family of transplant candidates, donors, recipients; or other individuals who are or were involved in the field of or regulation of organ donation and transplantation, including employees of institutional members.
== Leadership ==
UNOS, and by extension, the OPTN elects its presidents to a one-year term. Prior to serving that term, they serve for one year as Vice President. After their term as President, they then serve for one year as Immediate Past President. This allows for a more orderly transition between leadership.
=== List of UNOS/OPTN Presidents ===
1984-1985: G. Melville Williams, MD, Medical College of Virginia
1985-1986: Oscar Salvatierra Jr., MD
1986-1988: John C. McDonald, MD
1988-1989: H. Keith Johnson, MD
1989-1990: Robert Corry, MD
1990-1991: James S. Wolf, MD
1991-1992: Robert Mendez, MD
1992-1993: R. Randal Bolinger, MD
1993-1994: Douglas J. Norman, MD
1994-1995: Margaret D. Allen, MD
1995-1996: Bruce A. Lucas, MD
1996-1997: James Burdick, MD
1997-1998: Lawrence Hunsicker, MD
1998-1999: William Pfaff, MD
1999-2000: William D. Payne, MD
2000-2001: Patricia Adams, MD
2001-2002: Jeremiah G. Turcotte, MD, University of Michigan Medical Center
2002-2003: Clyde F. Barker, MD
2003-2004: Russell Wiesner, MD, Mayo Clinic
2004-2005: Robert A. Metzger, MD
2005-2006: Francis L. Delmonico, MD, FACS, Harvard Medical School
2006-2007: Sue V. McDiarmid, MD, UCLA Medical Center
2007-2008: Timothy L. Pruett, MD, University of Minnesota Medical Center
2008-2009: Robert S. D. Higgins, MD, Johns Hopkins School of Medicine
2009-2010: James Wynn, MD, Medical College of Georgia
2010-2011: Charles Alexander, RN, MSN, MBA, CPTC
2011-2012: John R. Lake, MD, University of Minnesota Medical Center
2012-2013: John P. Roberts, MD, University of California San Francisco Medical Center
2013-2014: Kenneth A. Andreoni, MD, Shands Hospital at University of Florida
2014-2015: Carl L. Berg, MD, Duke University Hospital
2015-2016: Betsy Walsh, JD, MPH, Novant Health
2016-2017: Stuart C. Sweet, MD, Washington University in St. Louis School of Medicine
2017-2018: Yolanda T. Becker, MD, University of Chicago Medicine
2018-2019: Sue Dunn, RN, BSN, Donor Alliance
2019-2020: Maryl R. Johnson, MD, FACC, UW School of Health
2020-2021: David Mulligan, MD, FACS, Yale School of Medicine
2021-2022: Matthew Cooper, MD, FACS, MedStar Georgetown University Hospital
2022-2023: Jerry McCauley, MD, MPH, Thomas Jefferson University Hospital
2023-2024: Dianne LaPointe Rudow ANP-BC, DNP, FAAN, Mount Sinai Medical Center
2024-2025: Richard Formica, MD, Yale New Haven Hospital
2025-2026: Lloyd Ratner, MD, MPH, FACS, FICS(Hon), Columbia University
== References ==
== External links ==
Official sites:
Main UNOS site.
Main OPTN site, with data reports and policies, operated by UNOS on behalf of the Health Resources and Services Administration.
Transplant Living, for post-transplant recipients and living donors.
UNOS Meeting Partners, an event-planning service for transplantation-related organizations, including UNOS itself.
National Donor Memorial
United for UNOS, which serves to facilitate UNOS community outreach.
Scientific Registry of Transplant Recipients, related statistical site also operated for the HRSA. | Wikipedia/United_Network_for_Organ_Sharing |
Diroximel fumarate, sold under the brand name Vumerity, is a medication used for the treatment of relapsing forms of multiple sclerosis (MS). It acts as an immunosuppressant and anti-inflammatory drug. Its most common adverse effects are flushing and gastrointestinal problems.
Diroximel fumarate was approved for medical use in the United States in October 2019, and in the European Union in November 2021.
== Medical uses ==
Diroximel fumarate is used for the treatment of relapsing-remitting multiple sclerosis. In the US, it is additionally approved for other relapsing forms of MS such as clinically isolated syndrome and active secondary progressive disease.
=== Available forms ===
The drug is available as a white delayed-release capsule that is resistant to gastric acid and only dissolves in the intestine.
== Contraindications ==
Under the European Union's label, the drug is contraindicated in people with progressive multifocal leukoencephalopathy (PML), a disease of the brain caused by a virus. In the US, combination with the closely related drug dimethyl fumarate is contraindicated.
== Side effects ==
No systematic studies of adverse effects under diroximel fumarate are available. The most common side effects in studies with dimethyl fumarate were flushing (in 34% of patients treated with the drug, versus 5% in the placebo group) and gastrointestinal effects such as diarrhoea (14% versus 10%), nausea (12% versus 9%), abdominal pain (9% versus 4%), vomiting (8% versus 5%), and indigestion (5% versus 3%). Three percent of patients stopped the treatment because of flushing, 4% because of gastrointestinal side effects. A rare but potentially fatal adverse effect may be PML, which has been observed under treatment with dimethyl fumarate.
== Overdose ==
No specific antidote is known. Adverse effects caused by overdosing diroximel fumarate are treated symptomatically.
== Interactions ==
Diroximel fumarate does not interact with cytochrome P450 enzymes or P-glycoprotein. Its active metabolite, monomethyl fumarate, has a relatively low plasma protein binding of 27 to 45%. Therefore, its potential for pharmacokinetic interactions is considered to be low.
Inactivated vaccines can be given under diroximel fumarate therapy, based on experience with other immunosuppressant drugs, such as studies with tetanus, pneumococcal and meningococcal vaccines. No studies regarding the effectiveness of these vaccines under diroximel fumarate have been conducted. No data are available regarding combination with live vaccines, chemotherapy or immunosuppressants. Nephrotoxicity could be increased when the drug is combined with aminoglycoside antibiotics, diuretics, NSAIDs or lithium.
== Pharmacology ==
=== Mechanism of action ===
The drug's mechanism of action is not well understood. In preclinical studies it activated nuclear factor erythroid 2-related factor 2 (NRF2), a transcription factor that is up-regulated under oxidative stress.
=== Pharmacokinetics ===
The pharmacokinetics of diroximel fumarate has been found to be practically identical to that of dimethyl fumarate. Both are prodrugs of monomethyl fumarate.
Taking the drug with a high-calorie, high-fat meal slows down absorption, but has no relevant effect on overall absorption. The US label recommends not taking the drug together with high-calorie and high-fat meals.
After ingestion, the substance is cleaved by esterase enzymes before reaching the systemic circulation, resulting in monomethyl fumarate (MMF), the active metabolite, and hydroxyethyl succinimide (HES), which is inactive. Diroximel fumarate itself is not present in the bloodstream. MMF reaches highest concentrations in the blood plasma 2.5 to 3 hours after ingestion. When in the bloodstream, 27 to 45% are bound to plasma proteins.
MMF is further metabolized to fumarate, citrate and glucose, ultimately entering the citric acid cycle and being broken down to carbon dioxide (CO2). About 60% of the substance leave the body as CO2 via the lungs, 15.5% are eliminated with the urine (according to another source, less than 0.3%), and 0.9% are eliminated with the faeces. The terminal half-life is one hour.
HES is eliminated mainly with the urine (58 to 63%).
== Chemistry ==
The substance is a white to off-white powder. It is slightly soluble in water; that is, its solubility is between 1:100 and 1:1000. The molecule is achiral. The double bond of the fumarate moiety has E configuration.
== History ==
This drug was formulated by Alkermes in collaboration with Biogen.
== Society and culture ==
=== Legal status ===
Diroximel fumarate was approved for medical use in the United States in October 2019.
In September 2021, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Vumerity, intended for the treatment of adults with relapsing remitting multiple sclerosis. The applicant for this medicinal product is Biogen Netherlands B.V. Diroximel fumarate was approved for medical use in the European Union in November 2021.
== References == | Wikipedia/Diroximel_fumarate |
The Trillium Gift of Life Network was an agency of the Government of Ontario responsible for the province's organ donation strategy, promotion, and supply. Ronnie Gavsie was the President & CEO. The agency maintained the BeADonor.ca website. It was subsequently subsumed under Ontario Health in 2019.
== Statistics ==
Statistics can be a great way to see the reasons behind needing certain registries in a country. The following are statistics on the wait-list and the transplants performed in Canada in 2008, 2009, and 2010. The data is from the Canadian Institute for Health Information that focuses on British Columbia, Alberta, Saskatchewan, Manitoba, Ontario, Quebec, and Nova Scotia.
From 2001 to 2010, kidney and liver waitlists decreased, respectively by 330 and 27 patients. The pancreas waitlist, however, increased by 24 patients since 2001. Heart, lung, and heart with lungs remained moderately stable. These trends are indicated in the Organ wait-list by organ for 2001 to 2010. Transplants from 2001 to 2010, however, indicated an increased trend by 275 operations in deceased and living kidney, kidney pancreas, deceased and living liver, heart and lung transplants. Heart with lung transplants remained stable. These trends are indicated in the Organ transplant by organ for 2001 to 2010.
=== Canadian organ wait-list ===
Looking at the statistics for Canada, one can see that there has been an increase in the number of people waiting for a transplant between 2009 and 2010, while between 2008 and 2009 there was a decrease in the number of people on the wait-list.
=== Ontario organ transplants ===
Since 2008 there has been a steady increase of people receiving transplants. Comparing the number of transplants performed to the number of people waiting in 2010, there are twice as many people waiting then there is transplants being performed. This may be a sign of what is to come in future years. If the wait-list continues to increase at a faster rate than the number of transplants performed, the demand is not going to meet the supply.
== References ==
== External links ==
Official website | Wikipedia/Trillium_Gift_of_Life_Network |
Dimethyl fumarate (DMF) is the methyl ester of fumaric acid and is named after the earth smoke plant (Fumaria officinalis). Dimethyl fumarate combined with three other fumaric acid esters (FAEs) is solely licensed in Germany as an oral therapy for psoriasis (brand name Fumaderm). Since 2013, it has been approved by the U.S. Food and Drug Administration (FDA) as a treatment option for adults with relapsing multiple sclerosis (brand name Tecfidera). In 2017, an oral formulation of dimethyl fumarate (brand name Skilarence) was approved for medical use in the European Union as a treatment for moderate-to-severe plaque psoriasis. Dimethyl fumarate is thought to have immunomodulatory properties without causing significant immunosuppression.
Dimethyl fumarate has also been applied as a biocide in furniture or shoes to prevent growths of mold during storage or transport in humid climates. However, due to cases of allergic reactions after skin contact, dimethyl fumarate-containing consumer products are no longer authorised to be manufactured (since 1998) or imported (since 2009) in the European Union. Dimethyl fumarate is available as a generic medication.
== Medical uses ==
In Germany, dimethyl fumarate is marketed for the treatment of psoriasis and is available as an oral formulation mixed with related compounds (Fumaderm); in the UK, it is available as a pure oral formulation (Skilarence). It is also available in the US as an oral formulation (Tecfidera) to treat adults with relapsing multiple sclerosis.
A 2015 Cochrane systematic review found moderate quality evidence of a reduction in the number of people with relapsing remitting MS that had relapses over a two-year treatment period with dimethyl fumarate versus placebo, as well as low quality evidence of a reduction in worsening disability, and an overall need for higher quality studies with longer follow-up.
== History ==
The first medical use of fumaric acid was described in 1959 by Walter Schweckendiek, a German chemist, and was a topical formulation for psoriasis. The Swiss company Fumapharm eventually brought Fumaderm, an oral formulation of dimethyl fumarate (along with some monoesters) to market for psoriasis in Germany in 1994.
Based on the efficacy and safety of this formulation, and evidence that dimethyl fumarate was the main active component, an oral formulation of dimethyl fumarate was developed by Almirall. This oral formulation, under the brand name Skilarence, was approved by the European Medicines Agency (EMA) in June 2017, for the treatment of moderate-to-severe plaque psoriasis in adults.
Initial clinical research on the use of dimethyl fumarate for the treatment of multiple sclerosis was conducted by Fumapharm in collaboration with Biogen Idec; Fumapharm was subsequently acquired by Biogen Idec in 2006. Aditech Pharma in Sweden had also been researching oral formulations of dimethyl fumarate for MS and in 2010, the Danish company Forward Pharma acquired Aditech's patents.
Biogen continued developing its oral formulation of dimethyl fumarate from Fumapharm under the code name BG-12; it was approved, under the trade name Tecfidera, for the treatment of adults with relapsing forms of MS in March 2013. Biogen priced the drug at $54,000 per year in the US. It was approved in Europe in 2014. In the UK NICE issued guidance recommending the drug as cost-effective, but only for patients who do not have highly active or rapidly evolving severe relapsing–remitting multiple sclerosis and only if Biogen agreed to provide it at a discount.
Forward and Biogen entered into patent litigation in many jurisdictions; in 2017, the companies settled the litigation, with Biogen paying Forward $1.25 billion, with the potential for up to 10% of royalties depending on what happened with the patents in various jurisdictions.
In June 2020, in a case between Biogen and Mylan, the U.S. District Court in West Virginia declared invalid Biogen's so-called "514" patent protecting Tecfidera from generic competition. The ruling gave Mylan the right to launch its own version of Tecfidera.
== Pharmacology ==
Dimethyl fumarate is metabolized to monomethyl fumarate (MMF) prior to entering systemic distribution. Dimethyl fumarate has been described a prodrug.
Dimethyl fumarate is a precursor of monomethyl fumarate. Other prodrugs that metabolize to monomethyl fumarate have been developed to treat relapse-remitting multiple sclerosis, including diroximel fumarate which was approved by the FDA in October 2019.
The precise mechanism of action of dimethyl fumarate is not clear. Dimethyl fumarate and monomethyl fumarate can activate the transcription factor (Nuclear factor erythroid-derived 2)-related factor 2 (Nrf2) pathway and monomethyl fumarate has been identified as a nicotinic acid receptor agonist in vitro. In mice that lack Nrf2 expression, however, dimethyl fumarate is still able to modulate the immune system, which indicates that Nrf2 is not required for its immunomodulatory action. For psoriasis, the mechanism of action is believed to be due to the interaction of monomethyl fumarate and the intracellular reduced glutathione of cells directly involved in the pathogenesis of psoriasis. The interaction with glutathione leads to the inhibition of nuclear translocation and the transcriptional activity of the nuclear factor kappa-light-chain-enhancer of activated B-cells (NF-κB).
Dimethyl fumarate and monomethyl fumarate have been shown to reduce the expression of micro-RNA-21, which is essential for the production of pathogenic cells in multiple sclerosis and psoriasis. This can be achieved because dimethyl fumarate and monomethyl fumarate, as cell-permeable metabolites, can epigenetically regulate the expression of micro-RNA-21 via the metabolic-epigenetic interplay in developing immune cells.
The main activity of dimethyl fumarate and monomethyl fumarate is considered to be immunomodulatory, resulting in a shift in T helper cells (Th) from the Th1 and Th17 profile to a Th2 phenotype. Inflammatory cytokine production is reduced by the induction of proapoptotic events, inhibition of keratinocyte proliferation, reduced expression of adhesion molecules and diminished inflammatory infiltrate within psoriatic plaques.
The primary route of elimination is via exhalation of CO2, with small amounts excreted through urine or faeces.
There is no evidence for dimethyl fumarate interaction with cytochrome P450 and the most common efflux and uptake transporters, and therefore no interactions are expected with medicinal products metabolised or transported by these systems.
== Synthesis and reactions ==
Several methods exist for the laboratory synthesis of dimethyl fumarate, with reported methods including alkene isomerization of dimethyl maleate, and Fischer esterification of fumaric acid.
Dimethyl fumarate is an old compound used in industrial chemistry and can be purchased by the ton; as of 2012, one could purchase it for $1 to $50 per metric ton, with a two-ton minimum purchase.
The compound undergoes electrohydrodimerization.
== Adverse effects ==
In the treatment of psoriasis, the most common adverse events are gastrointestinal events, flushing and lymphopenia, which are usually mild. Other adverse events include progressive multifocal leukoencephalopathy (PML) and Fanconi syndrome, which are considered rare. PML is probably caused by a combination of factors. A previous infection with the John-Cunningham virus (JCV) is considered a prerequisite for the development of PML. In a PML review, all confirmed cases were of patients exposed to periods of varying lymphopenia.
For multiple sclerosis, adverse effects include flushing and gastrointestinal events, such as diarrhoea, nausea and upper abdominal pain. The drug label includes warnings about the risk of anaphylaxis and angioedema, PML, lymphopenia and liver damage.
There is no information on how dimethyl fumarate affects the fetus during pregnancy; in animal tests there was fetal harm at clinically relevant doses.
== Consumer products ==
There have been cases of severe contact dermatitis which was likely related to a dimethyl fumarate contact allergy of newly acquired sofas and chairs. Dimethyl fumarate has been found to be an allergic sensitizer at very low concentrations, producing eczema by contact allergy that is difficult to treat. Concentrations as low as 1 ppm (parts-per-million) may produce allergic reactions in the most severe cases. There are only a handful of equally potent sensitisers.
The sensitizing risk was brought to public attention by the "poison chair" incident, where Chinese manufacturer Linkwise produced two-seater sofas with dimethyl fumarate sachets inside to inhibit mould while they were in storage or transport. In Finland where the chairs were sold from 2006 to 2007, 60 users sustained serious rashes. The cause was identified as dimethyl fumarate-induced allergic reaction by Tapio Rantanen from Finland and his original article became the cover story in the July 2008 issue of the British Journal of Dermatology. In the United Kingdom, sofas sold by Argos, Land of Leather and Walmsley Furnishing containing the chemical caused over a hundred injuries. Argos withdrew the sofas from stores and contacted buyers to collect those that had been sold — with Land of Leather withdrawing the sofas without notifying buyers and Walmsley saying they had removed the sachets from sofas they sold after the danger came to light. The danger came to public attention in 2008 when the BBC Watchdog programme alerted consumers to the sofas.
In the European Union, the use of dimethyl fumarate in consumer product manufacturing has been forbidden since 1998, and in 2009 the importation of consumer products containing dimethyl fumarate was also forbidden. EU Commission Decision 2009/251 of 17 March 2009 required member states to ensure that consumer products containing dimethyl fumarate were not placed or made available on the market from 1 May 2009. This definitely outlawed any marketing of consumer products containing dimethyl fumarate in the European Union. The ban on dimethyl fumarate as laid down in Decision 2009/251 establishes a maximum dimethyl fumarate concentration in products of 0.1 ppm. The decision dictated that consumer products containing more than 0.1 ppm dimethyl fumarate should be withdrawn from the market and recalled from consumers.
== Research ==
In 2021, dimethyl fumarate was evaluated as a treatment for COVID-19 as part of the RECOVERY Trial in the UK. The results of the trial found that dimethyl fumarate did not significantly improve clinical outcomes in hospitalized COVID-19 patients.
== References == | Wikipedia/Dimethyl_fumarate |
The Ragged Edge of Science is a science book by L. Sprague de Camp, illustrated by Don Simpson. It was first published by Owlswick Press in 1980.
The book is a collection of twenty-two articles (two of them book reviews) on various curiosities and wonders exploring the boundaries between science and pseudo-science. "The[ir] common thread is [their] skeptical takes on subjects that are often muddled by paranormal and pseudoscientific claims." De Camp viewed such phenomena from a skeptically rational viewpoint, pointing out the fallacies in supernatural and otherwise fantastic explanations. His debunking efforts were an important and characteristic feature of his nonfiction, and the present collection is a notable instance of it.
The book's constituent articles were originally published in a variety of science magazines, science fiction magazines, and other publications from 1950 to 1976.
== Contents ==
"Preface"
Long Ago and Far Away
"The Mayan Elephants" (from Astounding Science Fiction, v. 45, no. 4, Jun. 1950)
"Faery Lands Forlorn" (from Science Fiction Stories, v. 6, no. 3, Nov. 1955 and v. 6, no. 5, Mar. 1956)
"The Pyramids of Kush" (from Science Digest, v. 63, no. 4, Apr. 1968)
"The Falls of Troy" (from The Magazine of Fantasy & Science Fiction, v. 38, no. 3, Mar. 1970)
"The Quarter-Acre Round Table" (from The Magazine of Fantasy & Science Fiction, v. 39, no. 1, Jul. 1970)
"The Tower of Mystery" (from Science Digest, v. 68, no. 4, Oct. 1970)
"The Street of the Dead: Teotihuacan" (from Science Digest, v. 68, no. 6, Dec. 1970)
"Tula and the Vanished Toltecs" (from Science Digest, v. 71, no. 4, Apr. 1972)
Round About the Cauldron
"The Mystic Trance" (from Future Combined with Science Fiction Stories, v. 2, no. 4, Nov. 1951)
"The Mountain of Light" (from Science Fiction Quarterly, v. 1, no. 6, Aug. 1952)
"The Great Charlatans" (from Science Fiction Quarterly, v. 2, no. 2, Feb. 1953)
"A Modern Merlin" (from Dynamic Science Fiction, Jun. 1953)
"The Mysterious Kabbalah" (from Fate, No. 79, Oct. 1956)
"Bridey Murphy and the Martian Princess" (from Science Fiction Stories, v. 7, no. 4, Jan. 1957)
"The Great Satanist Plot" (from Exploring the Unknown, no. 20, Jun. 1953)
"So You Want to Be a Prophet?" (from the Philadelphia Sunday Bulletin, Feb. 20, 1966)
Science and Pseudo-Science
"Worlds in Collision" (book review) (from Astounding Science Fiction, v. 45, no. 2, Apr. 1950)
"The So-called Fourth Dimension" (from Future Combined with Science Fiction Stories, v. 2, no. 3, Sep. 1951)
"How to Talk Futurian" (from The Magazine of Fantasy & Science Fiction, v. 13, no. 4, Oct. 1957)
"The Great Pseudomath" (from Fantastic Universe, v. 8, no. 6, Dec. 1957)
"The Decline and Fall of Adam" (from The Magazine of Fantasy & Science Fiction, v. 45, no. 5, Nov. 1973)
"Chariots of the Gods?" (book review) (from Amra, v. 2, no. 65, Apr. 1976)
== Synopsis ==
The essays in the book fall into three general categories, dealing with ancient civilizations and certain unscientific theories regarding them, occult-related subjects, and pseudoscience in general. Anecdotes from history and de Camp's travels to some of the locales he writes about pepper the narrative.
The first eight chapters fall into the first category. Discussions of Bronze Age Troy and the ancient Sudanese civilization of Kush counter romantic speculations with a resume of what is known of them from historical sources and archaeological investigations. In contrast, the section on King Arthur, of whom little factual information has been established, puts to rest unverified notions regarding him by tracing the development and elaboration of his legend down through the ages. The chapter on the Maya debunks diffusionist theories seeking the origin of their culture in Old World civilizations rather than from indigenous factors. Later sections about Teotihuacan and the Toltecs serve more as general introductions to these cultures. There is also a brief discussion of the Tour Magne, a Roman ruin in Nîmes, France, and a chapter on myths that discounts them as reliable reportage of prehistoric events.
Chapters in the second category include discussions of memories of previous lives supposedly recovered via hypnosis, the Kabbalah, lives of famous charlatans claiming to have been magicians, such as Cagliostro and Aleister Crowley, the hoax perpetrated by Léo Taxil and others that purported to expose Freemasonry as devil worship, theosophist C. W. Leadbeater, the development of occultist cultism around Mount Shasta in Northern California (demonstrated to have a literary basis), and the origins of the mystic trance, with rational explanations for the visions experienced. A satirical chapter of advice on how to set one's self up as a prophet rounds out the section.
An account of the early history of Fundamentalist movement to prohibit the teaching of evolution in schools leads off the third category. There is also a biography of Populist politician Ignatius Donnelly focusing on his speculations regarding Atlantis and like matters, and then a speculative chapter regarding future languages, essentially a didactic piece on language change with application to science fictional treatments of time-travel. It leads into a discussion of nonscientific claims about the "fourth dimension" in general. This part of the book also includes reviews of Immanuel Velikovsky's Worlds in Collision and Erich von Däniken's Chariots of the Gods?, both of which de Camp discounts.
== Reception ==
Critical reviews of the book were generally positive. Writing in the wake of its release, Tom Easton observed in Analog Science Fiction/Science Fact that "[i]f you know L. Sprague de Camp's work at all, you know what to expect ... He's always readable and entertaining, as he sticks his thumbs into gaping holes of fact and logic ... He's full of the straight dope (though he often doesn't go into things as deeply as I would like)." He urged readers to "buy the book." Michael Schuyler, writing for Library Journal, took a more neutral stance, judging only that "[m]ost of these mysteries have been well documented elsewhere, and De Camp [sic] presents no revelations." The book was also reviewed by Darrell Schweitzer in Science Fiction Review v. 10, issue 1 (Spring, 1981), p. 22.
More recently, an exhaustive review from 2007 sums up the book as "a very pleasant and readable collection of essays, an excellent and classical example of skeptical writing and debunkery of various kinds of pseudoscientific and paranormal nonsense." The reviewer notes de Camp's "accessible, down-to-earth style," humor, and story-telling expertise, as well as "somewhat conservative opinions ... which occasionally show in his writing." Its conclusion is "[o]verall I highly recommend this book."
== Notes == | Wikipedia/The_Ragged_Edge_of_Science |
Voodoo Science: The Road from Foolishness to Fraud is a book published in 2000 by physics professor Robert L. Park, critical of research that falls short of adhering to the scientific method. Other people have used the term "voodoo science", but amongst academics it is most closely associated with Park. Park offers no explanation as to why he appropriated the word voodoo to describe the four categories detailed below. The book is critical of, among other things, homeopathy, cold fusion and the International Space Station.
== Categories ==
Park uses the term voodoo science (see the quote section below, Page 10) as covering four categories which evolve from self-delusion to fraud:
pathological science, wherein genuine scientists deceive themselves
junk science, speculative theorizing which bamboozles rather than enlightens
pseudoscience proper, work falsely claiming to have a scientific basis, which may be dependent on supernatural explanations
fraudulent science, exploiting bad science for the purposes of fraud
Park criticizes junk science as the creature of "scientists, many of whom have impressive credentials, who craft arguments deliberately intended to deceive or confuse."
== Examples cited ==
Perpetual motion, free energy suppression and fringe physics claims
Robert Fludd
Garabed T. K. Giragossian
The Energy Machine of Joseph Newman
Better World Technologies (Dennis Lee)
Blacklight Power, formerly HydroCatalysis (Randell Mills)
Cold fusion (Stanley Pons and Martin Fleischmann)
Patterson Power Cell (James Patterson)
Gravitational shielding (Eugene Podkletnov)
Human spaceflight (in terms of actual importance to science since the rise of robotic spacecraft)
International Space Station (for claims of necessity to conduct scientific research)
Gerard K. O'Neill, L5 Society and space colonization
Robert Zubrin, Mars Society, Biosphere 2 and a human mission to Mars
Voodoo science protected by government secrecy
Project Mogul and the Roswell UFO incident resulting in a loss of public trust, as well as the later alien autopsy video hoax
Edward Teller and Lowell Wood's work on the Strategic Defense Initiative (especially regarding the X-ray laser, but also "Brilliant Pebbles")
Great Oil Sniffer Hoax
Superstitions and pseudoscience
Mars effect (astrology) claimed by Michel Gauquelin
Parapsychology (e.g. Robert G. Jahn and Dean Radin)
Placebos and alternative medicine
Vitamin O
Homeopathy
water memory (proposed by Jacques Benveniste)
Animal magnetism
Magnet therapy
Therapeutic touch (debunked by Emily Rosa at age nine)
Other health claims
Maharishi Effect (using Transcendental Meditation (TM) to effect a decrease in societal violence; the spike in murders during the 1993 Washington D.C. study is specifically mentioned)
Deepak Chopra (who makes claims linking Ayurveda (traditional medicine native to India) with quantum mechanics)
Electromagnetic radiation and health (especially related to power lines and cancer risk)
"Paul Brodeur and Microwave News in particular, had given the public a seriously distorted view of the scientific facts." (Page 158)
Contributing factors
Mainstream media reporting voodoo science uncritically as infotainment
Abolition of the Office of Technology Assessment
Establishment of the National Center for Complementary and Alternative Medicine
Park also discusses the Daubert standard for excluding junk science from litigation.
== Quotes ==
I came to realize that many people choose scientific beliefs the same way they choose to be Methodists, or Democrats, or Chicago Cubs fans. They judge science by how well it agrees with the way they want the world to be. (Pages VIII-IX)
[P]ractitioners [of pseudoscience] may believe it to be science, just as witches and faith healers may truly believe they can call forth supernatural powers. What may begin as an honest error, however, has a way of evolving through almost imperceptible steps from self-delusion to fraud. The line between foolishness and fraud is thin. Because it is not always easy to tell when that line is crossed, I use the term voodoo science to cover them all: pathological science, junk science, pseudoscience and fraudulent science. This book is meant to help the reader to recognize voodoo science and to understand the forces that seem to conspire to keep it alive. (Page 10)
The integrity of science is anchored in the willingness of scientists to test their ideas and results in direct confrontation with their scientific peers. (Page 16)
America's astronauts have been left stranded in low-Earth orbit, like passengers waiting beside an abandoned stretch of track for a train that will never come, bypassed by the advance of science. (Page 91)
Few scientists or inventors set out to commit fraud. In the beginning, most believe they have made a great discovery. But what happens when they finally realize that things are not behaving as they believed? (Page 104)
[T]he uniquely American myth of the self-educated genius fighting against a pompous, close-minded establishment. (Page 112)
They are betting against the laws of thermodynamics. No one has ever won that wager. (Page 138)
== Warning signs ==
Drawing on examples used in Voodoo Science, Park outlined seven warning signs that a claim may be pseudoscientific in a 2003 article for The Chronicle of Higher Education:
Discoverers make their claims directly to the popular media, rather than to fellow scientists.
Discoverers claim that a conspiracy has tried to suppress the discovery.
The claimed effect appears so weak that observers can hardly distinguish it from noise. No amount of further work increases the signal.
Anecdotal evidence is used to back up the claim.
True believers cite ancient traditions in support of the new claim.
The discoverer or discoverers work in isolation from the mainstream scientific community.
The discovery, if true, would require a change in the understanding of the fundamental laws of nature.
== Reception ==
Matt Nisbet in the Skeptical Inquirer noted that the reaction to Voodoo Science has been mostly favorable.
Bob Goldstein in a book review for Nature Cell Biology described Park as an equivalent to Richard Dawkins and Stephen Jay Gould, scientific writers who have "talent for defending a view of the world that is perfectly rational and free of witchcraft and superstition."
American chemist Nicholas Turro wrote "the book is entertaining and provocative reading... Whether or not you agree with Park's take on voodoo science, a message of the book is that if scientists do not take a more significant role in the way that science is disseminated to the public and especially to politicians, voodoo science will continue to survive."
The mathematician Malcolm Sherman in the American Scientist gave the book a positive review stating "Park does more than analyze and expose various kinds of bad ("voodoo") science. He demonstrates how valid science is distorted or ignored by the media and by those (including scientists) seeking to influence public policy." The physicist Kenneth R. Foster also positively reviewed the book concluding "Park is an articulate and skeptical voice of reason about science."
Reviewing the book for The New York Times, Ed Regis compared it positively to the 1957 book by Martin Gardner, Fads and Fallacies in the Name of Science, calling Voodoo Science a "worthy successor" and praising it for explaining why various purportedly scientific claims were in fact impossible. Science writer Kendrick Frazier wrote "Robert Park has brought us a book that has a freshness and originality—and an importance and potential for influence—perhaps not seen since Gardner’s first."
Robin McKie for The Observer described it as "an admirable analysis: wittily written, vivid and put together without a hint of malice."
Rachel Hay in a review wrote that Park had "debunked expertly" pseudoscience topics such as homeopathy, cold fusion and perpetual motion machines but the book is not easily accessible to students. However, S. Elizabeth Bird an anthropology professor recommended it for "students who need to establish a grasp of the scientific method."
Bruce Lewenstein wrote a critical review claiming Park had lumped together pathological science, junk science, pseudoscience and fraud all together as voodoo science but this is problematic as "each category alone is fraught with definitional, historical, and analytical difficulties." Brian Josephson wrote that the book, while giving "the official story regarding a number of 'mistaken beliefs' ", did not provide "the additional information that might lead one to conclude that the official view does not tell the whole story."
== See also ==
=== Debunking ===
== References ==
== External links ==
"The rock that fell to Earth". The Verge. | Wikipedia/Voodoo_Science |
Conversion therapy is the pseudoscientific practice of attempting to change an individual's sexual orientation, romantic orientation, gender identity, or gender expression to align with heterosexual and cisgender norms. Methods that have been used to this end include forms of brain surgery, surgical or chemical (hormonal) castration, aversion therapy treatments such as electric shocks, nausea-inducing drugs, hypnosis, counseling, spiritual interventions, visualization, psychoanalysis, and arousal reconditioning. There is a scientific consensus that conversion therapy is ineffective at changing a person's sexual orientation or gender identity and that it frequently causes significant long-term psychological harm. An increasing number of jurisdictions around the world have passed laws against conversion therapy.
Historically, conversion therapy was the treatment of choice for individuals who disclosed same-sex attractions or exhibited gender nonconformity, which were formerly assumed to be pathologies by the medical establishment. When performed today, conversion therapy may constitute fraud, and when performed on minors, a form of child abuse. It has been described by experts as torture; cruel, inhuman, or degrading treatment; and contrary to human rights.
The position of current evidence-based medicine and clinical guidance is that homosexuality, bisexuality, and gender variance are natural and healthy aspects of human sexuality.
== Terminology ==
Medical professionals and activists consider "conversion therapy" a misnomer, as it does not constitute a legitimate form of therapy. Alternative terms include "sexual orientation change efforts" (SOCE) and "gender identity change efforts" (GICE)—together, sexual orientation and gender identity change efforts (SOGICE). According to researcher Douglas C. Haldeman, SOCE and GICE should be considered together because both rest on the assumption "that gender-related behavior consistent with the individual's birth sex is normative and anything else is unacceptable and should be changed". "Reparative therapy" may refer to conversion therapy in general, or to a subset thereof. Some sources prefer the term "conversion practices" to "conversion therapy", on the grounds that the practices in question are not actually therapeutic.
Advocates of conversion therapy do not necessarily use the term either, instead using phrases such as "healing from sexual brokenness" and "struggling with same-sex attraction".
== History ==
=== Sexual orientation change efforts (SOCE) ===
The term homosexual was coined by German-speaking Hungarian writer Karl Maria Kertbeny and was in circulation by the 1880s. Into the middle of the twentieth century, competing views of homosexuality were advanced by psychoanalysis versus academic sexology. Sigmund Freud, the founder of psychoanalysis, viewed homosexuality as a form of arrested development. Later psychoanalysts followed Sandor Rado, who argued that homosexuality was a "phobic avoidance of heterosexuality caused by inadequate early parenting". This line of thinking was popular in psychiatric models of homosexuality based on the prison population or homosexuals seeking treatment. In contrast, sexology researchers such as Alfred Kinsey argued that homosexuality was a normal variation in human development. In 1970, gay activists confronted the American Psychiatric Association, persuading the association to reconsider whether homosexuality should be listed as a disorder. The APA delisted homosexuality in 1973, which contributed to shifts in public opinion on homosexuality.
Despite their lack of scientific backing, some socially or religiously conservative activists continued to argue that if one person's sexuality could be changed, homosexuality was not a fixed class such as race. Borrowing from discredited psychoanalytic ideas about the cause of homosexuality, some of these individuals offered conversion therapy. In 2001, conversion therapy attracted attention when Robert L. Spitzer published a non-peer-reviewed study asserting that some homosexuals could change their sexual orientation. Many researchers made methodological criticisms of the study, and Spitzer later repudiated his own study.
=== Gender identity change efforts (GICE) ===
Gender Identity Change Efforts (GICE) refer to practices of healthcare providers and religious counselors with the goal of attempting to alter a person's gender identity or expression to conform to social norms. Examples include aversion therapy, cognitive restructuring, and psychoanalytic and talk therapies. Western medical-model narratives have historically institutionalized transphobia: systemically favoring a binary gender model and pathologizing gender diversity and non-conformity. This aided the development and proliferation of GICE.
Early interventions were rooted in psychoanalytic hypotheses. Robert Stoller advanced the theory that gender-nonconforming behavior and expression in children assigned male at birth (AMAB) was caused by being overly close to their mother. Richard Green continued his research; his methods for altering behavior included having the father spend more time with the child and mother less, expecting both to exhibit stereotypical gender roles, and having them praise their child's masculine behaviors, and shame their feminine and gender-nonconforming ones. These interventions resulted in depression in the children and feelings of betrayal from parents that the treatments failed.
In the 1970s, UCLA psychologist Richard Green recruited Ole Ivar Lovaas to adapt the techniques of Applied Behavior Analysis (ABA) therapy to attempt to prevent children from becoming transsexual. Deemed the "Feminine Boy Project", the treatments used operant conditioning to reward gender-conforming behaviors, and punish gender non-conforming behaviors.
Kenneth Zucker at the Centre for Addiction and Mental Health adopted Richard Green's methods, but narrowed the scope to attempting to prevent the child from identifying as transgender by modifying gender behavior and presentation to conform to the expectations of the assigned gender at birth, which he dubbed the "living in your own skin" model. His model used the same interventions as Green with the addition of psychodynamic therapy.
== Motivations ==
A frequent motivation for adults who pursue conversion therapy is religious beliefs that disapprove of same-sex relations, such as evangelical Christianity, Orthodox Judaism, and conservative interpretations of Islam. These adults prioritize maintaining a good relationship with their family and religious community.
Adolescents who are pressured by their families into undergoing conversion therapy also typically come from a conservative religious background. Youth from families with low socioeconomic status are also more likely to undergo conversion therapy.
== Theories and techniques ==
As societal attitudes toward homosexuality have become more tolerant over time, the most harsh conversion therapy methods such as aversion have been reduced. Secular conversion therapy is offered less often due to reduced medical pathologization of homosexuality, and religious practitioners have become more dominant.
=== Aversion therapy ===
Aversion therapy used on homosexuals included electric shock and nausea-inducing drugs during presentation of same-sex erotic images. Cessation of the aversive stimuli was typically accompanied by the presentation of opposite-sex erotic images, with the objective of strengthening heterosexual feelings. Another method used was the covert sensitization method, which involves instructing patients to imagine vomiting or receiving electric shocks, writing that only single case studies have been conducted, and that their results cannot be generalized. Haldeman writes that behavioral conditioning studies tend to decrease homosexual feelings, but do not increase heterosexual feelings, citing Rangaswami's "Difficulties in arousing and increasing heterosexual responsiveness in a homosexual: A case report", published in 1982, as typical in this respect.
Other methods of aversion therapy in addition to electric shock included ice baths, freezing, burning via metal coils, and hard labor. The intent was for the subject to associate homosexual feelings with pain and thus result in them being reduced. These methods have been concluded to be ineffective.
Aversion therapy was developed in Czechoslovakia between 1950 and 1962 and in the British Commonwealth from 1961 into the mid-1970s. In the context of the Cold War, Western psychologists ignored the poor results of their Czechoslovak counterparts, who had concluded that aversion therapy was not effective by 1961 and recommended decriminalization of homosexuality instead. Some men in the United Kingdom were offered the choice between prison and undergoing aversion therapy. It was also offered to a few British women, but was never the standard treatment for either homosexual men or women.
In the 1970s, behaviorist Hans Eysenck was one of the main advocates of counterconditioning with malaise-inducing drugs and electric shock for homosexuals. He wrote that this type of therapy was successful in nearly 50% of cases. However, his studies were disputed.
Behavior therapists, including Eysenck, used aversive methods. This led to a protest against Eysenck by gay activist Peter Tatchell in a London Medical Group Symposium in 1972. Tatchell said that the therapy promoted by Eysenck was a form of torture.
Tatchell denounced Eysenck's form of behavioral therapy as inducing depression and suicide among gay men who were subjected to it.
=== Brain surgery ===
In the 1940s and 1950s, U.S. neurologist Walter Freeman popularized the ice-pick lobotomy as a treatment for homosexuality. He personally performed as many as 3,439 lobotomy surgeries in 23 states, of which 2,500 used his ice-pick procedure, despite the fact that he had no formal surgical training.
In West Germany, a type of brain surgery usually involving destruction of the ventromedial nucleus of the hypothalamus was done to some homosexual men during the 1960s and 1970s. The practice was criticized by sexologist Volkmar Sigusch.
=== Castration and transplantation ===
In early twentieth century Germany, experiments were carried out in which homosexual men were subjected to unilateral orchiectomy and testicles of heterosexual men were transplanted. These operations were a complete failure.
Surgical castration of homosexual men was widespread in Europe in the first half of the twentieth century. SS leader Heinrich Himmler ordered homosexual men to be sent to concentration camps because he did not consider a time-limited prison sentence sufficient to eliminate homosexuality. Although theoretically voluntary, some homosexuals were subject to severe pressure and coercion to agree to castration. There was no age limit; some boys as young as 16 were castrated. Those who agreed to castration after a Paragraph 175 conviction were exempted from being transferred to a concentration camp after completing their legal sentence. Some concentration camp prisoners were also subjected to castration. An estimated 400 to 800 men were castrated.
Endocrinologist Carl Vaernet attempted to change homosexual concentration camp prisoners' sexual orientations by implanting a pellet that released testosterone. Most of the victims, non-consenting prisoners at Buchenwald, died shortly thereafter.
An unknown number of men were castrated in West Germany and chemical castration was used in other Western countries, notably against Alan Turing in the United Kingdom.
=== Ex-gay/ex-trans ministries ===
Ex-gay ministries are religious groups that attempt to use religion to eliminate or change somebody's sexual orientation. The ex-gay umbrella organization Exodus International in the United States ceased activities in June 2013, and the three member board issued a statement which repudiated its aims and apologized for the harm their pursuit had caused to LGBT people. Ex-trans organizations often overlap and portray being trans as inherently sinful or against God's design, or pathologize gender variance as due to trauma, social contagion, or "gender ideology".
=== Hypnosis ===
Hypnosis was used in conversion therapy since the 19th century by Richard von Krafft-Ebing and Albert von Schrenck-Notzing. In 1967, Canadian psychiatrist Peter Roper published a case study of treating 15 homosexual (some of which would probably be considered bisexual by modern standards) people with hypnosis. Allegedly, 8 showed "marked improvement" (they reportedly lost sexual attraction towards the same sex altogether), 4 mild improvements (decrease of "homosexual tendencies"), and 3 no improvement after hypnotic treatment; he concluded that "hypnosis may well produce more satisfactory results than those obtainable by other means", depending on the hypnotic susceptibility of the subjects.
=== Psychoanalysis ===
Haldeman writes that psychoanalytic treatment of homosexuality is exemplified by the work of Irving Bieber et al. in Homosexuality: A Psychoanalytic Study of Male Homosexuals. They advocated long-term therapy aimed at resolving the unconscious childhood conflicts that they considered responsible for homosexuality. Haldeman notes that Bieber's methodology has been criticized because it relied upon a clinical sample, the description of the outcomes was based upon subjective therapist impression, and follow-up data were poorly presented. Bieber reported a 27% success rate from long-term therapy, but only 18% of the patients in whom Bieber considered the treatment successful had been exclusively homosexual to begin with, while 50% had been bisexual. In Haldeman's view, this makes even Bieber's unimpressive claims of success misleading.
Haldeman discusses other psychoanalytic studies of attempts to change homosexuality. Curran and Parr's "Homosexuality: An analysis of 100 male cases", published in 1957, reported no significant increase in heterosexual behavior. Mayerson and Lief's "Psychotherapy of homosexuals: A follow-up study of nineteen cases", published in 1965, reported that half of its 19 subjects were exclusively heterosexual in behavior four and a half years after treatment, but its outcomes were based on patient self-report and had no external validation. In Haldeman's view, those participants in the study who reported change were bisexual at the outset, and its authors wrongly interpreted capacity for heterosexual sex as change of sexual orientation.
=== Reparative therapy ===
The term "reparative therapy" has been used as a synonym for conversion therapy generally, but according to Jack Drescher it properly refers to a specific kind of therapy associated with the psychologists Elizabeth Moberly and Joseph Nicolosi.
For example, he wrote:
. . . the pursuit of fulfillment through same-sex eroticism is spurred by the fearful anticipation that their masculine self-assertion will inevitably fail and result in humiliation.
The term reparative refers to Nicolosi's postulate that same-sex attraction is a person's unconscious attempt to "self-repair" feelings of inferiority.
After California banned conversion practices, Nicolosi argued that "reparative therapy" didn't attempt to directly change sexual orientation but instead encourage exploration into its underlying causes, which he believed was often childhood trauma.
A phone study by Robert Spitzer reported that "about 66 percent of the men respondents and 44 percent of the women were able to function as heterosexuals after the therapy," while conceding that "his subjects did not constitute a study population representative of the gay and lesbian population in the U.S."
=== Marriage therapy ===
Previous editions of the World Health Organization's ICD included "sexual relationship disorder", in which a person's sexual orientation or gender identity makes it difficult to form or maintain a relationship with a sexual partner. The belief that their sexual orientation has caused problems in their relationship may lead some people to turn to a marriage therapist for help to change their sexual orientation. Sexual orientation disorder was removed from the most recent ICD, ICD-11, after the Working Group on Sexual Disorders and Sexual Health determined that its inclusion was unjustified.
=== Gender exploratory therapy ===
Gender exploratory therapy (GET) is a form of conversion therapy characterized by requiring mandatory extended talk therapy attempting to find pathological roots for gender dysphoria while simultaneously delaying social and medical transition and viewing it as a last resort. Practitioners of GET propose their patient's dysphoria is caused by factors such as homophobia, social contagion, sexual trauma, and autism. Some practitioners of GET avoid using their patients' chosen names and pronouns while questioning their identification. Commenting on gender exploratory therapy in 2022, bioethicist Florence Ashley argued that its framing as an undirected exploration of underlying psychological issues bore similarities to gay conversion practices such as "reparative" therapy. States that have banned gender-affirming care for minors in the United States have called expert witnesses to argue that exploratory therapy should be the alternative treatment.
There are no known empirical studies examining psychosocial or medical outcomes following GET. Concerns have been raised that by not providing an estimated length of time for the therapy, the delays in medical interventions may compound mental suffering in trans youth, while the gender-affirming model of care already promotes gender identity exploration without favoring any particular identity, and individualized care. GET proponents deny this.
In 2017, Richard Green published a legal strategy which called for circumventing bans on conversion therapy by labelling the practice "gender identity exploration or development". Multiple groups now exist worldwide to promote GET and have been successful in influencing legal discussions and clinical guidance in some regions. The Gender Exploratory Therapy Association (GETA) asserts that "psychological approaches should be the first-line treatment for all cases of gender dysphoria", that medical interventions for transgender youth are "experimental and should be avoided if possible", and that social transition is "risky". All of GETA's leaders are members of Genspect, a "gender-critical" group that promotes GET and argues that gender-affirming care should not be available to those under 25. In late 2023, GETA changed their name to "Therapy First".
GETA also shares a large overlap with the Society for Evidence-Based Gender Medicine (SEGM), which promotes GET as first-line treatment for those under 25. GETA co-founder Lisa Marchiano stated U.S. President Joe Biden's executive order safeguarding trans youth from conversion therapy would have a "chilling effect" on GET practices. GETA also opposed Biden's Title IX changes protecting trans students from discrimination, stating allowing trans youth in restrooms would harm the mental health of their peers. The American College of Pediatricians, a small group aligned with the Christian Right, has cited numerous studies from SEGM to claim GET is necessary to restore transgender people's "biological integrity".
== Effects ==
There is a scientific consensus that conversion therapy is ineffective at changing a person's sexual orientation.
Conversion therapy can cause significant, long-term psychological harm. This includes significantly higher rates of depression, substance abuse, and other mental health issues in individuals who have undergone conversion therapy than their peers who did not, including a suicide attempt rate nearly twice that of those who did not.
After conversion therapy has failed to change someone's sexual orientation or gender identity, participants often feel increased shame that they already felt over their sexual orientation or gender identity.
Modern-day practitioners of conversion therapy—primarily from a conservative religious viewpoint—disagree with current evidence-based medicine and clinical guidance that does not view homosexuality and gender variance as unnatural or unhealthy.
Advocates of conversion therapy rely heavily on testimonials and retrospective self-reports as evidence of effectiveness. Studies purporting to validate the effectiveness of efforts to change sexual orientation or gender identity have been criticized for methodological flaws.
In 2020, ILGA World published a world survey and report Curbing Deception listing consequences and life-threatening effects by associating specific public testimonies with different types of methods used to practice conversion therapies.
A 2022 study estimated that conversion therapy of youth in the United States cost $650.16 million annually with an additional $9.5 billion in associated costs such as increased suicide and substance abuse. Youth who undergo conversion therapy from a religious provider have more negative mental health outcomes than those who had consulted a licensed healthcare provider.
== Public opinion ==
Opinion polls have found that conversion therapy bans enjoy popular support among the U.S. population. As of 2019, no nationwide opinion poll has been carried out, though surveys in three states (Florida, New Mexico and Virginia) show support varying between 60% and 75%. According to a 2014 national poll, only 8% of the U.S. population believed conversion therapies to be successful.
A 2020 survey carried out on US adults found majority support for banning conversion therapy for minors.
A 2022 YouGov poll found majority support in England, Scotland, and Wales for a conversion therapy ban for both sexual orientation and gender identity, with opposition ranging from 13 to 15 percent.
== Legal status ==
Some jurisdictions have criminal bans on the practice of conversion therapy, including Canada, Ecuador, France, Germany, Malta, Mexico and Spain. In other countries, including Albania, Brazil, Chile, Vietnam and Taiwan, medical professionals are barred from practicing conversion therapy.
In some states, lawsuits against conversion therapy providers for fraud have succeeded, but in other jurisdictions those claiming fraud must prove that the perpetrator was intentionally dishonest. Thus, a provider who genuinely believes conversion therapy is effective could not be convicted.
Conversion therapy on minors may amount to child abuse.
=== Human rights ===
In 2020, the International Rehabilitation Council for Torture Victims released an official statement that conversion therapy is torture. The same year, UN Independent Expert on sexual orientation and gender identity, Victor Madrigal-Borloz, said that conversion therapy practices are "inherently discriminatory, that they are cruel, inhuman and degrading treatment, and that depending on the severity or physical or mental pain and suffering inflicted to the victim, they may amount to torture". He recommended that it should be banned across the world. In 2021, Ilias Trispiotis and Craig Purshouse argue that conversion therapy violates the prohibition against degrading treatment under Article 3 of the European Convention on Human Rights, leading to a state obligation to prohibit it. In February 2023 Commissioner for Human Rights, Dunja Mijatović, qualified those practices as “irreconcilable with several guarantees under the European Convention on Human Rights" and having no place in a human rights-based society urging the Member States of the Council of Europe to ban them for both adults and minors, later in July 2023 she advocated for clear actions during a public hearing at the European Parliament studying different approaches to legally ban "conversion therapies" in the European Union. In September 2024 it was reported that the European Union is considering banning "conversion therapies" across its Member States, while a European Citizens' Initiative that started collecting signatures in May 2024 is also calling on the European Commission to outlaw such practices.
== In media ==
Efforts to change sexual orientation have been depicted and discussed in popular culture and various media. More recent examples include: Boy Erased, The Miseducation of Cameron Post, Book of Mormon musical, Ratched, and documentary features Pray Away, Homotherapy: A Religious Sickness.
== Medical views ==
National health organizations around the world have uniformly denounced and criticized sexual orientation and gender identity change efforts. They state that there has been no scientific demonstration of "conversion therapy's" efficacy. They find that conversion therapy is ineffective, risky and can be harmful. Anecdotal claims of cures are counterbalanced by assertions of harm, and the American Psychiatric Association, for example, cautions ethical practitioners under the Hippocratic oath to do no harm and to refrain from attempts at conversion therapy. Furthermore, they state that conversion therapy is harmful and that it often exploits individual's guilt and anxiety, thereby damaging self-esteem and leading to depression and even suicide.
There is also concern in the mental health community that the advancement of conversion therapy can cause social harm by disseminating inaccurate views about gender identity, sexual orientation, and the ability of LGBT people to lead happy, healthy lives. Various medical bodies prohibit their members from practicing conversion therapy.
== See also ==
Christianity and homosexuality
Corrective rape
Recovering from Religion
Sexual orientation change efforts and the LDS Church
== Notes ==
== References ==
== Bibliography ==
== Further reading ==
Haldeman, Douglas C. (2021). Sexual Orientation and Gender Identity Change Efforts: Evidence, Effects, and Ethics. Columbia University Press. ISBN 978-1-939594-36-5. | Wikipedia/Conversion_therapy |
The rapid prompting method (RPM) is a pseudoscientific technique that attempts to aid people with autism or other disabilities to communicate through pointing, typing, or writing. Also known as Spelling to Communicate, it is closely related to the scientifically discredited technique facilitated communication (FC). Practitioners of RPM have failed to assess the issue of message agency using simple and direct scientific methodologies, saying that doing so would be stigmatizing and that allowing scientific criticisms of the technique robs people with autism of their right to communicate. The American Speech-Language-Hearing Association has issued a statement opposing the practice of RPM.
Soma Mukhopadhyay is credited with creating RPM, though others have developed similar techniques, known as informative pointing or alphabet therapy. RPM users report unexpected literacy skills in their clients, as well as a reduction in some of the behavioral issues associated with autism. As noted by Stuart Vyse, although RPM differs from facilitated communication in some ways, "it has the same potential for unconscious prompting because the letter board is always held in the air by the assistant. As long as the method of communication involves the active participation of another person, the potential for unconscious guidance remains."
Critics warn that RPM's over-reliance on prompts (verbal and physical cuing by facilitators) may inhibit development of independent communication in its target population. As of April 2017, only one scientific study attempting to support Mukhopadhyay's claims of efficacy has been conducted, though reviewers found the study had serious methodological flaws. Vyse has noted that rather than proponents of RPM subjecting the methodology to properly controlled validation research, they have responded to criticism by going on the offensive, claiming that scientific criticisms of the technique rob people with autism of their right to communicate, while the authors of a 2019 review concluded that "...until future trials have demonstrated safety and effectiveness, and perhaps more importantly, have first clarified the authorship question, we strongly discourage clinicians, educators, and parents of children with ASD from using RPM."
== Overview ==
RPM founder Mukhopadhyay purports to base RPM on psychological, developmental and behavioral theories put forth by Jean Piaget (developmental psychology) and Anna Jean Ayres (sensory integration), the goal of which is to "establish functional independent pointing-based communication in people who are otherwise nonverbal due to severe autism or other developmental disabilities." RPM users employ elements of Applied Behavior Analysis (ABA), but reject the documentation and evaluation procedures integral to ABA as being unnecessary and stigmatizing. Mukhopadhyay postulates that, by observing student's self-stimulatory behaviors (as in the case of autism, the "sensory preoccupations that drive and develop them"), she can identify each student's "dominant learning channel" (visual, tactile, or auditory) and individualize a program to match his or her needs. RPM facilitators "presume competence" in their (often nonspeaking) communication partners; the assumption being that people with autism "are likely to possess considerable hidden knowledge that they cannot express" and that prompting will address these individuals' hypothesized difficulties with motor planning and self-stimulatory behaviors. RPM is a "low-tech approach that requires only an instructor, student, paper, and pencil".
=== Certification and licensing ===
As of April 2017, RPM is not recognized as a clinical profession nor does it have recognized standards for registering, licensing or certifying treatment providers. Practitioners appear to be self-taught or have participated in workshops and camps offered by Mukhopadhyay, Heather Clare (Informative Pointing), or Vanderbilt Kennedy Center Angelman Program (Alphabet Therapy).
Professionals applying for RPM workshops are required to submit 10-min video samples of the use of rapid prompting, a resume, and a letter explaining the "reason for wanting to attend course".
=== Targeted populations ===
RPM literature indicates that, along with autism, the technique has been tried with people who have Fragile X syndrome, blindness, deafness, Angelman syndrome, Down syndrome, Williams syndrome, and Prader-Willi syndrome.
=== Practices and procedures ===
Beginning with a "teach-ask" protocol, the facilitator presents the student with a concept (i.e., The chair is yellow), then immediately follows up with a question (i.e., "What color is the chair?"). The student is then given prompts (i.e., two pieces of paper, with choices written on each) to represent the answer. This procedure is repeated, using a combination of prompts provided by the facilitator to elicit a response. Prompts may include physical (i.e. words written on paper), auditory (i.e. the sound of paper tearing), verbal (i.e. spoken directives), and visual (i.e. gestures by the facilitator). Choices move from two, three, to four and so on, with increased difficulty. The student progresses from making choices, to spelling on a letter board held by the facilitator, to spelling on a letter board (flat on a table or held by the student) or voice-output device, independently.
== Historical background ==
The rapid prompting method (also known as RPM, Rapid Prompting, Soma®RPM, Informative Pointing, Spelling To Communicate (STC) and Alphabet Therapy) is largely credited to Soma Mukhopadhyay, who has a master's degree in chemistry and a bachelor's in education. By trial and error, Mukhopadhyay combined various behavioral and communication techniques to help her son, Tito, who has a diagnosis of autism and exhibits limited speaking abilities. Mukhopadhyay posits that autism is a manifestation in which a child's cognitive abilities are undermined by poor sensory integration abilities and that RPM serves to "activate the reasoning part of the brain" and, therefore, distracts the student into learning. Proponents of RPM and related techniques claim to be able to help people with disabilities express untapped intellectual abilities and advance communication skills through a system of pointing, typing, or writing with verbal and physical prompts from a facilitator. This is, purportedly, "the most direct and unlimited path to learning and communicating." RPM proponents point to the "sole study of RPM", "Harnessing repetitive behaviours to engage attention and learning in a novel therapy for autism: An exploratory analysis", published in the journal Frontiers in Psychology (2012), as proof of the method's efficacy.
In 2001, Mukhopadhyay brought RPM to the United States, in conjunction with a fellowship from the Cure Autism Now Foundation, led by Portia Iversen and Jon Shestack.
In 2004, Mukhopadhyay and Helping Autism through Learning and Outreach (HALO) collaborated to expand RPM's reach nationally. Mukhopadhyay owns the trademark for RPM.
In 2005, Mukhopadhyay moved from California to Austin, Texas, where she established the Halo-Soma Institute. There, she provides clinical services, offers workshops and promotes RPM internationally. Evaluation research is not conducted by the institute. Mukhopadhyay is the author of Rapid Prompting: an Instructional Guide, Understanding Autism through Rapid Prompting (2008) and Curriculum Guide for Autism Using Rapid Prompting Method: with Lesson Plan Suggestions (2011).
After some initial collaboration with Mukhopadhyay, Iversen developed the Informative Pointing Method. She also wrote a book called Strange Son: Two Mothers, Two Sons, and the Quest to Unlock the Hidden World of Autism, which, as one reviewer stated, expresses her "absorbing and speculative views" on autism which are "at once compelling and controversial." Iversen spends much of the book discussing Tito's communications and documenting her own son, Dov's, introduction to RPM.
Alphabet Therapy was developed and is promoted by Vanderbilt University and focuses specifically on people with Angelman Syndrome.
== Organizations opposing rapid prompting method ==
The American Association on Intellectual and Developmental Disabilities (AAIDD)
The Board of Directors concludes that rather than helping people express their thoughts, desires, and choices, FC and RPM have the potential to effectively take away people's voices. This is due to the risk of facilitator influence/authorship as well as the potential to displace efforts to access scientifically valid communication modes, such as those associated with the field of Augmentative and Alternative Communication (AAC).
The American Speech-Language-Hearing Association (ASHA)
It is the position of the American Speech-Language-Hearing Association (ASHA) that use of the Rapid Prompting Method (RPM) is not recommended because of prompt dependency and the lack of scientific validity. Furthermore, information obtained through the use of RPM should not be assumed to be the communication of the person with a disability.
The Association for Science in Autism Treatment
While the lack of evidence from previously conducted studies does not necessarily indicate that RPM is not effective at developing communication skills and reducing stereotypic behaviors in learners with autism, use of this intervention should not be used or recommended by practitioners until the claims made can be substantiated by peer reviewed research studies.
The Irish Association of Speech and Language Therapists (IASLT)
Since the broadcast of the RTE documentary ‘Autism and Me’ on March 13th 2017 there has been much discussion about the Rapid Prompting Method (RPM) which was used to facilitate communication for one teenage boy featured on the programme. IASLT wish to put on record our position in relation to this method - primarily our concern that there is no evidence to support its use.
Speech-Language and Audiology Canada (SAC)
There is a lack of substantive research evidence demonstrating that FC and RPM are valid forms of augmentative or alternative communication ... Research studies show that facilitators consciously and/or unconsciously influence the message being communicated ... thereby exposing people with communication disorders to risk of harm by preventing genuine self-expression ... For these reasons, SAC members and associates should not use FC and RPM in clinical practice.
== Criticism ==
=== Empirical evidence ===
RPM proponents point to one study to support their claims of efficacy: "Harnessing repetitive behaviours to engage attention and learning in a novel therapy for autism: An exploratory analysis, as proof of the method's efficacy". In this peer-reviewed, quantitative study using videotaped sessions of Mukhopadhyay working with clients, the study authors attempted to measure how RPM influenced participants' attention to their facilitator and the materials being presented (joint attention) and the effect of RPM on restrictive and stereotypic behaviors (RSB). Although RSBs reduced as joint attention increased, the authors were unable to show that RPM itself had a direct correlation to the behaviors exhibited by the participants or that joint attention increased as a result of its use. Correct answers were observed while students were not engaged with the activity, leading reviewers of the study to ask: "How does the client know how to answer, what the answer options are, or where the letters are located if the client is not looking at the facilitator or at the moving letter board?" The study authors postulated that "direct gaze [at the facilitator or letter board] may actually inhibit the ability to respond correctly," The authors did not investigate authorship of the communications produced during the RPM sessions.
According to reviewers, RPM method does make use of concepts such as errorless learning, response interruption, and redirection. However, these behavioral intervention components are not implemented in a manner consistent with the research-base. Practitioners claim to be responsive to each individual's dominant open sensory channel, the "basic features of training" to not appear to be distinctively different across the channels. Studying RPM's efficacy is made difficult by policies that prevent videotaping of RPM sessions (even of one's own child) and instructional workshops.
Jaswal et al. also continued the pattern of proponents studying the issue of agency in the use of RPM by using indirect, rather than direct (message passing) methodologies. The study found that the non-verbal (according to their reports) autistic individuals in their study (1) made anticipatory eye movements to the next letter in a word prior to touching the letter, (2) had longer pauses in their letter-touching within words than between words, and (3) were faster at touching common letter patterns in sequence than was the case for less common letter patterns. Based upon these indirect indices of message agency, it was concluded that the autistic individuals, rather than the assistants who held the letter boards, were the agents of the messages. Vyse, however, argued that none of these findings provides clear evidence regarding message agency. For example, the longer pauses between words could simply have resulted from the fact that the assistant voiced each word aloud after the final letter of each word was touched. Vyse also argued that the authors have not provided a compelling reason why simpler, and more direct, methods of assessing message agency (some form of message passing methodology) were not used in the study, and why simple controls that could bolster the authors' claims (e.g. placing the letterboard on a stand instead of it being held by the assistant or putting a blindfold on the assistant) were not utilized.
Accordingly, to date, RPM proponents, by resisting participation in studies, have failed to produce methodologically sound, evidence-based studies demonstrating that RPM provides people with autism and other developmental disabilities a reliable and independent method for communicating.
=== Unexpected literacy and extraordinary communication abilities ===
Critics of RPM are concerned that, sometimes even on the first attempt at using the method, people with profound communication and/or developmental disabilities achieve levels of communication or understanding of subject matter beyond what their expected age or exposure to formal education would predict. In some cases, students, with prompting, produce results in a language other than the one he or she has been exposed, indicating facilitator, rather than student authorship. Facilitators, sympathetic to the RPM goals of ensuring student success, may unknowingly, unintentionally, or unconsciously move the letter board to achieve the desired communication outcome.
=== Prompt dependency ===
In order to point, type or write using RPM, people with disabilities rely on an aide or facilitator to give verbal or gestural prompts and/or hold a letter board during the sessions, which precludes independent communication. Prompts may include verbal reprimands, trial termination, physical redirection, slapping or shaking the letter board against the subject's face or chest, and blocking escape by positioning the subject between the table and walls. Some of the verbal and gestural prompting procedures used in RPM are similar to the Pinchbeck Technique used by conjurers to "create the illusion of letter-by-letter communication."
"It is possible that no actual academic skills are taught to participants in RPM. Instead, participants may only learn how to better follow subtle, rhythmic, and frequent prompts. The danger, of course, is that an untrained observer might not be able to readily recognize such subtle prompts and may mistakenly assume that prompted responses accurately reflect the true preferences, academic abilities, and emotions of the individual. Such an outcome would make RPM equally as dangerous and inhumane as facilitated communication (FC), a thoroughly debunked method that creates a powerful illusion that seems notably similar to RPM."
Critics point out that there are no procedures in place to prevent students' over reliance on their facilitator. Likewise, there is no purposeful or systematic fading of prompts with RPM, though research-based techniques exist to support transference of prompt-reliant behaviors to "naturally occurring discriminitive stimuli". This reliance on prompts creates a dependency that, essentially, reduces independent communication and increases the chances that the facilitators are authoring the messages. In other words, "accurate responding may not occur unless the aide knows the answers."
Proponents assert that "prompt dependency is preferable to no response" from the subjects.
With advanced computer technology capable of allowing people access to communication with eye movements, critics also question "the validity of any communication method that requires the physical help of someone else." Critics counter this assertion. Prompt dependency creates an active participation in the communication process. Therefore, the "potential for unconscious guidance remains".
=== Facilitated communication ===
Facilitated communication, a technique in which a facilitator supports a person with disabilities at the arm, wrist or hand during the process of typing on a letter board, is closely related to RPM. Controlled studies in the 1990s determined that, when facilitators did not know the answers to questions being asked through FC, the answers were "routinely inaccurate". Facilitators were (unconsciously) authoring the messages.
Proponents of RPM deny similarities with FC because the aide or facilitator in RPM holds the letter board but "does not touch the person typing" and that the prompts are "nonspecific." However, critics of RPM point out that subtle cuing takes place during RPM that makes it "highly susceptible to facilitator influence."
Other similarities between RPM and FC include: reluctance or refusal to test facilitator/client pairs in controlled settings (purportedly because the process breaks the trust between the pair), presumed competence, reliance on anecdotal accounts as proof of efficacy, maintenance of practices, techniques and claims that are inconsistent with the known body of work around the behavior and communication skills of individuals with developmental disabilities or proven remediation techniques, claims of extraordinary literacy or intellectual breakthroughs, unconscious verbal or physical cuing by facilitators to obtain the expected responses, inadequate or non-existent protocols to fade supported or facilitated prompts.
== Media ==
RPM has been featured in several documentary and on several television news programs including: 60 Minutes II, CNN, PBS (How does the autistic brain work?), and National Geographic (Mind Tree Poems, 2005). Mukhopadhyay's son, Tito, featured prominently in a BBC Documentary, Tito's Story, and is given credit for co-authoring (with his mother using RPM), "two poetry books, a collection of short stories, and a book describing his sensory experience." Print sources discussing RPM and the Mukhopadhyays, include The New York Times and Scientific American, the latter of which criticized active proponents for not attempting a scientific study of the method.
The August 2014 documentary film, A Mother's Courage: Talking Back to Autism, was adapted from a 2009 Icelandic film entitled Solskinsdrengurrin (The Sunshine Boy) by Margrét Dagmar Ericsdóttir and Friðrik Þór Friðriksson. The film follows Margret, an Icelandic woman, in her quest to find answers for her 11-year-old son who is severely impaired. Her search leads her to Austin, TX, Mukhopadhyay and RPM.
RPM was featured in an Apple Inc. commercial, which led to criticism of Apple for promoting pseudoscience.
Critics of this type of media attention point out that these programs portray autism as "mysterious in nature", offer anecdotal evidence (i.e., Tito's poetry) as proof that RPM works, and downplay the fact that RPM "does not have research to support it at this time."
== Bibliography ==
=== Articles ===
Evidence does not support the use of Rapid Prompting Method (RPM) as an intervention for students with autism spectrum disorder and further primary research is not justified
Harnessing repetitive behaviours to engage attention and learning in a novel therapy for autism: An exploratory analysis
Rapid Prompting Method (RPM): A suitable intervention for students with ASD?
Voices from the Past: Comparing the Rapid Prompting Method and Facilitated Communication
Rapid Prompting Method Is Not Consistent with Evidence-Based Reading Instruction for Students with Autism
=== Book chapters ===
Old horses in new stables: Rapid prompting, facilitated communication, science, ethics, and the history of magic.
== References == | Wikipedia/Rapid_prompting_method |
Pathological science is an area of research where "people are tricked into false results ... by subjective effects, wishful thinking or threshold interactions." The term was first used by Irving Langmuir, Nobel Prize-winning chemist, during a 1953 colloquium at the Knolls Research Laboratory. Langmuir said a pathological science is an area of research that simply will not "go away"—long after it was given up on as "false" by the majority of scientists in the field. He called pathological science "the science of things that aren't so."
In his 2002 book, Undead Science, sociology and anthropology Professor Bart Simon lists it among practices that are falsely perceived or presented to be science, "categories ... such as ... pseudoscience, amateur science, deviant or fraudulent science, bad science, junk science, pathological science, cargo cult science, and voodoo science." Examples of pathological science include the Martian canals, N-rays, polywater, and cold fusion. The theories and conclusions behind all of these examples are currently rejected or disregarded by the majority of scientists.
== Definition ==
Pathological science, as defined by Langmuir, is a psychological process in which a scientist, originally conforming to the scientific method, unconsciously veers from that method, and begins a pathological process of wishful data interpretation (see the observer-expectancy effect and cognitive bias). Some characteristics of pathological science are:
The maximum effect that is observed is produced by a causative agent of barely detectable intensity, and the magnitude of the effect is substantially independent of the intensity of the cause.
The effect is of a magnitude that remains close to the limit of detectability, or multiple measurements are necessary because of the low statistical significance of the results.
There are claims of great accuracy.
Fantastic theories contrary to experience are suggested.
Criticisms are met by ad hoc excuses.
The ratio of supporters to critics rises and then falls gradually to oblivion.
Langmuir never intended the term to be rigorously defined; it was simply the title of his talk on some examples of "weird science". As with any attempt to define the scientific endeavor, examples and counterexamples can always be found.
== Langmuir's examples ==
=== N-rays ===
Langmuir's discussion of N-rays has led to their traditional characterization as an instance of pathological science.
In 1903, Prosper-René Blondlot was working on X-rays (as were other physicists of the era) and noticed a new visible radiation that could penetrate aluminium. He devised experiments in which a barely visible object was illuminated by these N-rays, and thus became "more visible". Blondlot claimed that N-rays were causing a small visual reaction, too small to be seen under normal illumination, but just visible when most normal light sources were removed and the target was just barely visible to begin with.
N-rays became the topic of some debate within the science community. After a time, American physicist Robert W. Wood decided to visit Blondlot's lab, which had moved on to the physical characterization of N-rays. An experiment passed the rays from a 2 mm slit through an aluminum prism, from which he was measuring the index of refraction to a precision that required measurements accurate to within 0.01 mm. Wood asked how it was possible that he could measure something to 0.01 mm from a 2 mm source, a physical impossibility in the propagation of any kind of wave. Blondlot replied, "That's one of the fascinating things about the N-rays. They don't follow the ordinary laws of science that you ordinarily think of." Wood then asked to see the experiments being run as usual, which took place in a room required to be very dark so the target was barely visible. Blondlot repeated his most recent experiments and got the same results—despite the fact that Wood had reached over and covertly sabotaged the N-ray apparatus by removing the prism.
=== Other examples ===
Langmuir offered additional examples of what he regarded as pathological science in his original speech:
The Davis–Barnes effect (1929; after Professor Bergen Davis from Columbia University)
Mitogenetic rays (1923; Alexander Gurwitsch and others)
The Allison effect (1927; after Fred Allison). (b) (c) (d) (e)
Extrasensory perception (1934), where Rhine consciously discarded contrary test results because he felt they could not be correct.
=== Later examples ===
A 1985 version of Langmuir's speech offered more examples, although at least one of these (polywater) occurred entirely after Langmuir's death in 1957:
Water dowsing
Martian canals (Observed in late 19th century and early 20th century, they turned out to be optical illusions.)
Certain reported photomechanical and electromechanical effects
Polywater
Biological effects of magnetic fields (see magnetobiology and magnet therapy) except magnetoception
== Newer examples ==
Since Langmuir's original talk, a number of newer examples of what appear to be pathological science have appeared. Denis Rousseau, one of the main debunkers of polywater, gave an update of Langmuir in 1992, and he specifically cited as examples the cases of polywater, Martin Fleischmann's cold fusion and Jacques Benveniste's "infinite dilution".
=== Polywater ===
Polywater was a form of water which appeared to have a much higher boiling point and much lower freezing point than normal water. During the 1960s, a number of articles were published on the subject, and research on polywater was done around the world with mixed results. Eventually it was determined that some of the properties of polywater could be explained by biological contamination. When more rigorous cleaning of glassware and experimental controls were introduced, polywater could no longer be produced. It took several years for the concept of polywater to die in spite of the later negative results.
=== Cold fusion ===
In 1989, Martin Fleischmann and Stanley Pons announced the discovery of a simple and cheap procedure to obtain room-temperature nuclear fusion. Although there were multiple instances where successful results were reported, they lacked consistency and hence cold fusion came to be considered to be an example of pathological science. Two panels convened by the US Department of Energy, one in 1989 and a second in 2004, did not recommend a dedicated federal program for cold fusion research. A small number of researchers continue working in the field.
=== Water memory ===
Jacques Benveniste was a French immunologist who in 1988 published a paper in the prestigious scientific journal Nature describing the action of high dilutions of anti-IgE antibody on the degranulation of human basophils, findings which seemed to support the concept of homeopathy. Biologists were puzzled by Benveniste's results, as only molecules of water, and no molecules of the original antibody, remained in these high dilutions. Benveniste concluded that the configuration of molecules in water was biologically active. Subsequent investigations have not supported Benveniste's findings.
== See also ==
Fringe science
Protoscience
Scientific misconduct
List of experimental errors and frauds in physics
List of topics characterized as pseudoscience
== Notes ==
== References ==
Carroll, Robert Todd, "pathological science". The Skeptic's Dictionary.
Biberian, Jean-Paul (2007). "Condensed Matter Nuclear Science (Cold Fusion): An Update" (PDF). International Journal of Nuclear Energy Science and Technology. 3 (1): 31–43. CiteSeerX 10.1.1.618.6441. doi:10.1504/IJNEST.2007.012439.
Kirby, Geoff., "Forum: Now you see it...Now you don't – A pathological tendency among astronomers", New Scientist, 24 February 1990
Kowalski, Ludwik, "Pathological Science" (N-rays story). Montclair State University, Upper Montclair, N.J.
Langmuir, I. and R. N. Hall., "Pathological Science". Colloquium at The Knolls Research Laboratory, December 18, 1953.
Langmuir, Irving, and Robert N. Hall. "Pathological science". Physics Today 42 (10): 36–48. 1989.
Turro, Nicholas J., "Toward a general theory of pathological science". 21stC: Issue 3.4 Strange Science.
Wilson, James R., "Doctoral colloquium keynote address: conduct, misconduct, and cargo cult science". Department of Industrial Engineering, North Carolina State University. Raleigh, North Carolina.
Wynne, B., "G. G. Barkla and the J-Phenomenon: a Case Study of the Treatment of Deviance in Physics", Social Studies of Science, Vol. 6, 1976, pp. 307–304 (abstract) | Wikipedia/Pathological_science |
Communal reinforcement is a social phenomenon in which a concept or idea is repeatedly asserted in a community, regardless of whether sufficient empirical evidence has been presented to support it. Over time, the concept or idea is reinforced to become a strong belief in many people's minds, and may be regarded by the members of the community as fact. Often, the concept or idea may be further reinforced by publications in the mass media, books, or other means of communication. The phrase "millions of people can't all be wrong" is indicative of the common tendency to accept a communally reinforced idea without question, which often aids in the widespread acceptance of factoids. A very similar term to this term is community-reinforcement, which is a behavioral method to stop drug addiction.
== In addiction treatment ==
The community-reinforcement approach (CRA) is a behaviourist alcoholism treatment approach that aims to achieve abstinence by eliminating positive reinforcement for drinking and enhancing positive reinforcement for sobriety. CRA integrates several treatment components, including building the client's motivation to quit drinking, helping the client initiate sobriety, analyzing the client's drinking pattern, increasing positive reinforcement, learning new coping behaviors, and involving significant others in the recovery process. These components can be adjusted to the individual client's needs to achieve optimal treatment outcome. In addition, treatment outcome can be influenced by factors such as therapist style and initial treatment intensity. Several studies have provided evidence for CRA's effectiveness in achieving abstinence. Furthermore, CRA has been successfully integrated with a variety of other treatment approaches, such as family therapy and motivational interviewing, and has been tested in the treatment of other drug abuse. Community reinforcement and family training (CRAFT) is an adaptation of CRA that is aimed at giving the Concerned Significant Others (CSOs) of alcoholics skills to help them get the alcoholic into treatment.
== In other applications ==
In Chris E. Stout's book The Psychology of Terrorism: Theoretical Understandings and Perspective, Stout explains how community reinforcement is present in the psychotic state of terrorists. "The individual would feel less charged, validated, courageous, sanctified, and zealous, and would feel exposed as an individual." It is believed that the group mentality of a terrorist organization solidifies the mission of the group through communal reinforcement. Members are more likely to stay dedicated and follow through with the event of terror if they receive support from fellow terrorist members. An individual might abandon the mission in terror, but with the reinforcement of his peers, a member is more likely to stay involved.
== See also ==
== References == | Wikipedia/Communal_reinforcement |
A biography, or simply bio, is a detailed description of a person's life. It involves more than just basic facts like education, work, relationships, and death; it portrays a person's experience of these life events. Unlike a profile or curriculum vitae (résumé), a biography presents a subject's life story, highlighting various aspects of their life, including intimate details of experience, and may include an analysis of the subject's personality.
Biographical works are usually non-fiction, but fiction can also be used to portray a person's life. One in-depth form of biographical coverage is called legacy writing. Works in diverse media, from literature to film, form the genre known as biography.
An authorized biography is written with the permission, cooperation, and at times, participation of a subject or a subject's heirs. An unauthorized biography is one written without such permission or participation. An autobiography is written by the person themselves, sometimes with the assistance of a collaborator or ghostwriter.
== History ==
At first, biographical writings were regarded merely as a subsection of history with a focus on a particular individual of historical importance. The independent genre of biography as distinct from general history writing, began to emerge in the 18th century and reached its contemporary form at the turn of the 20th century.
=== Historical biography ===
Biography is the earliest literary genre in history. According to Egyptologist Miriam Lichtheim, writing took its first steps toward literature in the context of the private tomb funerary inscriptions. These were commemorative biographical texts recounting the careers of deceased high royal officials. The earliest biographical texts are from the 26th century BC.
In the 21st century BC, another famous biography was composed in Mesopotamia about Gilgamesh. One of the five versions could be historical.
From the same region a couple of centuries later, according to another famous biography, departed Abraham. He and his 3 descendants became subjects of ancient Hebrew biographies whether fictional or historical.
One of the earliest Roman biographers was Cornelius Nepos, who published his work Excellentium Imperatorum Vitae ("Lives of outstanding generals") in 44 BC. Longer and more extensive biographies were written in Greek by Plutarch, in his Parallel Lives, published about 80 A.D. In this work famous Greeks are paired with famous Romans, for example, the orators Demosthenes and Cicero, or the generals Alexander the Great and Julius Caesar; some fifty biographies from the work survive. Another well-known collection of ancient biographies is De vita Caesarum ("On the Lives of the Caesars") by Suetonius, written about AD 121 in the time of the emperor Hadrian. Meanwhile, in the eastern imperial periphery, Gospel described the life of Jesus.
In the early Middle Ages (AD 400 to 1450), there was a decline in awareness of the classical culture in Europe. During this time, the only repositories of knowledge and records of the early history in Europe were those of the Roman Catholic Church. Hermits, monks, and priests used this historic period to write biographies. Their subjects were usually restricted to the church fathers, martyrs, popes, and saints. Their works were meant to be inspirational to the people and vehicles for conversion to Christianity (see Hagiography). One significant secular example of a biography from this period is the life of Charlemagne by his courtier Einhard.
In Medieval Western India, there was a Sanskrit Jain literary genre of writing semi-historical biographical narratives about the lives of famous persons called Prabandhas. Prabandhas were written primarily by Jain scholars from the 13th century onwards and were written in colloquial Sanskrit (as opposed to Classical Sanskrit). The earliest collection explicitly titled Prabandha- is Jinabhadra's Prabandhavali (1234 CE).
In Medieval Islamic Civilization (c. AD 750 to 1258), similar traditional Muslim biographies of Muhammad and other important figures in the early history of Islam began to be written, beginning the Prophetic biography tradition. Early biographical dictionaries were published as compendia of famous Islamic personalities from the 9th century onwards. They contained more social data for a large segment of the population than other works of that period. The earliest biographical dictionaries initially focused on the lives of the prophets of Islam and their companions, with one of these early examples being The Book of The Major Classes by Ibn Sa'd al-Baghdadi. And then began the documentation of the lives of many other historical figures (from rulers to scholars) who lived in the medieval Islamic world.
By the late Middle Ages, biographies became less church-oriented in Europe as biographies of kings, knights, and tyrants began to appear. The most famous of such biographies was Le Morte d'Arthur by Sir Thomas Malory. The book was an account of the life of the fabled King Arthur and his Knights of the Round Table. Following Malory, the new emphasis on humanism during the Renaissance promoted a focus on secular subjects, such as artists and poets, and encouraged writing in the vernacular.
Giorgio Vasari's Lives of the Artists (1550) was the landmark biography focusing on secular lives. Vasari made celebrities of his subjects, as the Lives became an early "bestseller". Two other developments are noteworthy: the development of the printing press in the 15th century and the gradual increase in literacy.
Biographies in the English language began appearing during the reign of Henry VIII. John Foxe's Actes and Monuments (1563), better known as Foxe's Book of Martyrs, was essentially the first dictionary of the biography in Europe, followed by Thomas Fuller's The History of the Worthies of England (1662), with a distinct focus on public life.
Influential in shaping popular conceptions of pirates, A General History of the Pyrates (1724), by Charles Johnson, is the prime source for the biographies of many well-known pirates.
A notable early collection of biographies of eminent men and women in the United Kingdom was Biographia Britannica (1747–1766) edited by William Oldys.
The American biography followed the English model, incorporating Thomas Carlyle's view that biography was a part of history. Carlyle asserted that the lives of great human beings were essential to understanding society and its institutions. While the historical impulse would remain a strong element in early American biography, American writers carved out a distinct approach. What emerged was a rather didactic form of biography, which sought to shape the individual character of a reader in the process of defining national character.
=== Emergence of the genre ===
The first modern biography, and a work that exerted considerable influence on the evolution of the genre, was James Boswell's The Life of Samuel Johnson, a biography of lexicographer and man-of-letters Samuel Johnson published in 1791.
While Boswell's personal acquaintance with his subject only began in 1763, when Johnson was 54 years old, Boswell covered the entirety of Johnson's life by means of additional research. Itself an important stage in the development of the modern genre of biography, it has been claimed to be the greatest biography written in the English language. Boswell's work was unique in its level of research, which involved archival study, eye-witness accounts and interviews, its robust and attractive narrative, and its honest depiction of all aspects of Johnson's life and character – a formula which serves as the basis of biographical literature to this day.
Biographical writing generally stagnated during the 19th century – in many cases there was a reversal to the more familiar hagiographical method of eulogizing the dead, similar to the biographies of saints produced in Medieval times. A distinction between mass biography and literary biography began to form by the middle of the century, reflecting a breach between high culture and middle-class culture. However, the number of biographies in print experienced a rapid growth, thanks to an expanding reading public. This revolution in publishing made books available to a larger audience of readers. In addition, affordable paperback editions of popular biographies were published for the first time. Periodicals began publishing a sequence of biographical sketches.
Autobiographies became more popular, as with the rise of education and cheap printing, modern concepts of fame and celebrity began to develop. Autobiographies were written by authors, such as Charles Dickens (who incorporated autobiographical elements in his novels) and Anthony Trollope (his Autobiography appeared posthumously, quickly becoming a bestseller in London), philosophers, such as John Stuart Mill, churchmen – John Henry Newman – and entertainers – P. T. Barnum.
=== Modern biography ===
The sciences of psychology and sociology were ascendant at the turn of the 20th century and would heavily influence the new century's biographies. The demise of the "great man" theory of history was indicative of the emerging mindset. Human behavior would be explained through Darwinian theories. "Sociological" biographies conceived of their subjects' actions as the result of the environment, and tended to downplay individuality. The development of psychoanalysis led to a more penetrating and comprehensive understanding of the biographical subject, and induced biographers to give more emphasis to childhood and adolescence. Clearly these psychological ideas were changing the way biographies were written, as a culture of autobiography developed, in which the telling of one's own story became a form of therapy. The conventional concept of heroes and narratives of success disappeared in the obsession with psychological explorations of personality.
British critic Lytton Strachey revolutionized the art of biographical writing with his 1918 work Eminent Victorians, consisting of biographies of four leading figures from the Victorian era: Cardinal Manning, Florence Nightingale, Thomas Arnold, and General Gordon. Strachey set out to breathe life into the Victorian era for future generations to read. Up until this point, as Strachey remarked in the preface, Victorian biographies had been "as familiar as the cortège of the undertaker", and wore the same air of "slow, funereal barbarism." Strachey defied the tradition of "two fat volumes ... of undigested masses of material" and took aim at the four iconic figures. His narrative demolished the myths that had built up around these cherished national heroes, whom he regarded as no better than a "set of mouth bungled hypocrites". The book achieved worldwide fame due to its irreverent and witty style, its concise and factually accurate nature, and its artistic prose.
In the 1920s and 1930s, biographical writers sought to capitalize on Strachey's popularity by imitating his style. This new school featured iconoclasts, scientific analysts, and fictional biographers and included Gamaliel Bradford, André Maurois, and Emil Ludwig, among others. Robert Graves (I, Claudius, 1934) stood out among those following Strachey's model of "debunking biographies." The trend in literary biography was accompanied in popular biography by a sort of "celebrity voyeurism", in the early decades of the century. This latter form's appeal to readers was based on curiosity more than morality or patriotism. By World War I, cheap hard-cover reprints had become popular. The decades of the 1920s witnessed a biographical "boom."
American professional historiography gives a limited role to biography, preferring instead to emphasize deeper social and cultural influences. Political biographers historically incorporated moralizing judgments into their work, with scholarly biography being an uncommon genre before the mid-1920s. Allan Nevins was a major contributor in the 1930s to the multivolume Dictionary of American Biography. Nevins also sponsored a series of long political biographies. Later biographers sought to show how political figures balanced power and responsibility. However, many biographers found that their subjects were not as morally pure as they originally thought, and young historians after 1960 tended to be more critical. The exception is Robert Remini whose books on Andrew Jackson idolize its hero and fends off criticisms. The study of decision-making in politics is important for scholarly political biographers, who can take different approaches such as focusing on psychology/personality, bureaucracy/interests, fundamental ideas, or societal forces. However, most documentation favors the first approach, which emphasizes personalities. Biographers often neglect the voting blocs and legislative positions of politicians and the organizational structures of bureaucracies. A more promising approach is to locate a person's ideas through intellectual history, but this has become more difficult with the philosophical shallowness of political figures in recent times. Political biography can be frustrating and challenging to integrate with other fields of political history.
The feminist scholar Carolyn Heilbrun observed that women's biographies and autobiographies began to change character during the second wave of feminist activism. She cited Nancy Milford's 1970 biography Zelda, as the "beginning of a new period of women's biography, because "[only] in 1970 were we ready to read not that Zelda had destroyed Fitzgerald, but Fitzgerald her: he had usurped her narrative." Heilbrun named 1973 as the turning point in women's autobiography, with the publication of May Sarton's Journal of a Solitude, for that was the first instance where a woman told her life story, not as finding "beauty even in pain" and transforming "rage into spiritual acceptance," but acknowledging what had previously been forbidden to women: their pain, their rage, and their "open admission of the desire for power and control over one's life."
=== Recent years ===
In recent years, multimedia biography has become more popular than traditional literary forms. Along with documentary biographical films, Hollywood produced numerous commercial films based on the lives of famous people. The popularity of these forms of biography have led to the proliferation of TV channels dedicated to biography, including A&E, The Biography Channel, and The History Channel.
CD-ROM and online biographies have also appeared. Unlike books and films, they often do not tell a chronological narrative: instead they are archives of many discrete media elements related to an individual person, including video clips, photographs, and text articles. Biography-Portraits were created in 2001, by the German artist Ralph Ueltzhoeffer. Media scholar Lev Manovich says that such archives exemplify the database form, allowing users to navigate the materials in many ways. General "life writing" techniques are a subject of scholarly study.
In recent years, debates have arisen as to whether all biographies are fiction, especially when authors are writing about figures from the past. President of Wolfson College at Oxford University, Hermione Lee argues that all history is seen through a perspective that is the product of one's contemporary society and as a result, biographical truths are constantly shifting. So, the history biographers write about will not be the way that it happened; it will be the way they remembered it. Debates have also arisen concerning the importance of space in life-writing.
Daniel R. Meister in 2017 argued that:
Biography Studies is emerging as an independent discipline, especially in the Netherlands. This Dutch School of biography is moving biography studies away from the less scholarly life writing tradition and towards history by encouraging its practitioners to utilize an approach adapted from microhistory.
=== Biographical research ===
Biographical research is defined by Miller as a research method that collects and analyses a person's whole life, or portion of a life, through the in-depth and unstructured interview, or sometimes reinforced by semi-structured interview or personal documents. It is a way of viewing social life in procedural terms, rather than static terms. The information can come from "oral history, personal narrative, biography and autobiography" or "diaries, letters, memoranda and other materials". The central aim of biographical research is to produce rich descriptions of persons or "conceptualise structural types of actions", which means to "understand the action logics or how persons and structures are interlinked". This method can be used to understand an individual's life within its social context or understand the cultural phenomena.
=== Critical issues ===
There are many largely unacknowledged pitfalls to writing good biographies, and these largely concern the relation between firstly the individual and the context, and, secondly, the private and public. Paul James writes:
The problems with such conventional biographies are manifold. Biographies usually treat the public as a reflection of the private, with the private realm being assumed to be foundational. This is strange given that biographies are most often written about public people who project a persona. That is, for such subjects the dominant passages of the presentation of themselves in everyday life are already formed by what might be called a 'self-biofication' process.
== Book awards ==
Several countries offer an annual prize for writing a biography such as the:
Drainie-Taylor Biography Prize – Canada
National Biography Award – Australia
Pulitzer Prize for Biography or Autobiography – United States
Whitbread Prize for Best Biography – United Kingdom
J. R. Ackerley Prize for Autobiography – United Kingdom
Prix Goncourt de la Biographie – France
== See also ==
Historiography
Historiography of science
Historiography of the United Kingdom
Historiography of the United States
Legal biography
Letter collection
Psychobiography
Autobiography
== Notes ==
== References ==
== Further reading ==
Gosse, Edmund William (1911). "Biography" . In Chisholm, Hugh (ed.). Encyclopædia Britannica. Vol. 3 (11th ed.). Cambridge University Press. pp. 952–954.
Sidney Lee (1911), Principles of Biography, London: Cambridge University Press, Wikidata Q107333538
Solomon, Maynard (2001). "Biography". Grove Music Online. Oxford: Oxford University Press. doi:10.1093/gmo/9781561592630.article.41156. ISBN 978-1-56159-263-0. (subscription, Wikilibrary access, or UK public library membership required)
== External links ==
"Biography", In Our Time, BBC Radio 4 discussion with Richard Holmes, Nigel Hamilton and Amanda Foreman (June 22, 2000). | Wikipedia/Biographies |
Cupping therapy is a form of pseudoscience in which a local suction is created on the skin using heated cups. As alternative medicine it is practiced primarily in Asia but also in Eastern Europe, the Middle East, and Latin America. There is no conclusive evidence supporting the claimed health benefits of cupping, and critics have characterized the practice as quackery.
Cupping practitioners attempt to use cupping therapy for a wide array of medical conditions including fevers, chronic low back pain, poor appetite, indigestion, high blood pressure, acne, atopic dermatitis, psoriasis, anemia, stroke rehabilitation, nasal congestion, infertility, and menstrual period cramping.
Despite the numerous ailments for which practitioners claim cupping therapy is useful, there is insufficient evidence demonstrating any health benefits. Cupping is generally not harmful for most people. However, there are some risks of harm, especially from wet cupping and fire cupping. Bruising and skin discoloration are among the adverse effects of cupping and are sometimes mistaken for child abuse. In rare instances, the presence of these marks on children has led to legal action against parents who had their children receive cupping therapy.
== History ==
The origin of cupping is unclear. Iranian traditional medicine uses wet-cupping practices, with the belief that cupping with scarification may eliminate scar tissue, and cupping without scarification would cleanse the body through the organs.
In ancient Greece, Hippocrates (c. 460 – c. 370 BC) used cupping for internal disease and structural problems, and Roman surgeons used it for bloodletting. The method was highly recommended by Islamic Prophet Muhammad and hence well-practiced by Muslim scientists who elaborated and developed the method further. Consequently, this method in its multiple forms spread into medicine throughout Asian and European civilizations. In China, the earliest use of cupping that is recorded is from the Taoist alchemist and herbalist Ge Hong (281–341 AD). Cupping was also mentioned in Maimonides' book on health and was used within the Eastern European Jewish community. William Osler recommended its use for pneumonia and acute myelitis in the early twentieth century.
The practice has been used in hospitals in China since the 1950s as a traditional Chinese medicine modality.
== Scientific evaluation ==
The American Cancer Society notes that "available scientific evidence does not support claims that cupping has any health benefits" and also that the treatment carries a small risk of burns. A review of literature in 2011 determined that "the effectiveness of cupping is currently not well-documented for most conditions", and that systematic reviews showing efficacy for the treatment of pain "were based mostly on poor quality primary studies." This was further supported by a review in 2014 which demonstrated that previous evidence supporting cupping has resulted from "unreasonable design and poor research quality". There is a lack of evidence to support the use of cupping therapy for acne. Additionally, cupping is often practiced along with other acupuncture therapies and therefore cannot exclusively account for resultant positive benefits. Many reviews suggest there is insufficient scientific evidence to support the use of cupping techniques to combat relevant diseases and chronic pain. Cupping has been characterized as quackery.
The lack of apparent benefits of cupping treatments are discussed by Simon Singh and Edzard Ernst in their 2008 book Trick or Treatment.
As a pseudoscientific detoxification ritual, proponents of cupping falsely claim that it can remove unspecified toxins from the body. Proponents also falsely claim that cupping "improves blood flow" to help sore muscles. James Hamblin notes that a bruise caused by cupping "is a blood clot, though, and clotted blood is definitionally not flowing."
Critics of alternative medicine have spoken out against cupping therapy. Harriet Hall and Mark Crislip have characterized cupping as "pseudoscience nonsense", "a celebrity fad", and "gibberish", and observed that there is no evidence that cupping works any better than a placebo. Pharmacologist David Colquhoun writes that cupping is "laughable... and utterly implausible." Practicing surgeon David Gorski observes that "it's all risk for no benefit. It has no place in modern medicine, or at least shouldn't."
== Safety ==
Cupping is generally considered safe for most people when performed by trained practitioners; however, it may not be suitable for everyone.
In 2016, the Cambodian Ministry of Health warned that cupping could be a health risk and particularly dangerous for people with high blood pressure or heart problems. According to the NCCIH "Cupping can cause side effects such as persistent skin discoloration, scars, burns, and infections, and may worsen eczema or psoriasis".
Cupping causes breaks in the capillaries (small blood vessels) in the papillary dermis layer of the skin, resulting in the appearance of petechiae and purpura. These marks are sometimes mistaken for signs of child abuse when cupping is performed on children.
Cupping therapy adverse events can be divided into local and systemic adverse events. The local adverse events may include scar formation, burns, linear bruising or streaks (wet cupping), skin ulcers, undesired darkening of the skin, panniculitis, erythema ab igne, induction of the Koebner phenomenon in susceptible individuals with psoriasis, and pain at the cupping site. A theoretical risk of infection exists but there are no reports of this as of 2012.
== Claimed uses ==
Cupping practitioners use cupping therapy for a wide array of medical conditions including fevers, pain, poor appetite, indigestion, high blood pressure, acne, atopic dermatitis, psoriasis, anemia, stroke rehabilitation, nasal congestion, infertility, and dysmenorrhea.
There is low to moderate evidence that cupping can reduce pain associated with musculoskeletal pain and myofascial pain syndrome, although the benefits may be indistinguishable from those of a placebo.
== Claimed mechanism of action ==
Proponents claim cupping has a therapeutic effect and removes unspecified "toxins", stagnant blood, or "vital energy" when used over acupuncture points with the goal of improving blood circulation.
== Methods ==
Modern suction devices are sometimes used instead of the traditional cups.
While details vary between practitioners, societies, and cultures, the practice consists of drawing tissue into a cup placed on the targeted area by creating a partial vacuum – either by the heating and subsequent cooling of the air in the cup or via a mechanical pump. The cup is usually left in place for somewhere between five and fifteen minutes.
Cupping therapy types can be classified using four distinct methods of categorization. The first categorization system relates to "technical types" including dry, wet, massage, and flash cupping therapy. The second categorization relates to "the power of suction-related types" including light, medium, and strong cupping therapy. The third categorization relates to "the method of suction-related types" including fire, manual suction, and electrical suction cupping therapy. The fourth categorization relates to "materials inside cups" including herbal products, water, ozone, moxa, needle, and magnetic cupping therapy.
Further categories of cupping were developed later. The fifth relates to areas treated including facial, abdominal, female, male, and orthopedic cupping therapy. The sixth relates to "other cupping types" that include sports and aquatic cupping.
=== Dry cupping ===
Dry cupping involves the application of a heated cup on the skin of the back, chest, abdomen, or buttocks. The cooling of the air is then thought to create a suction effect. Bamboo and other materials are sometimes used as alternatives to glass cups.
=== Fire cupping ===
Fire cupping involves soaking a cotton ball in almost pure alcohol. The cotton is clamped by a pair of forceps and lit via match or lighter, and, in one motion, placed into the cup and quickly removed, while the cup is placed on the skin. The fire heats the air in the cup which, after cooling reduces in volume creating a negative pressure inside the cup. The cup is then quickly placed onto the body and the negative pressure "sucks" the skin up. Massage oil may be applied to create a better seal as well as allow the cups to glide over muscle groups (e.g. trapezius, erectors, latissimus dorsi, etc.) in an act called "gliding cupping" or "sliding cupping". Dark circles may appear where the cups were placed because of capillary rupture under the skin. There are documented cases of burns caused by fire cupping.
=== Wet cupping ===
Wet cupping, also known as hijama (Arabic: حجامة lit. "sucking") or medicinal bleeding, is where blood is drawn by local suction from a small skin incision.
The first reported usages are found in the Islamic hadith, sayings attributed to or describing the actions of the Islamic prophet Muhammad. Hadith from Muhammad al-Bukhari, Muslim ibn al-Hajjaj Nishapuri and Ahmad ibn Hanbal support its recommendation and use by Muhammad. As a result, wet cupping has remained a popular remedy practiced in many parts of the Muslim world.
In Finland, wet cupping has been done since the 15th century, and it is done traditionally in saunas. The cups were made of cattle horns with a valve mechanism inside to create a partial vacuum by sucking the air out. Cupping is still practiced in Finland as part of relaxing and/or health regimens.
The points used in wet and dry cupping are varied and intended to correspond to areas of pain and blockage. Over the years treatment plans have been created but, due to their holistic nature, the points used may vary depending on the individual.
=== Traditional Chinese medicine ===
In Chinese, cupping is known as "pulling-up jars" (Chinese: 拔罐; pinyin: báguàn). According to traditional Chinese medicine (TCM), cupping is done to dispel stagnation (stagnant blood and lymph), thereby improving qi flow, to treat respiratory diseases such as the common cold, pneumonia and bronchitis. Cupping is used on the back, neck, shoulder, and other musculoskeletal conditions. Its advocates claim it has other applications as well. Cupping is not advised, in TCM, over skin ulcers or to the abdominal or sacral regions of pregnant women.
== Society and culture ==
Cupping has gained publicity in modern times due to its use by American sport celebrities including National Football League player DeMarcus Ware and Olympians Alex Naddour, Natalie Coughlin, and Michael Phelps. Medical doctor Brad McKay wrote that Team USA was doing a great disservice to their fans who might "follow their lead", calling cupping an "ancient (but useless) traditional therapy." Steven Novella noted "It is unfortunate that elite athletics, including the Olympics, is such a hotbed for pseudoscience."
There is a description of cupping in George Orwell's essay "How the Poor Die", where he was surprised to find the antiquated practice applied to another patient in a Paris hospital. In the 1964 Hollywood film, Zorba the Greek cupping is depicted with the character Zorba, played by Anthony Quinn, performing it on the character played by Lila Kedrova.
The perceived benefits of cupping have often been perpetuated by celebrities and athletes who use these therapeutic interventions in their daily lives. Professional swimmer Michael Phelps received publicity during the 2016 Olympics for the purple bruises evident on his back resulting from cupping. He has been known to "do it before every meet he goes to to "speed up recovery". Celebrity endorsements such as these may bias individuals to feel benefits from the practice.
== See also ==
Bloodletting
Ear candling
Gua sha
List of ineffective cancer treatments
Moxibustion
== References ==
== External links ==
Dunning, Brian (April 23, 2013). "Skeptoid #359: Cupping for the Cure". Skeptoid. | Wikipedia/Cupping_therapy |
Sasquatch: Legend Meets Science is a documentary television film written and directed by Minnesota-based wildlife researcher and film producer Doug Hajicek. The program originally aired on the Discovery Channel on January 9, 2003 and features scientists from various disciplines analyzing evidence for the existence of Bigfoot, including the 1967 Patterson–Gimlin film, the 1996 Memorial Day Bigfoot footage, and the 2000 Skookum cast.
The documentary has since been released on VHS and DVD. In 2006, a companion book of the same title was published by Tom Doherty Associates (ISBN 0-7653-1216-6), authored by Idaho State University anatomist and physical anthropologist Jeffrey Meldrum, who was featured in the documentary.
== Companion book ==
In 2006, Meldrum released a companion book of the same name. In the book, Meldrum goes more in depth into the Bigfoot phenomenon, arguing that there is enough scientific evidence to warrant a serious discussion and exploration regarding the subject.
Following the release of the book, Meldrum was criticized for defending the Bigfoot phenomenon, with many labeling the work as pseudoscientific. Meldrum still defends his position as a scientist seeking to establish the possibility of an undiscovered great ape species living in North America and other places. His book was reviewed and analyzed by anthropologist Matt Cartmill.
== References ==
== External links ==
The official homepage of Sasquatch: Legend Meets Science.
IMDb Sasquatch: Legend Meets Science.
Sasquatch: Legend Meets Science trade paperback (2007). | Wikipedia/Sasquatch:_Legend_Meets_Science |
The biorhythm theory is the pseudoscientific idea that peoples' daily lives are significantly affected by rhythmic cycles with periods of exactly 23, 28 and 33 days, typically a 23-day physical cycle, a 28-day emotional cycle, and a 33-day intellectual cycle. The idea was developed by German otolaryngologist Wilhelm Fliess in the late 19th century, and was popularized in the United States in the late 1970s. The proposal has been independently tested and, consistently, no validity for it has been found.
According to the notion of biorhythms, a person's life is influenced by rhythmic biological cycles that affect his or her ability in various domains, such as mental, physical, and emotional activity. These cycles begin at birth and oscillate in a steady (sine wave) fashion throughout life, and by modeling them mathematically, it is suggested that a person's level of ability in each of these domains can be predicted from day to day. It is built on the idea that the biofeedback chemical and hormonal secretion functions within the body could show a sinusoidal behavior over time.
Most biorhythm models use three cycles: a 23-day physical cycle, a 28-day emotional cycle, and a 33-day intellectual cycle. These cycles are to be adjusted based on the person's personal day clock which may run from 22 hours to 27 hours although 23-25 is the norm. Two ways one can find their personal day clock is to test one's grip and body temperature every 15 minutes for a few days or the same time each day for a few months. Although the 28-day cycle is the same length as the average woman's menstrual cycle and was originally described as a "female" cycle (see below), the two are not necessarily in synchronization. Each of these cycles varies between high and low extremes sinusoidally, with days where the cycle crosses the zero line described as "critical days" of greater risk or uncertainty.
The numbers from +100% (maximum) to -100% (minimum) indicate where on each cycle the rhythms are on a particular day. In general, a rhythm at 0% is crossing the midpoint and is thought to have no real impact on one's life, whereas a rhythm at +100% (at the peak of that cycle) would give one an edge in that area, and a rhythm at -100% (at the bottom of that cycle) would make life more difficult in that area. There is no particular meaning to a day on which one's rhythms are all high or all low, except the obvious benefits or hindrances that these rare extremes are thought to have on one's life.
In addition to the three popular cycles, various other cycles have been proposed, based on linear combination of the three, or on longer or shorter rhythms.
== Calculation ==
Theories published state the equations for the cycles as:
physical:
sin
(
2
π
t
/
23
)
{\displaystyle \sin(2\pi t/23)}
,
emotional:
sin
(
2
π
t
/
28
)
{\displaystyle \sin(2\pi t/28)}
,
intellectual:
sin
(
2
π
t
/
33
)
{\displaystyle \sin(2\pi t/33)}
,
where
t
{\displaystyle t}
indicates the number of days since birth. Basic arithmetic shows that the combination of the simpler 23- and 28-day cycles repeats every 644 days (or 13⁄4 years), while the triple combination of 23-, 28-, and 33-day cycles repeats every 21,252 days (or 58.18+ years).
== History ==
The 23- and 28-day rhythms used by biorhythmists were first devised in the late 19th century by Wilhelm Fliess, a Berlin physician and friend of Sigmund Freud. Fliess believed that he observed regularities at 23- and 28-day intervals in a number of phenomena, including births and deaths. He labeled the 23-day rhythm "male" and the 28-day rhythm "female", matching the menstrual cycle.
In 1904, Viennese psychology professor Hermann Swoboda came to similar conclusions. Alfred Teltscher, professor of engineering at the University of Innsbruck, developed Swoboda's work and suggested that his students' good and bad days followed a rhythmic pattern; he believed that the brain's ability to absorb, mental ability, and alertness ran in 33-day cycles. One of the first academic researchers of biorhythms was Estonian-born Nikolai Pärna, who published a book in German called Rhythm, Life and Creation in 1923.
The practice of consulting biorhythms was popularized in the 1970s by a series of books by Bernard Gittelson, including Biorhythm—A Personal Science, Biorhythm Charts of the Famous and Infamous, and Biorhythm Sports Forecasting. Gittelson's company, Biorhythm Computers, Inc., made a business selling personal biorhythm charts and calculators, but his ability to predict sporting events was not substantiated.
Charting biorhythms for personal use was popular in the United States during the 1970s; many places (especially video arcades and amusement areas) had a biorhythm machine that provided charts upon entry of date of birth. Biorhythm programs were a common application on personal computers; and in the late 1970s, there were also handheld biorhythm calculators on the market, the Kosmos 1 and the Casio Biolator.
== Critical views ==
There have been some three dozen published studies of biorhythm theory, but according to a study by Terence Hines, all of those either supported the null hypothesis that there is no correlation of human experience and the supposed biorhythms beyond what can be explained by coincidence, or, in cases where authors claimed to have evidence for biorhythm theory, methodological and statistical errors invalidated their conclusions. Hines therefore concluded that the theory is not valid.
Supporters continued to defend the theory in spite of the lack of corroborating scientific evidence, leading to the charge that it had become a kind of pseudoscience due to its proponents' rejection of empirical testing:
An examination of some 134 biorhythm studies found that the theory is not valid (Hines, 1998). It is empirically testable and has been shown to be false. Terence Hines believes that this fact implies that biorhythm theory 'can not be properly termed a pseudoscientific theory'. However, when the advocates of an empirically testable theory refuse to give up the theory in the face of overwhelming evidence against it, it seems reasonable to call the theory pseudoscientific. For, in fact, the adherents to such a theory have declared by their behaviour that there is nothing that could falsify it, yet they continue to claim the theory is scientific. (from Carroll's The Skeptic's Dictionary): 175
The physiologist Gordon Stein in the book Encyclopedia of Hoaxes (1993) wrote:Both the theoretical underpinning and the practical scientific verification of biorhythm theory are lacking. Without those, biorhythms became just another pseudoscientific claim that people are willing to accept without required evidence. Those pushing biorhythm calculators and books on a gullible public are guilty of making fraudulent claims. They are hoaxers of the public if they know what they are saying has no factual justification.A 1978 study of the incidence of industrial accidents found neither empirical nor theoretical support for the biorhythm model.
In Underwood Dudley's book, Numerology: Or What Pythagoras Wrought, he provides an example of a situation in which a magician provides a woman her biorhythm chart that supposedly included the next two years of her life. The women sent letters to the magician describing how accurate the chart was. The magician purposely sent her a biorhythm chart based on a different birthdate. After he explained that he sent the wrong chart to her, he sent her another chart, also having the wrong birthdate. She then said that this new chart was even more accurate than the previous one. This kind of willful credulous belief in vague or inaccurate prognostication derives from motivated reasoning backed up by fallacious acceptance of confirmation bias, post hoc rationalization, and suggestibility.
Wilhelm Fliess "was able to impose his number patterns on virtually everything" and worked to convince others that cycles happen within men and women every 23 and 28 days. Mathematically, Fliess's equation, n = 23x +28y is unconstrained as there are infinitely many solutions for x and y, meaning that Fliess and Sigmund Freud (who adopted this idea in the early 1890s) could predict anything they wanted with the combination.
The skeptical evaluations of the various biorhythm proposals led to a number of critiques lambasting the subject published in the 1970s and 1980s. Biorhythm advocates who objected to the takedowns claimed that because circadian rhythms had been empirically verified in many organisms' sleep cycles, biorhythms were just as plausible. However, unlike biorhythms, which are claimed to have precise and unaltering periods, circadian rhythms are found by observing the cycle itself and the periods are found to vary in length based on biological and environmental factors. Assuming such factors were relevant to biorhythms would result in chaotic cycle combinations that remove any "predictive" features.
=== Additional studies ===
Several controlled, experimental studies found no correlation between the 23, 28 and 33 day cycles and academic performance. These studies include:
==== James (1984) ====
James hypothesized that if biorhythms were rooted in science, then each proposed biorhythm cycle would contribute to task performance. Further, he predicted that each type of biorhythm cycle (i.e., intellectual, physical, and emotional) would be most influential on tasks associated with the corresponding cycle type. For example, he postulated that intellectual biorhythm cycles would be most influential on academic testing performance. In order to test his hypotheses, James observed 368 participants, noting their performance on tasks associated with intellectual, physical, and emotional functioning. Based on data collected from his experimental research, James concluded that there was no relation between subjects' biorhythmic status (on any of the three cycle types), and their performance on the associated practical tests.
==== Peveto (1980) ====
Peveto examined the proposed relationship between biorhythms and academic performance, specifically in terms of reading ability. Through examination of the data collected, Peveto concluded that there were no significant differences in the academic performance of the students, in regards to reading, during the high, low, or critical positions of neither the physical biorhythm cycle, the emotional biorhythm cycle, nor the intellectual biorhythm cycle. As a result, it was concluded that biorhythm cycles have no effect on the academic performance of students, when academic performance was measured using reading ability.
== See also ==
Biological rhythm
Chronotherapy (treatment scheduling)
Circadian rhythm
Mood ring
== References ==
== Further reading ==
Hines, T.M., "Comprehensive review of biorhythm theory". Psychology Department, Pace University, Pleasantville, NY. Psychol Rep. 1998 Aug;83(1):19–64. (ed. concluded that biorhythm theory is not valid.)
D'Andrea, V.J., D.R. Black, and N.G. Stayrook, "Relation of the Fliess-Swoboda Biorhythm Theory to suicide occurrence". J Nerv Ment Dis. 1984 Aug;172(8):490–4. (ed. concluded that there was a validity to biorhythm when the innovative methods of the study are put to use.)
Laxenaire M., and O. Laurent, "What is the current thinking on the biorhythm theory?" Ann Med Psychol (Paris). 1983 Apr;141(4):425–9. [French] (ed. Biorhythm theory is disregarded by the medical world though it has achieved a bit of fame with the public)
Wolcott, J.H.; McMeekin, R.R.; Burgin, R.E.; Yanowitch, R.E. (Jun 1977). "Correlation of general aviation accidents with the biorhythm theory". Hum Factors. 19 (3): 283–93. doi:10.1177/001872087701900311. PMID 873528. S2CID 27406764.
Khalil, T.M.; Kurucz, C.N. (Jul 1977). "The influence of 'biorhythm' on accident occurrence and performance". Ergonomics. 20 (4): 389–98. doi:10.1080/00140137708931641. PMID 908322. | Wikipedia/Biorhythm_(pseudoscience) |
A torsion field (also called axion field, spin field, spinor field, and microlepton field) is a reoccurring feature of many pseudoscientific proposals. It posits that the quantum spin of particles can be used to cause emanations to carry information through vacuum orders of magnitude faster than the speed of light.
== History ==
The first torsion field proposals were proposed in the late Soviet Union by a group of physicists in the 1980s who loosely based their ideas on Einstein–Cartan theory and some variant solutions of Maxwell's equations that do not have a solid grounding in scientific fact. The group, led by Anatoly Akimov and Gennady Shipov, began the research as the state-sponsored Center for Nontraditional Technologies. They disbanded in 1991 when their research was exposed by physicist Eugene Alexandrov as a fraud and an embezzlement of government funding. Akimov and Shipov received financing for torsion field research from the Russian Ministry of Science from 1992 to 1995 and from the Russian Ministry of Defense from 1996 to 1997, and secretly continued their research, with a private enterprise called The International Institute for Theoretical and Applied Physics (later called UVITOR).
Presently championed exclusively outside of reputable scientific research due to its lack of evidence and absence of sound theoretical underpinning, the theory has been used to proclaim faster-than-light travel (FTL), extra-sensory perception (ESP), homeopathy, levitation, and other paranormal phenomena, and has been used to provide a rationale for the purported functioning of miracle cures and similar products. These claims have no independent backing.
== Description ==
In physics, a field is an assignment of a quantity (vector, tensor, or spinor) to every point of the space containing it. The word "torsion" refers to any variable that describes rotation. Thus, torsion fields (i.e., fields of any physical value reasonably described as "torsion") do exist in established physics aside from in this pseudoscientific case, where the terms have been misappropriated. For example, an electromagnetic wave with circular polarization or the stress tensor of a solid body under torsion stress can be described as torsion fields, although such usage is rare. The torsion tensor is a quantity in general relativity, and plays an important role in Einstein–Cartan theory. Spinor fields, in particular fermionic fields, are existing concepts from particle physics and quantum field theory.
Advocates for the existence of the spinor field or torsion field as described here claim that spin-spin interaction – itself a well-studied quantum phenomenon – can be transmitted through space similar to electromagnetic waves, but transmitting no mass or energy but only information, and does so at speeds of up to a billion times the speed of light, in explicit violation of special relativity. At the same time they claim that spin-spin interaction is carried by neutrinos – which have very little mass and high energy and interact with matter through the weak interaction – that it does not interact with matter but, at the same time, can be generated and detected easily.
== Claimed applications ==
Despite the several obvious contradictions with established physics along with associated statements by believers criticized as being "nonsensical" by reputable scientists, torsion fields have been embraced as an explanation for claims of homeopathic cures, telepathy, telekinesis, levitation, clairvoyance, ESP, and other paranormal phenomena. The harnessing of torsion fields has been claimed to make everything possible from miracle cure devices (including devices that cure alcohol addiction) to working perpetual motion machines, stargates, UFO propulsion analogs, and weapons of mass destruction (WMDs). Some such devices, in particular the miracle cure boxes, have been patented, manufactured and sold.
== Funding of torsion-field-related projects ==
Proponents of torsion field have sought large-scale government and military contracts at different times, starting with the 1987 application to the Ministry of Defence of the USSR requesting funding to develop "highly-reliable detection of an enemy strategic weapons (ICBM, nuclear submarine, aircraft, etc.); the long-range destruction of enemy strategic weapons without contact; covert jamming-resistant communications with objects in outer space, on Earth, underground, and underwater; mobile equipment on gravitational principles; and psychophysical and biomedical influence on troops and the population" The Soviet government allocated 500 million rubles (about US$7 million at today's exchange rate) for this research.
Another example of such funding applications was an experiment conducted in 1994 by the Russian private research group "VENT" (VEnture for Non-traditional Technologies,) which claimed to lower the resistivity of copper to as little as 1/80 of its normal value after exposing it to a torsion field generator. The group applied to the government of the Russian Federation for funding to open a factory, and promised great savings in energy consumption. The samples of exposed and unexposed copper were independently tested in presence of a VENT representative and their resistivities were not only found to be identical [(2.08±0.02)×10−7 Ωm and (2.05±0.02)×10−7 Ωm], but worse than industrial copper as well (1.7×10−8 Ωm).
In 2002, an application was made for oil drilling licenses in Russia and the UK using "microlepton technologies".
On 23 May 2008, the Khrunichev State Research and Production Space Center launched the Yubileiny satellite. On it was installed a reactionless drive engine (along with other regular engines) based on "torsion field" technologies. In a debate after the launch, scientist and member of the Russian Academy of Sciences, Eduard Kruglyakov, concluded that the installed engine had not changed the satellite's orbit by even a micron.
In 2011, National Research Council of Thailand approved a 4 million baht (around $130,000) fund for "Torsion Field Technologies" research at Chulalongkorn University.
== References ==
== Further reading ==
Kruglyakov, Edward P. (2004). Э.П.Кругляков. Чем угрожает обществу лженаука? [How Is Pseudoscience A Threat To Society?] (PDF). Proceedings of the Russian Academy of Sciences (in Russian). 74 (1). | Wikipedia/Torsion_field_(pseudoscience) |
Anti-vaccine activism, which collectively constitutes the "anti-vax" movement, is a set of organized activities expressing opposition to vaccination, and these collaborating networks have often sought to increase vaccine hesitancy by disseminating vaccine misinformation and/or forms of active disinformation. As a social movement, it has utilized multiple tools both within traditional news media and also through various forms of online communication. Activists have primarily (though far from entirely) focused on issues surrounding children, with vaccination of the young receiving pushback, and they have sought to expand beyond niche subgroups into national political debates.
Ideas that would eventually coalesce into anti-vaccine activism have existed for longer than vaccines themselves. Various myths and conspiracy theories (alongside outright disinformation and misinformation) have been spread by the anti-vaccination movement and fringe doctors. These have been spread in a way that has significantly increased vaccine hesitancy (and altered public policy around ethical, legal, and medical matters related to vaccines). However, no serious sense of hesitancy or of debate (in the broad sense) exists within mainstream medical circles about the benefits of vaccination. The scientific consensus in favor of vaccines is "clear and unambiguous". At the same time, however, the anti-vax movement has partially succeeded in distorting common understandings of science in popular culture.
== Strategies and tactics ==
=== Arguments used ===
In a 2002 paper in the British Medical Journal, two medical historians suggested that the arguments made against the safety and effectiveness of vaccines in the late 20th century are similar to those of the early anti-vaccinationists. Both the 19th and 20th century arguments included "vaccine safety issues, vaccine failures, infringement of personal liberty, and an unholy alliance between the medical establishment and the government to reap huge profits for the medical establishment at the expense of the public." However, the authors only considered the use of "newspaper articles and letters, books, journals, and pamphlets to warn against the dangers of vaccination", and did not address the impact of the internet. Comments on YouTube videos during the COVID-19 pandemic clustered similarly around "concerns about side-effects, effectiveness, and lack of trust in corporations and government".
=== Misrepresentation ===
In some instances, anti-vaccine organizations have used names intended to sound non-partisan on the issue: e.g. National Vaccine Information Center (USA), Vaccination Risk Awareness Network (Canada), Australian Vaccination Network. In November 2013 the Australian Vaccination Network was ordered by the New South Wales Administrative Decisions Tribunal to change their name so that consumers are aware of the anti-vaccination nature of the group. Lateline reported that former AVN president Meryl Dorey "claimed she was a victim of hate groups and vested interests" in response to the ruling.
=== Information quality ===
Although physicians and nurses are still rated as the most trusted source for vaccine information, some vaccine-hesitant individuals report being more comfortable discussing vaccines with providers of complementary and alternative medical (CAM) treatments. With the rise of the internet, many people have turned online for medical information. In some instances, anti-vaccine activists seek to steer people away from vaccination and health-care providers and towards alternative medicines sold by certain activists.
Anti-vaccination writings on the internet have been argued to be characterized by a number of differences from medical and scientific literature. These include:
Promiscuous copying and reduplication.
Ignoring corrections, even when an initial report or data point is shown to be false.
Lack of references, difficulty in checking sources and claims.
Personal attacks on individual doctors.
A high degree of interlinkage between sites.
Dishonest or fallacious arguments.
For example, a 2020 study examined Instagram posts related to the HPV vaccine, which can prevent some types of cancer. Anti-vaccine posts were more likely than pro-vaccine posts to be sent by non-healthcare individuals, to include personal narratives, and to reference other Instagram users, links, or reposts. Anti-vaccine posts were also more likely to involve concealment or distortion, particularly conspiracy theories and unsubstantiated claims. In total, 72.3% of antivaccine posts made inaccurate claims, including exaggerating the risks of vaccines and minimizing risks of disease.
=== Disinformation tactics ===
A number of specific disinformation tactics have been noted in anti-vaccination messaging, including:
Asserting that the existence of the 1986 National Childhood Vaccine Injury Act implies that the risk of injury by vaccines is high, rather than very low
Claiming to fail to access clinical trial data
Conspiracy theories alleging lies, trickery, cover-ups, and secret knowledge
Messages crafted for psychological appeal rather than truthfulness
Fake experts
Impossible expectations: claiming that anything less than 100% certainty in a scientific claim implies doubt and that doubt means there is no consensus
Selective use and interpreting of evidence ("cherry-picking"): using obscure or debunked sources while ignoring counter-evidence and scientific consensus
Shifting hypotheses: Continually introducing new theories about vaccines being harmful; moving to new claims when existing ones are shown to be false
Misrepresentation, false logic and illogical analogies
Personal attacks on critics, ranging from online criticism, publicly revealing personal details, and threats, to offline activities such as legal actions, targeting of employers, and violence
Targeting China's vaccine: During the pandemic, as retaliation for China's attempts to blame the United States for the pandemic, The Pentagon targeted China's Sinovac COVID-19 vaccine by spreading anti-vaccine misinformation in the Philippines.
=== Economics of vaccine disinformation ===
Information is more likely to be believed after repeated exposure. Disinformers use this illusory truth effect as a tactic, repeating false information to make it feel familiar and influence belief. Anti-vaccine activists have leveraged social media to develop interconnected networks of influencers that shape people's opinion, recruit allies, impact policy and monetize vaccine-related disinformation.
In 2022, the Journal of Communication published a study of the political economy underlying vaccine disinformation. Researchers identified 59 English-language "actors" that provided "almost exclusively anti-vaccination publications". Their websites monetized disinformation through appeals for donations, sales of content-based media and other merchandise, third-party advertising, and membership fees. Some maintained a group of linked websites, attracting visitors with one site and appealing for money and selling merchandise on others. Their activities to gain attention and obtain funding displayed a "hybrid monetization strategy". They attracted attention by combining eye-catching aspects of "junk news" and online celebrity promotion. At the same time, they developed campaign-specific communities to publicize and legitimize their position, similar to radical social movements.
=== Misrepresentation of the Vaccine Adverse Event Reporting System ===
In the United States, the Vaccine Adverse Event Reporting System (VAERS) is used to gather information on potential vaccine adverse reactions, but is susceptible to unverified reports, misattribution, underreporting, and inconsistent data quality. Raw, unverified data from VAERS has often been used by the anti-vaccine community to justify misinformation regarding the safety of vaccines; it is generally not possible to find out from VAERS data if a vaccine caused an adverse event, or how common the event might be.
=== Legal action ===
After Republicans gained a majority in the U.S. House of Representatives in January 2023, the House Judiciary Committee used legal action to oppose both disinformation research and government involvement in fighting disinformation. One of the projects targeted was the Virality Project, which has examined the spread of false claims about vaccines. The House Judiciary Committee sent letters, subpoenas, and threats of legal action to researchers, demanding notes, emails and other records from researchers and even student interns, dating back to 2015. Institutions subjected to such inquiries included the Stanford Internet Observatory at Stanford University, the University of Washington, the Atlantic Council's Digital Forensic Research Lab and the social media analytics firm Graphika. Researchers emphasized that they have academic freedom to study disinformation as well as freedom of speech to report their results.
Despite conservative claims that the government acted to censor speech online, "no evidence has emerged that government officials coerced the companies to take action against accounts". The actions of the House Judiciary Committee have been described as an "attempt to chill research,” creating a "chilling effect" through increased time demands, legal costs and online harassment of researchers.
=== Harassment ===
Persons undertaking efforts to counter vaccine misinformation, including public health experts who use social media, have been targeted for harassment by anti-vaccine activists such as blogger Paul Thacker.
For example, Slovakian physician Vladimír Krčméry was a prominent member of the government advisory team during the COVID-19 pandemic in Slovakia, and was the first person in that country to receive a COVID-19 vaccine. Due to his prominent role in the vaccination campaign, Krčméry and his family became a target of anti-vaccine activists, who physically threatened him and his family.
In June 2023, Texas-based physician and researcher Peter Hotez tweeted his concerns about Robert F. Kennedy Jr. sharing misinformation about vaccines on Joe Rogan's podcast. Rogan, Kennedy, and Twitter owner Elon Musk asked Hotez to participate in a debate on the podcast. Upon declining the invitation, Hotez was harassed by their fans, with anti-vaccine activist Alex Rosen confronting him at his home.
In his book The Deadly Rise of Anti-science: A Scientist's Warning, Hotez describes how he and other scientists who publicly defend vaccines have been attacked on social media, harassed with threatening emails, intimidated, and confronted physically by opponents of vaccination. He attributes the increase in aggressiveness of the anti-vaccination movement to the influence of the extreme wing of the Republican Party. Hotez estimates that roughly 200,000 preventable deaths from COVID-19, mainly among Republicans, occurred in the US because of refusal to be vaccinated.
At the extreme end, opposition to vaccination has resulted in substantial violence against vaccinators. In Pakistan, "more than 200 polio team workers have lost their lives" (team members include not only vaccinators but police and security personnel) from "targeted killing and terrorism" while working on polio vaccination campaigns.
== Countering anti-vaccine activism ==
Various efforts have been suggested and undertaken to address concerns about vaccines and counter anti-vaccine disinformation. Efforts include social media advertising campaigns, by public health organizations, in support of public health goals.
Best practices for combating vaccine mis- and disinformation include addressing issues openly, clearly identifying areas of scientific consensus and areas of uncertainty, and being sensitive to the cultural and religious values of communities. In countering anti-vaccine disinformation, both factual and emotional aspects need to be addressed.
Whether people will update a mistaken belief is complicated and involves psychological factors and social goals as well as accuracy of information. There is some evidence that both debunking and "pre-bunking" of disinformation can be effective, at least in the short term. Elements that may help to correct inaccurate information include: warning people before they are exposed to misinformation; high perceived credibility of message sources, affirmations of identity and social norms; graphical presentation; and focusing attention on clear core messages.
Alternative explanations of a situation need to fit plausibly into the original scenario and ideally indicate why the incorrect explanation was previously thought to be correct.
The cultivation of critical thinking, health and science awareness, and media literacy skills are all recommended to help people more critically assess the credibility of the information they see. People who seek out multiple reputable news sources at local and national levels are more likely to detect disinformation than those who rely on few sources from a particular viewpoint. Particularly on social media, beware of sensational headlines that appeal to emotion, fact-check information broadly (not just through your usual sources), and consider possible agendas or conflicts of interest of those relaying information.
=== Operation of social media ===
Other suggestions for countering anti-vaccine activism focus on changing the operation of social media platforms. Interventions such as accuracy nudges and source labeling change the context in which information is presented. For example, correct information can be directly presented to counter disinformation.
Other possibilities include flagging or removing misleading information on social media platforms. Research suggests that a majority of individuals in the United States would support the removal of harmful misinformation posts and the suspension of accounts. This position is less popular with Republicans than Democrats.
While private entities like Facebook, Twitter and Telegram could legally establish guidelines for moderation of information and disinformation on their platforms (subject to local and international laws) such companies do not have strong incentives to control disinformation or to self-regulate. Algorithms that are used to maximize user engagement and profits can lead to unbalanced, poorly sourced, and actively misleading information.
Criticized for its role in vaccine hesitancy, Facebook announced in March 2019 that it would provide users with "authoritative information" on the topic of vaccines. Facebook introduced several policies chosen to reduce the impact of anti-vaccine content, without actually removing it. These included reducing the ranking of anti-vaccine sources in searches and not recommending them; rejecting ads and targeted advertising that contained vaccine misinformation; and using banners to present vaccine information from authoritative sources. A study examined the six months before and after the policy changes. It found a moderate but significant decrease in the number of likes for anti-vaccine posts following the policy changes. Likes of pro-vaccine posts were unchanged. Facebook has been criticized for not being more aggressive in countering disinformation. In response to efforts to police misinformation, anti-vaccine communities on social media have adopted coded language to refer to vaccinated persons and the vaccines themselves.
Supply-side interventions reduce circulation of misinformation directly at their sources through actions such as application of social media policies, regulation, and legislation.
A study published in the journal Vaccine examined advertisements posted in the three months prior to the Facebook's 2019 policy changes. It found that 54% of the anti-vaccine advertisements on Facebook were placed by just two organizations, funded by well-known anti-vaccination activists. The Children's Health Defense / World Mercury Project chaired by Robert F. Kennedy Jr. and Stop Mandatory Vaccination, run by campaigner Larry Cook, posted 54% of the advertisements. The ads often linked to commercial products, such as natural remedies and books. Kennedy was suspended from Facebook in August 2022, but reinstated in June 2023.
In 2023, however, state governments that were politically aligned with anti-vaccine activists successfully sought a preliminary injunction to prevent the Biden Administration from seeking to pressure social media companies into fighting misinformation. The order issued by United States Court of Appeals for the Fifth Circuit "severely limits the ability of the White House, the surgeon general, [and] the Centers for Disease Control and Prevention... to communicate with social media companies about content related to Covid-19... that the government views as misinformation". In October 2023, this injunction was paused by the Supreme Court of the United States, pending further litigation.
=== Use of algorithms and data ===
Algorithms and user data can be used to identify selected subgroups who can then be provided with specialized content. This type of approach has been used both by anti-vaccine activists
and by health providers who hope to counter vaccine-related disinformation.
For example, in the United States, the CDC's Social Vulnerability Index (SVI) has been used to identify communities that have traditionally been under-served or are at elevated risk for infection, morbidity, and mortality. Programs have been developed in such communities to address disinformation and vaccine hesitancy.
=== Community engagement ===
Steps have been taken to counter anti-vaccine messaging by directly engaging with communities. Outreach efforts include call centers and texting campaigns, partnering with local community leaders, and holding community-based vaccine clinics. Creating digital and science literacy resources and distributing them via schools, libraries, municipal offices, churches and other community groups can help to counter misinformation in under-resourced communities.
The Black Doctors COVID-19 Consortium in Philadelphia is one example of a successful direct outreach initiative. Another is the New York State Vaccine Equity Task Force.
In line with the Strategic Advisory Group of Experts (SAGE)'s 3C's model, outreach to communities has focused on addressing mistrust and increasing Confidence, providing information to improve risk assessment (Complacency), and improving access to COVID-19 vaccines (Convenience). It has been necessary to counter disinformation in all three areas.
Recommendations for combating vaccine disinformation include increasing the presence of trusted health agencies and credible information on social media, partnering with social media platforms to promote evidence-based public health information, and identifying and responding to emerging concerns and disinformation campaigns.
Networked communities of public health officials and other stakeholders, connecting with the public through a variety of credible and trusted messengers, are recommended. Sharing of messages through such networks could help to debunk and counter highly networked and coordinated disinformation attacks.
A networked community approach would differ from the current model of US public health communication, which tends to rely on a single credible messenger (e.g. Anthony Fauci) and is susceptible to disinformation attacks. To deal with disinformation, community networks would need to address issues of liberty and human rights as well as vaccine safety, effectiveness and access. Networks could also help to show support for those attacked by anti-vaccine activists.
== History ==
=== 18th and 19th century ===
Ideas that would eventually coalesce into anti-vaccine activism have existed for longer than vaccines themselves. Some philosophical approaches (e.g. homeopathy, vitalism) are incompatible with the microbiological paradigm that explains how the immune system and vaccines work. Vaccine hesitancy and anti-vaccine activism exist within a broader context that involves cultural tradition, religious belief, approaches to health and disease, and political affiliation.
Opposition to variolation for smallpox (a predecessor to vaccination) was organized as early as the 1720s around the premise that vaccination was unnatural and an attempt to thwart divine judgment. Religious arguments against inoculation, the earliest arguments against vaccination, were soon advanced. For example, in a 1722 sermon entitled "The Dangerous and Sinful Practice of Inoculation", the English theologian Reverend Edmund Massey argued that diseases are sent by God to punish sin and that any attempt to prevent smallpox via inoculation is a "diabolical operation". It was customary at the time for popular preachers to publish sermons, which reached a wide audience. This was the case with Massey, whose sermon reached North America, where there was early religious opposition, particularly by John Williams. A greater source of opposition there was William Douglass, a medical graduate of Edinburgh University and a Fellow of the Royal Society, who had settled in Boston.: 114–22
Vaccination itself was invented by British physician Edward Jenner, who published his findings on the efficacy of the practice for smallpox in 1798. By 1801, the practice had been widely endorsed in the scientific community, and by several world leaders. Philadelphia physician John Redman Coxe, noting that even then false accounts were circulated of negative effects of vaccination, wrote,
"Such are the falsehoods which impede the progress of the brightest discovery which has ever been made! But the contest is in vain! Time has drawn aside the veil which obstructed our knowledge of this invaluable blessing; and in the examples of the Emperor of Constantinople, of the Dowager Empress of Russia, and the King of Spain, we may date the downfall of further opposition."
Coxe's expectation of an end to opposition to vaccination proved premature, and through much of the nineteenth century, the principles, practices and impact of vaccination were matters of active scientific debate. The principles behind vaccination were not clearly understood until the end of the nineteenth century. The importance of hygiene in the preparation, storage, and administration of vaccines was not always understood or practiced. Reliable statistics on vaccine efficacy and side effects were difficult to obtain before the 1930s.
==== Anti-Compulsory Vaccination League ====
In the United Kingdom, the Vaccination Act 1853 (16 & 17 Vict. c. 100) required that every child be vaccinated within three or four months of birth. It set a precedent for the state regulation of physical bodies, and was fiercely resisted.
The following year, in 1854, John Gibbs published the first anti-compulsory-vaccination pamphlet, Our Medical Liberties.
By the 1860s, anti-vaccinationism in Britain was active in the working class, labor aristocracy, and lower middle class. It had become associated with alternative medicine and was part of a larger culture of social and political dissent that included both labor unions and religious dissenters.
In June 1867, the publication "Human Nature" campaigned in the United Kingdom against "The Vaccination Humbug", reporting that many petitions had been presented to Parliament against Compulsory Vaccination for smallpox, including from parents who alleged that their children had died through the procedure, and complaining that these petitions had not been made public. The journal reported the formation of the Anti-Compulsory Vaccination League "To overthrow this huge piece of physiological absurdity and medical tyranny", and quoted Richard Gibbs (a cousin of John Gibbs) who ran the Free Hospital at the same address as stating "I believe we have hundreds of cases here, from being poisoned with vaccination, I deem incurable. One member of a family dating syphilitic symptoms from the time of vaccination, when all the other members of the family have been clear. We strongly advise parents to go to prison, rather than submit to have their helpless offspring inoculated with scrofula, syphilis, and mania".
Notable members of the Anti-Compulsory Vaccination League included James Burns, George Dornbusch and Charles Thomas Pearce. After the death of Richard B. Gibbs in 1871, the Anti-Compulsory Vaccination League "languished" until 1876 when it was revived under the leadership of Mary Hume-Rothery and the Rev. W. Hume-Rothery. The Anti-Compulsory Vaccination League published the Occasional Circular which later merged into the National Anti-Compulsory Vaccination Reporter.
==== Anti-Vaccination Society of America ====
In the United States, many states and local school boards established immunization requirements, beginning with a compulsory school vaccination law in Massachusetts in 1855.
The Anti-Vaccination Society of America was founded in 1879, after a visit to the United States by British anti-vaccine activist William Tebb, and opposed compulsory smallpox vaccination for smallpox from the final decades of the 19th century through the 1910s. During this period, smallpox vaccination was the only form of vaccination that was widely practiced, and the society published a periodical opposing it, called Vaccination.
A series of American legal cases, beginning in various states and culminating with that of Henning Jacobson of Massachusetts in 1905, upheld the mandating of compulsory smallpox vaccination for the good of the public. The court ruled in Jacobson v. Massachusetts that "the liberty secured by the Constitution of the United States to every person within its jurisdiction does not import an absolute right in each person to be, at all times and in all circumstances, wholly freed from restraint. There are manifold restraints to which every person is necessarily subject for the common good".
==== London Society for the Abolition of Compulsory Vaccination ====
In 1880, William Tebb enlarged and reorganized the Anti-Compulsory Vaccination League in the UK with the formation of the London Society for the Abolition of Compulsory Vaccination, with William Young as secretary. The Vaccination Inquirer, established by Tebb in 1879, was adopted as the official organ of the Society. A series of fourteen "Vaccination Tracts" was begun by Young in 1877 and completed by Garth Wilkinson in 1879. William White was the first editor of the Vaccination Inquirer and after his death in 1885, he was succeeded by Alfred Milnes. Frances Hoggan and her husband authored an article for the Vaccination Inquirer in September 1883 which argued against compulsory vaccination. The London Society focused on lobbying parliamentary support in the 1880s and early 1890s. They gained support from several members of the House of Commons of which the most prominent was Peter Alfred Taylor, the member for Leicester, which was described as the "Mecca of antivaccination".
==== The National Anti-Vaccination League ====
The UK movement grew, and as the influence of the London Society overshadowed the Hume-Rotherys and it took the national lead, it was decided in February 1896 to re-form the Society as The National Anti-Vaccination League. Arthur Phelps was elected as president. In 1898, the league took on a school leaver named Lily Loat, who was elected as the league's Secretary by 1909. In 1906, George Bernard Shaw wrote a supportive letter to the National Anti-Vaccination League, equating methods of vaccination with "rubbing the contents of the dustpan into the wound".
==== Anti-Vaccination League of America ====
In 1908, the Anti-Vaccination League of America was created by Charles M. Higgins and industrialist John Pitcairn Jr., with anti-vaccination campaigns focused on New York and Pennsylvania. Members were opposed to compulsory vaccination laws. Higgins was the League's chief spokesman and pamphleteer. Historian James Colgrove noted that Higgins "attempted to overturn the New York State's law mandating vaccination of students in public schools". The League should not be confused with the Anti-Vaccination Society of America, that was formed in 1879. Higgins was criticized by medical experts for spreading misinformation and ignoring facts as to the efficacy of vaccination. The League dissolved after the death of Higgins in 1929.
=== 20th century ===
Anti-vaccine activism ebbed for much of the twentieth century, but never completely vanished. In the UK, the National Anti-Vaccination League continued to publish new issues of its journal until 1972, by which time the global campaign for smallpox eradication through vaccination had made the disease so uncommon that compulsory vaccination for smallpox was no longer required in the United Kingdom.
New vaccines were developed and used against diseases such as diphtheria and whooping cough. In the UK, these were often introduced on a voluntary basis, without arousing the same kind of anti-vaccination response that had accompanied compulsory smallpox vaccination.
In the United States, numerous measles outbreaks occurred in the 1960s and 1970s, and were shown to be more frequent in states that lacked mandatory vaccination requirements. This led to calls in the 1970s for a national level vaccination requirement for children entering schools.
Joseph A. Califano Jr. appealed to state governors, and by 1980, all 50 states legally required vaccination for school entrance. Many of these laws allowed exemptions in response to lobbyists. In New York State, a 1967 law allowed exemptions from receiving polio vaccine for members of religious organizations such as Christian Scientists.
=== 21st century ===
==== Lancet MMR autism fraud ====
Anti-vaccine activism in the 2000s regained prominence through exploratory research by Andrew Wakefield based on 12 selected cases. He then made claims about a link between the MMR vaccine and autism. These claims were subsequently extensively investigated and found to be false, and the original study turned out to be based on faked data. The scientific consensus is that there is no link between the MMR vaccine and autism, and that the MMR vaccine's benefits in preventing measles, mumps, and rubella greatly outweigh its potential risks.
The idea of an autism link was first suggested in the early 1990s and came to public notice largely as a result of the 1998 Lancet MMR autism fraud, which Dennis K Flaherty at the University of Charleston characterized as "perhaps the most damaging medical hoax of the last 100 years". The fraudulent research paper authored by Wakefield and published in The Lancet falsely claimed the vaccine was linked to colitis and autism spectrum disorders. The paper was retracted by Lancet in 2010 but is still cited by anti-vaccine activists.
The claims in the paper were widely reported, leading to a sharp drop in vaccination rates in the UK and Ireland. Promotion of the claimed link, which continued in anti-vaccination propaganda for the next three decades despite being refuted, was estimated to have led to an increase in the incidence of measles and mumps, resulting in deaths and serious permanent injuries. Following the initial claims in 1998, multiple large epidemiological studies were undertaken. Reviews of the evidence by the Centers for Disease Control and Prevention, the American Academy of Pediatrics, the Institute of Medicine of the US National Academy of Sciences, the UK National Health Service, and the Cochrane Library all found no link between the MMR vaccine and autism. Physicians, medical journals, and editors have described Wakefield's actions as fraudulent and tied them to epidemics and deaths.
An investigation by journalist Brian Deer found that Wakefield, the author of the original research paper linking the vaccine to autism, had multiple undeclared conflicts of interest, had manipulated evidence, and had broken other ethical codes. After a subsequent 2.5-year investigation, the General Medical Council ruled that Wakefield had acted "dishonestly and irresponsibly" in doing his research, carrying out unauthorized procedures for which he was not qualified, and acting with "callous disregard" for the children involved.
Wakefield was found guilty by the General Medical Council of serious professional misconduct in May 2010, and was struck off the Medical Register, meaning he could no longer practise as a physician in the UK.
The Lancet paper was partially retracted in 2004 and fully retracted in 2010, when Lancet's editor-in-chief Richard Horton described it as "utterly false" and said that the journal had been deceived. In January 2011, Deer published a series of reports in the British Medical Journal, in which a signed editorial stated of the journalist, "It has taken the diligent scepticism of one man, standing outside medicine and science, to show that the paper was in fact an elaborate fraud." A 2011 journal article described the vaccine-autism connection as "the most damaging medical hoax of the last 100 years".
Wakefield continues to promote anti-vaccine beliefs and conspiracy theories in the United States.
In February 2015, Wakefield denied that he bore any responsibility for the measles epidemic that started at Disneyland among unvaccinated children that year. He also reaffirmed his discredited belief that "MMR contributes to the current autism epidemic". By that time, at least 166 measles cases had been reported. Paul Offit disagreed, saying that the outbreak was "directly related to Dr. Wakefield's theory".
Wakefield and other anti-vaccine activists were active in the American-Somali community in Minnesota, where a drop in vaccination rates was followed by the largest measles outbreak in the state in nearly 30 years in 2017.
The anti-vaccination movement was historically apolitical, but in the 2010s and 2020s the movement in the United States has increasingly targeted conservatives. As measles outbreaks increased, so did calls to eliminate exemptions from vaccine administration. As of 2015, 19 American states had suggested legislation to eliminate or increase the difficulty of exemptions, including California. Concurrently, American anti-vaccine activists reached out to libertarian and right-leaning groups such as the Tea Party movement to broaden their base. While earlier anti-vaccination activists focused on health impacts and safety of vaccines, recent themes increasingly involve philosophical arguments about liberty, medical freedom and parental rights.
With the growing anti-vaccine movement from the 2010s onwards, the United States has seen a resurgence of certain vaccine-preventable diseases. The measles virus lost its elimination status in the US as the number of measles cases continued to rise in the late 2010s with a total of 17 outbreaks in 2018 and 465 outbreaks in 2019 (as of April 4, 2019).
==== 2019 measles outbreaks ====
Vaccine hesitancy led to declining rates of vaccination for measles, culminating in the 2019–2020 measles outbreaks. The most significant of these in proportion to national population was the 2019 Samoa measles outbreak.
In July 2018, two 12-month-old children died in Samoa after receiving incorrectly prepared MMR vaccinations. These two deaths were picked up by anti-vaccine groups and used to incite fear towards vaccination on social media, causing the government to suspend its measles vaccination programme for ten months, despite advice from the WHO. The incident caused many Samoan residents to lose trust in the healthcare system. UNICEF and the World Health Organization estimate that the measles vaccination rate in Samoa fell from 74% in 2017 to 34% in 2018, similar to some of the poorest countries in Africa.
In August 2019, an infected passenger on one of the more than 8,000 annual flights between New Zealand and Samoa probably brought the disease from Auckland to Upolu. A full outbreak of measles began on the island in October 2019 and continued for the next four months. As of January 6, 2020, there were over 5,700 cases of measles and 83 deaths, out of a Samoan population of 200,874. Over three percent of the population were infected. The cause of the outbreak was attributed to decreased vaccination rates, from 74% in 2017 to 31–34% in 2018, even though nearby islands had rates near 99%. a rate of 14.3 deaths per 1000 infected) and 5,520 cases (2.75% of the population) of measles in Samoa. Sixty-one out of the first 70 deaths were four years old and under, and all but seven were under 15. After the outbreak, anti-vaxxers employed racist tropes and misinformation to credit the scores of measles deaths to poverty and poor nutrition or even to the vaccine itself, but this has been discounted by the international emergency medical support that arrived in November and December. There was no evidence of acute malnutrition, clinical vitamin A deficiency, or immune deficiency as claimed by various anti-vaxxers.
==== COVID-19 pandemic activism ====
During the COVID-19 pandemic, anti-vaccine activists undertook various efforts to hinder people who wanted to receive the vaccines, with such activities occurring in countries including Australia, Israel, the United Kingdom, and the United States. These included attempts to physically blockade vaccination sites, and making false reservations for vaccination appointments to clog up vaccination booking systems. Protests were also organized by the activists to raise awareness for their cause.
In some instances, anti-vaccine rhetoric has been traced to state-sponsored internet troll activities designed to create social dissension. Worldwide, foreign disinformation campaigns have been associated with declining vaccination rates in target countries.
Anti-vaccine activism online both before and during the pandemic has been linked to extreme levels of falsehoods, rumors, hoaxes, and conspiracy theories.
Anti-vaccine activists have falsely claimed in social media posts that numerous deaths or injuries had to do with reactions to vaccines. In one highly publicized instance in early 2023, after Buffalo Bills football player Damar Hamlin experienced an in-game episode of commotio cordis, there was an increase in rhetoric and disinformation from figures such as Charlie Kirk and Drew Pinsky making unfounded claims about Hamlin's cardiac arrest and COVID-19 vaccines. In another 2023 incident, college basketball player Bronny James experienced cardiac arrest at the Galen Center at the University of Southern California, leading to assertions that this was a result of receiving a COVID-19 vaccine; it was later revealed that the episode had been caused by a congenital heart defect. Also, anti-vaccine activists believed Foo Fighters drummer Taylor Hawkins died in 2022 from the COVID-19 vaccine, while in actuality it was a drug overdose. In December 2023, The New York Times published a detailed investigation of the distortion and misrepresentation of the circumstances surrounding the death of 24-year-old George Watts Jr. by Robert F. Kennedy Jr. and other anti-vaccine activists. Some unvaccinated persons opposed to COVID-19 vaccination began referring to themselves in social media groups as "purebloods", a term historically connoting racial purity.
Prominent biomedical researcher Peter Hotez, asserted that he and other American scientists who publicly defend vaccines have been attacked on social media, harassed with threatening emails, intimidated, and confronted physically by opponents of vaccination. He further attributes the increase in aggressiveness of the anti-vaccination movement to the influence of the extreme wing of the Republican Party. Hotez estimates that roughly 200,000 preventable deaths from COVID-19, mainly among Republicans, occurred in the US because of refusal to be vaccinated. A 2023 study published in the Journal of the American Medical Association found "evidence of higher excess mortality for Republican voters compared with Democratic voters in Florida and Ohio after, but not before, COVID-19 vaccines were available to all adults in the US".
== See also ==
Anti-vaccinationism in chiropractic
Big Pharma conspiracy theories
COVID-19 vaccine misinformation and hesitancy
Germ theory denialism
List of anti-vaccination groups
Oral polio AIDS hypothesis
Vaccine misinformation
Vaccines and autism
MMR vaccine and autism
Thiomersal and vaccines
== References == | Wikipedia/Anti-vaccine_movement |
Primal therapy is a trauma-based psychotherapy created by Arthur Janov during the 1960s, who argued that neurosis is caused by the repressed pain of childhood trauma. Janov argued that repressed pain can be sequentially brought to conscious awareness for resolution through re-experiencing specific incidents and fully expressing the resulting pain during therapy. Primal therapy was developed as a means of eliciting the repressed pain; the term Pain is capitalized in discussions of primal therapy when referring to any repressed emotional distress and its purported long-lasting psychological effects. Janov believed that talking therapies deal primarily with the cerebral cortex and higher-reasoning areas and do not access the source of Pain within the more basic parts of the central nervous system.
Primal therapy is used to re-experience childhood pain—i.e., felt rather than conceptual memories—in an attempt to resolve the pain through complete processing and integration, becoming real. An intended objective of the therapy is to lessen or eliminate the hold early trauma exerts on adult behaviour.
Primal therapy became very influential during a brief period in the early 1970s after the publication of Janov's first book, The Primal Scream. It inspired hundreds of spin-off clinics worldwide and served as an inspiration for many popular cultural icons. Singer-songwriter John Lennon, actor James Earl Jones, and pianist Roger Williams were prominent advocates of primal therapy. Primal therapy has since declined in popularity, partly because Janov had not demonstrated in research the outcomes necessary to convince psychologists of its effectiveness. Furthermore, primal therapy is not accepted in the field of psychology, largely due to the lack of research. However, proponents of the methodology continue to advocate and practice the therapy or variations of it.
== Concepts ==
Janov stated that neurosis is the result of suppressed pain, which is the result of trauma, usually trauma of childhood origin. According to Janov, the only way to reverse neurosis is for the neurotic to recall their trauma in a therapeutic setting. Janov contended that the neurotic can thereby re-experience their feelings in response to the original traumatic incidents but can now express the emotions that at that time were repressed, thereby resolving the trauma.
Janov believed that there is only one source of mental illness (besides genetic defects): imprinted pain. He argued that this unitary source of neurosis implies that there can be only one effective cure: re-experiencing.
=== Pain ===
In primal theory, "Primal Pain is deprivation or injury which threatens the developing child. A parent's warning is not necessarily a Primal Pain for the child. Utter humiliation is... An infant left to cry it out in the crib is in Pain... It is not hurt as such which defines Primal Pain but rather the context of the hurt or its meaning to the impressionable developing consciousness of the child."
Janov described "Pain" as the pain that does not hurt because, as soon as the person goes into it, it becomes simply feeling. Most of the suffering is in the blockage or repression, not the Pain itself.
=== Needs ===
Janov believed that much of the pain of childhood is the result of needs going unmet. Drawing from earlier psychologists, he described his take on the basic needs in his books. "Our first needs are solely physical ones for nourishment, safety and comfort. Later we have emotional needs for affection, understanding and respect for our feelings. Finally, intellectual needs to know and to understand emerge."
Janov asserted that when needs go unfulfilled for too long, pain is the result.
=== Consciousness and repression ===
In primal theory, consciousness is not simply awareness but refers to a state of the entire organism, including the brain, in which there is "fluid access" between the parts. Using the triune brain work by Paul D. MacLean and adapting it to Primal Theory, three levels of consciousness are recognized in Primal Theory.
The following table summarizes some of the fundamental ideas and terms Janov (J) has used as well as conventional terms used in general and scientific papers.
Janov described defenses as the agents of repression that protect the system from the catastrophic Pain of unfulfilled need. When referring to Pain or defense the word line is used instead of level; e.g. first-line Pain = early trauma imprinted in the brainstem usually involving physical injury, third line defense = intellectual defense.
The brainstem has also often been referred to as the reptilian brain as it is the structure which mammals have in common with reptiles.
First-line imprints occur before intellectual abilities, such as the use of verbal language, have developed. They are at the level of pure sensation and visceral (or gut) reaction. The brainstem is capable of processing the most primitive emotions of rage and terror, and these can be experienced very early in life.
According to Janov, Primal Pains are imprinted in the lower brain first, then later the limbic system, and still later intellectual defenses are formed by the cortex simply because this is the sequence of neurological development. The therapy therefore occurs in the reverse sequence: "There is no way to go deep without first going shallow." In primal therapy, medication is prescribed for some "overloaded" patients, so they do not overshoot into first-line pains that they are not ready to feel, thereby allowing them to feel the more recent pains first.
=== Origins of neurosis ===
Primal theory contends that many or most people suffer from some degree of neurosis. This neurosis begins very early in life (especially in the "critical period"—birth plus the first three years) as a result of needs not being met. There may be one or more isolated traumatic events, but more often, it is a case of daily neglect or abuse.
Neurosis therefore may begin to develop at birth, or even before, with first-line Pains. Subsequent Pain is thought to be added on top of previous pain in what is called "compounding" the Pain.
Throughout childhood, more elaborate "defenses" develop, as the early unmet needs keep pressing for satisfaction in symbolic, and therefore inevitably unsatisfying, ways.
== Format and process ==
The overall strategy of primal therapy has hardly changed from the early days. The therapy begins with an intensive three weeks of fifteen open-ended sessions with one therapist. After this, the patient joins group meetings with other patients and therapists once or twice a week for as long as is needed. Private sessions are still available, though not every day. The length of time needed in formal therapy varies from person to person.
=== Primal ===
As a noun or a verb, the word primal denotes the reliving of an early painful feeling. A complete primal has been found, according to Janov and Holden, to be marked by a "pre-primal" rise in vital signs such as pulse, core body temperature, and blood pressure leading up to the feeling experience and then a falling off of those vital signs to a more normal level than where they began. After the primal ("post-primal"), Janov claimed the patient will be flooded with his own insights.
Based on Janov's own in-house studies, Janov and Holden concluded that the pre-primal rise in vital signs indicates the person's neurotic defenses are being stretched by the ascending Pain to the point of producing an "acute anxiety attack" (the conventional description), and the fall to more normal levels than pre-primal levels indicates a degree of resolution of the Pain.
Janov distinguished the primal from emotional Catharsis or abreaction, an abreaction being a "pseudo-primal". A primal may be referred to as a "connected feeling", but a complete connected feeling will usually take months or even years to feel in many primals. Psychiatrist Anthony Storr claimed that primal therapy techniques have much in common with abreaction.
=== Duration ===
In The Primal Scream (published in January 1970), Janov wrote, "By the time someone has reached his eighth month he is generally well...Many patients finish before the eight months; some remain in therapy for ten or eleven months. It all depends on how sick they were to begin with."
A therapist working for Janov stated in 1973: "The need for therapy really never ends. Nobody is ever able to flush all the pain from his body." According to this source, there were patients who stayed in therapy for as long as two years.
In The New Primal Scream (published in 1991), Janov wrote that after a year to a year and a half, patients are able to continue therapy on their own, with only sporadic follow-up necessary.
=== Cost ===
In The Primal Scream (Chapter 8), Janov wrote: "Primal therapy is much more economical than conventional insight therapy—not only in financial terms but also in the time involved. The total financial outlay is about one-fifth the cost of a psychoanalysis."
In 1971, the three-week intensive (two to four daily hours) had a cost of $1,650 USD. In 1973, the cost—payable in advance—was US$6,000 for six months of therapy. In 1978, a year of primal therapy had a cost of US$6,600.
== Reports ==
Over the decades since Janov's first book on the subject, there have been several reports and critiques relating to primal therapy in books and peer-reviewed journals.
Janov initiated from the outset small-scale research using questionnaires and measures of EEG, body temperature, blood pressure, and pulse from his patients. A 1971 Pittsburgh Press article cited a University of California at Irvine study on primal therapy patients that showed a slowing of brain waves. Janov claimed that primal therapy reduced, in some patients, the frequency and the amplitude of Alpha waves, core body temperature (as much as three degrees) and blood pressure (as much as 30 percent). Two Brain Research Institute (UCLA) scientists confirmed that there were brain-wave changes in primal patients.
Authors Prochaska and Norcross called the research by Janov "largely uncontrolled, non comparative and short term."
A small uncontrolled outcome study of 13 primal patients showed that 8 were definitively improved on all outcome measures, with 1 bad outcome. The authors concluded that primal therapy warrants further study.
=== Tomas Videgård's The Success and Failure of Primal Therapy ===
In an early account of the results of primal therapy, Tomas Videgård reported on a study of a sample of 32 patients who entered therapy at The Primal Institute in 1975 and 1976.
The outcome evaluation for the patients was 4 Very Good, 9 Good, 8 Medium, 6 Bad (including one suicide), and 5 Unavailable for post-testing (left therapy prematurely). Patients in the sample had been in therapy for between 15 and 32 months. Patients were evaluated based on patients' answers to questions and some projective tests interpreted by Videgård himself.
Videgård concluded that therapy at The Primal Institute was marginally better than the Tavistock Clinic and markedly better than the Menninger Foundation—the two psychotherapy clinics he used for comparison. Videgård wrote, "The outcome is about half as good as Janov claims the results of PT to be," calculating a 40 percent success rate, compared with a 98–100 percent success rate claimed by Janov.
== Criticism ==
Primal therapy is not accepted in the field of psychology. It is regarded as one of the least credible forms of psychotherapy and has been classified in a 2006 APA Delphi poll as "discredited". It has been frequently criticized as lacking outcome studies to substantiate its effectiveness. Some researchers have suggested that Janov's claim that adults can recall infantile experiences is refuted.
In a 1982 paper published in the journal Zeitschrift für Psychosomatische Medizin und Psychoanalyse, Ehebald and Werthmann report that, following a review of the scientific literature, they found "no on-going reports of primal therapy's therapeutic results, no statistical studies and no follow-up studies." Concluding that primal therapy is not a valid therapeutic technique, they stated that most psychotherapists in the Federal Republic of Germany believe it to be questionable in theory and dangerous in practice.
Alice Miller was a strong proponent of primal therapy. Later, however, she developed some misgivings and hesitations about it. She stated that primal therapy could be dangerous when conducted by inadequately trained therapists, that there was "too much faith" in cathartic discharge, and that the structure of the initial three-week intensive could provide opportunities for unscrupulous therapists.
According to Stanislav Grof, many patients stayed in primal therapy for years with no substantial progress. According to Grof, the clinical state of some patients actually worsened.
In 1996, authors Starker and Pankratz published in Psychological Reports a study of 300 randomly sampled psychologists. Participants were asked for their views about the soundness of methods of mental health treatment. Primal therapy was identified as one of the approaches "most in question as to soundness."
Martin Gardner wrote a critical article called Primal Therapy: A Persistent New Age Therapy in the Skeptical Inquirer. Gardner claims there is not even the "slightest evidence" that adults can recall memories of the first few years of life. Gardner also details a protest over the publication of Janov's book The Biology of Love, which is referred to as "Bogus Psychiatry".
== History ==
Primal Therapy began in 1967, when Janov had a pivotal psychotherapy session with Danny Wilson (a pseudonym). Danny Wilson was very disturbed over an experimental theater performance he had recently seen, during which the performer shouted "Mama!" repeatedly. Janov insistently encouraged Danny Wilson to shout "Mama!" again during the therapy session. Wilson did so, and eventually fell to the floor in emotional pain for half an hour. Janov taped the session and reheard it repeatedly. He did not understand its meaning until years later.
Janov later asked another therapy patient to shout "Mama!" at a pivotal moment, and that patient also achieved some kind of emotional release. Janov subsequently experimented with his patients in 1967 and 1968. Janov developed a theory of psychopathology that neurosis is caused by repressed emotional memories of childhood trauma and could be resolved by re-experiencing and expressing.
In 1968, The Primal Institute was founded by Arthur Janov and his first wife, Vivian. In 1970, Arthur Janov published his first book, The Primal Scream. In March, Arthur and Vivian started treating John Lennon and Yoko Ono.
Primal therapy became very influential during a brief period in the early 1970s, after the publication of The Primal Scream. It inspired hundreds of spin-off clinics worldwide and served as an inspiration for many popular cultural icons.
In 1971, two trainee primal therapists, Joseph Hart and Richard Corriere, abandoned Arthur Janov and started the Center for Feeling Therapy. Hart claimed: "When we left Janov, forty percent of the patients came with us....we found that most had been faking their primals."
== Notable patients ==
A number of prominent actors and performers underwent primal therapy during the 1970s and later advocated it. Actor James Earl Jones, pianist Roger Williams, and actress Dyan Cannon underwent primal therapy and advocated it.
Apple Inc. co-founder Steve Jobs experimented with primal therapy, but later "grew bored and disdainful" of it.
The Scottish rock band Primal Scream was named after the type of cry heard in primal therapy. The British pop band Tears for Fears was directly inspired by Janov's writings.
=== John Lennon ===
Beatles member John Lennon and his wife Yoko Ono went through primal therapy in 1970. A copy of the just-released The Primal Scream arrived in the mail at Lennon's home Tittenhurst Park. Lennon was impressed, and he requested primal therapy to be started at Tittenhurst. Lennon and Ono had three weeks of intensive treatment in England before Janov returned to Los Angeles, where they had four months of therapy.
Lennon ended primal therapy after four or five months. Lennon commented after therapy, "I still think that Janov's therapy is great, you know, but I do not want to make it a big Maharishi thing" and "I just know myself better, that's all. I can handle myself better." and "I no longer have any need for drugs, the Maharishi or the Beatles. I am myself and I know why." Janov himself, said that, "We had opened him up, and we didn't have time to put him back together again."
Shortly after therapy, Lennon produced his album John Lennon/Plastic Ono Band. (Ono recorded a parallel album, Yoko Ono/Plastic Ono Band, from her experiences.) Lennon's album featured a number of songs that were directly affected by his experience in therapy, including "Remember", "I Found Out", "Isolation", "God", "Mother", "My Mummy's Dead", "Well Well Well," and "Working Class Hero", as were a number of songs from his Imagine album, including "How?", "Crippled Inside", and his rewriting of "Oh My Love".
== See also ==
Primal Scream (disambiguation)
Attachment therapy
Center for Feeling Therapy
Pre- and perinatal psychology
Primal integration
List of topics characterized as pseudoscience
== References ==
== Bibliography ==
Alexander, Theresa (1997). Facing the Wolf: Inside the Process of Deep Feeling Therapy. Plume. ISBN 0452275210.
Holden, E. Michael; Janov, Arthur (1975). Primal man: the new consciousness. New York: Crowell. ISBN 978-0-690-01015-2.
Janov, Arthur (1970). The Primal Scream (A Delta Book). Dell Publishing Company. ISBN 978-0-349-11829-1.
Janov, Arthur (1991). The new primal scream: primal therapy 20 years on. [Wilmington, Del.]: Enterprise Pub. ISBN 978-0-942103-23-6.
Janov, Arthur (2006). Primal Healing: Access the Incredible Power of Feelings to Improve Your Health. Franklin Lakes, N.J.: New Page Books. ISBN 978-1-56414-916-9.
Reese, Robert T. (1988). Healing fits: the cure of an epileptic. Los Angeles: Big Sky Press. ISBN 978-0-944592-00-7.
Videgård, Tomas (1984). The success and failure of primal therapy: 32 patients treated at the Primal Institute (Janov) viewed in the perspective of object relations theory. Stockholm: Almqvist & Wiksell International. ISBN 978-91-22-00698-5.
Complete list of books by Arthur Janov
== External links ==
Dr. Arthur Janov's Primal Center home page
The Primal Institute directed by Vivian Janov
The Primal Psychotherapy Page – A Resource For Those With Interests In the Regressive Deep-Feeling Psychotherapies
A look at four psychology fads — a comparison of est, primal therapy, Transcendental Meditation and lucid dreaming at the Los Angeles Times
John Lennon – Primal therapy | Wikipedia/Primal_therapy |
The California Academy of Sciences is a research institute and natural history museum in San Francisco, California, that is among the largest museums of natural history in the world, housing over 46 million specimens. The academy began in 1853 as a learned society and still carries out a large amount of original research. The institution is located in Golden Gate Park on the West Side of San Francisco.
Completely rebuilt in 2008, the academy's primary building in Golden Gate Park covers 400,000 square feet (37,000 m2). In early 2020, before the COVID-19 pandemic, the California Academy of Sciences had around 500 employees and an annual revenue of about $33 million.
The museum is accessible via public transit on the N Judah Metro line. The westbound 9th Avenue and Irving station is located about 0.5 miles from the Academy of Sciences. Three Muni bus lines also serve the museum, the 44, 5, and 7 lines.
== Governance ==
The California Academy of Sciences, California's oldest operating museum and research institution for the natural sciences, is governed by a 41-member board of trustees who are nominated and chosen by the California Academy of Sciences Fellows. The Academy Fellows are in turn, "[n]ominated by their colleagues and appointed by the Board of Trustees...the Fellows remain members of the Fellowship for life." The board of trustees is then responsible for appointing the executive management of the academy, who in turn are responsible for overseeing the academy's overall operation and the hiring of its other managers and employees.
=== Institute for Biodiversity Science and Sustainability (IBSS) ===
Besides its function as a source of public science education through its museum, the California Academy of Sciences also operates the Institute for Biodiversity Science and Sustainability (IBSS) as its research arm, conducting research in the fields of taxonomy, phylogenetics, and biodiversity studies. Although one aspect of the IBSS is available for viewing by museum patrons at the science "project lab" exhibit, most of the research happens in laboratories and facilities, "behind the scenes", and not observable by the public. In fact, unbeknownst to most patrons, research and administrative facilities occupy nearly 50% of the Academy's physical structure.
== Exhibits ==
The main thrust of the exhibits is natural history. The venues of the museum include the following:
Kimball Natural History Museum – generally encompasses the entire museum outside the planetarium, rainforest, and aquarium, and includes Africa Hall (the Academy's oldest running exhibit), the East Wing (includes a Foucault pendulum, also a carry-over exhibit from the older, pre-2008 renovation of the Academy), the West Wing (which as of 2020 housed several geophysical exhibits), as well as several smaller exhibits distributed throughout the remainder of the Academy building.
Morrison Planetarium – features a digitally controlled planetarium dome measuring 90 feet (27 m) in diameter with a 75 feet (23 m) diameter screen.
Rainforests of the World – rainforest exhibit enclosed in a 90-foot (27 m) glass dome.
Steinhart Aquarium – includes exhibits of coral reefs, tide pools, and swamp habitats.
Penguin Habitat – features a colony of African penguins.
Besides its museum programs, the California Academy of Sciences offers many educational and community outreach programs to members of the public at large.
== Research ==
Academy scientists, under the Academy's Institute for Biodiversity Science and Sustainability, conduct systematic and conservation research in several different fields, including anthropology, marine biology, botany, entomology, herpetology, ichthyology, invertebrate zoology, mammalogy, ornithology, geology, and paleontology. There also is a strong emphasis on environmental concerns, with all the various departments collaborating closely to focus on systematic biology and biodiversity. Academy researchers study life around the world: a 2011 expedition to the Philippines discovered an estimated 300 species new to science. There is also research pertaining to new technology being used by the general public. Mushroom identification applications were being used which may have caused an increase of poisonings. To combat this Academy researchers studied the accuracies of three of the most popular applications. The Academy publishes the peer-reviewed journal Proceedings of the California Academy of Sciences, as well as Occasional Papers, Memoirs, and Special Publications.
== History ==
=== Early years ===
The California Academy of Natural Sciences was founded in 1853, only three years after California joined the United States, becoming the first society of its kind in the Western US. Its stated aim was to undertake "a thorough systematic survey of every portion of the State and the collection of a cabinet of her rare and rich productions." It was renamed as the more inclusive California Academy of Sciences in 1868.
The academy had a forward-thinking view towards women in science, passing a resolution in its first year that the members "highly approve of the aid of females in every department of natural science, and invite their cooperation." This policy led to several women being hired into professional positions as botanists, entomologists, and other occupations during the 19th century, when opportunities for women in the sciences were limited, and often, those that existed were restricted to menial cataloging and calculation work. In 1892, Alice Eastwood, a botanist, was hired by the academy and worked there until she retired in 1949. She created the collection of rare plants, which was saved when the academy was destroyed in the 1906 San Francisco earthquake
The academy's first official museum opened in 1874 at the corner of California and Dupont Streets (now Grant Avenue) in what is now Chinatown, and drew up to 80,000 visitors a year. To accommodate its increasing popularity, the academy moved to a new and larger building on Market Street in 1891, funded by the legacy of James Lick, a 19th-century San Francisco real estate mogul, entrepreneur, and philanthropist.
However, only fifteen years later, the Market Street facility fell victim to the 1906 San Francisco earthquake and three days of fire, which also wiped out all but a wheelbarrow full of the academy's library and specimen collections. In the widespread destruction occurring in the aftermath of the quake, academy curators and staffers only were able to retrieve a single cart of materials, including academy minute books, membership records, and 2,000 type specimens. The 1905–1906 scientific collecting expedition to the Galápagos Islands (the first of several sponsored by the academy to the archipelago) already was underway, and it returned seven months later, providing replacement collections for those lost.
=== Golden Gate Park site ===
In 1916, the Academy moved to the North American Hall of Birds and Mammals in Golden Gate Park, the first building on the site that was to become its permanent home. In 1923, the Steinhart Aquarium was added, followed in 1934 by the Simson African Hall.
During World War II, the Academy contributed to the American war effort by using its workshop facilities to repair optical and navigational equipment for United States Navy ships; San Francisco was a major port for the Pacific War arena.
The post-war years saw a flurry of new construction on the site; the Science Hall was added in 1951, followed by the Morrison Planetarium in 1952. The Morrison Planetarium was the seventh major planetarium to open in the United States and featured a one-of-a-kind star projector, built by Academy staff members (in part using the expertise gained doing the optical work for the US Navy during World War II). The Academy Projector projected irregularly shaped stars, rather than the circular stars projected by many optical star projectors. The irregular shapes were created by placing variously sized grains of silicon carbide onto the glass star plates by hand, then aluminizing the plates, and brushing away the silicon carbide grains.
In 1959, the Malliard Library, Eastwood Hall of Botany, and Livermore Room all were added. Throughout the 1960s, universities concentrating on the new field of molecular biology divested themselves of their traditional specimen collections, entrusting them to the academy and leading to a rapid growth of the Academy's holdings.
In 1969, another new building, Cowell Hall, was added to the site. In 1976, several new galleries were opened, and the following year, in 1977, the "fish roundabout" was constructed.
Before the old building being torn down in 2005, there was a Life through Time gallery, housing a large display on evolution and paleontology. There was a Gem and Mineral Hall, a section on Earthquakes, and a Gary Larson exhibit.
=== Earthquake damage and new building ===
The academy buildings were damaged significantly in the 1989 Loma Prieta earthquake. Subsequently, the Bird Hall building was closed to ensure public safety. The inadequately engineered Steinhart Aquarium suffered dramatic seismic damage from the 1989 earthquake, as well.
As plans were made to repair the damage and make the buildings seismically stable, it was realized that a considerable amount of work would be needed to bring the buildings up to modern standards. This led to the idea of giving the academy a complete overhaul, thus motivating the closing of the main site.
Construction began on the new $500 million building on September 12, 2005, while the exhibits were moved to 875 Howard Street for a temporary museum.
The academy reopened with a free day on September 27, 2008. For most of the day, the line for admittance was over a mile (nearly two kilometers) long, and although over 15,000 people were admitted, several thousands more had to be turned away.
In May 2020, during the COVID-19 pandemic, the Academy announced that it would lay off 105 of its then 504 employees, furlough 96 others, and enact pay cuts among part of the rest. Due to the COVID-19 lockdown's effect on ticket sales, the organization was expecting its revenue to decrease by around $12 million (36%) in the next fiscal year.
== Environmental design of new building ==
The design architect for the museum replacement project was Renzo Piano. His design was awarded the Urban Land Institute (ULI) Award for Excellence for the Americas region in 2008, as well as the Holcim Award Silver for sustainable construction projects in the North America region in 2005. One critic praised the building as a "blazingly uncynical embrace of the Enlightenment values of truth and reason", and a "comforting reminder of the civilizing function of great art in a barbaric age".
The new building emphasizes environmentally friendly design, in keeping with the academy's focus on ecological concerns and environmental sustainability. It received Platinum certification under the LEED program. This project was featured on the Discovery Channel Extreme Engineering series in 2006, the National Geographic Channel Man-Made series in July 2008, and Smithsonian Channel's How Do They Build That? in August 2022.
The new building includes an array of environmentally friendly features:
Produces 50 percent less waste water than previously
Recycles rainwater for irrigation
Uses 60,000 photovoltaic cells
Supports a green roof with an area of 2.5 acres (1.0 hectare)
Uses natural lighting in 90 percent of occupied spaces
Was constructed of over 20,000 cubic yards (15,000 m3) of recycled concrete
Construction includes 11 million pounds (5,000 t) of recycled steel
Wall insulation made from scraps of recycled denim
=== Green roof ===
The California Academy of Sciences green roof has several environmentally friendly features and a sustainable design. Renzo Piano was inspired by seven major hills of San Francisco, which typically refers to: Telegraph Hill, Nob Hill, Russian Hill, Rincon Hill, Mount Sutro, Twin Peaks and Mount Davidson. The living green roof was planted with 1.7 million California native plants. The museum's central piazza lies beneath a massive glass ceiling on the roof, which opens to allow cool night air to flow into the building below; by using this kind of natural ventilation instead of air conditioning to regulate interior temperature, the building becomes more energy efficient. Renzo Piano and SWA Group won the American Society of Landscape Architects (ASLA) Award in design in 2009.
== Notable people ==
Notable staff members of the academy include:
Alice Eastwood (botanist), 1892–1949
Frank Talbot (ichthyologist and marine biologist), director, 1982–1989
== Gallery ==
== See also ==
49-Mile Scenic Drive
Green museum
== References ==
== Further reading ==
"Natural Phenomenon", by Matt Tyrnauer, Vanity Fair, May 2008
Cutting Edge Construction—National Geographic Channel
"Concrete and Strawberries" Archived 2008-09-14 at the Wayback Machine, California magazine, September 2008
"Beyond Green", California Home + Design, September 2008
"A Look at the Cal Academy of Sciences of 1891–1906". Bearings (blog). July 16, 2009. Retrieved July 19, 2009.
== External links ==
Official website
Calacademy.org: PDFs on national media reports of Academy's construction
California Academy of Sciences at Google Cultural Institute
ASLA 2009 Design Award | Wikipedia/California_Academy_of_Sciences |
The chemtrail conspiracy theory is the erroneous belief that long-lasting condensation trails left in the sky by high-flying aircraft are actually "chemtrails" consisting of chemical or biological agents, sprayed for nefarious purposes undisclosed to the general public. Believers in this conspiracy theory say that while normal contrails dissipate relatively quickly, contrails that linger must contain additional substances. Those who subscribe to the theory speculate that the purpose of the chemical release may be solar radiation management, weather modification, psychological manipulation, human population control, biological or chemical warfare, or testing of biological or chemical agents on a population, and that the trails are causing respiratory illnesses and other health problems.
The claim has been dismissed by the scientific community. There is no evidence that purported chemtrails differ from normal water-based contrails routinely left by high-flying aircraft under certain atmospheric conditions. Proponents have tried to prove that chemical spraying occurs, but their analyses have been flawed or based on misconceptions. Because of the conspiracy theory's persistence and questions about government involvement, scientists and government agencies around the world have repeatedly explained that the supposed chemtrails are in fact normal contrails.
== History ==
Chemtrail conspiracy theories began to circulate after the United States Air Force (USAF) published a 1996 report about weather modification. In the late 1990s, the USAF was accused of "spraying the U.S. population with mysterious substances" from aircraft "generating unusual contrail patterns." The theories were posted on Internet forums by people including Richard Finke and William Thomas and were among many conspiracy theories popularized by late-night radio host Art Bell, starting in 1999. As the chemtrail conspiracy theory spread, federal officials were flooded with angry calls and letters.
A multi-agency response attempting to dispel the rumors was published in 2000 by the Environmental Protection Agency (EPA), the Federal Aviation Administration (FAA), the National Aeronautics and Space Administration (NASA) and the National Oceanic and Atmospheric Administration (NOAA). Many chemtrail believers interpreted agency fact sheets as further evidence of the existence of a government cover-up. The EPA refreshed its posting in 2015.
In the early 2000s, the USAF released an undated fact sheet that stated the conspiracy theories were a hoax fueled in part by citations to a 1996 strategy paper drafted within their Air University titled Weather as a Force Multiplier: Owning the Weather in 2025. The paper was presented in response to a military directive to outline a future strategic weather modification system for the purpose of maintaining the United States' military dominance in the year 2025, and identified as "fictional representations of future situations/scenarios." The USAF further clarified in 2005 that the paper "does not reflect current military policy, practice, or capability" and that it is "not conducting any weather modification experiments or programs and has no plans to do so in the future." Additionally, the USAF states that the "'chemtrail' hoax has been investigated and refuted by many established and accredited universities, scientific organizations, and major media publications."
The conspiracy theories are seldom covered by the mainstream media, and when they are, they are usually cast as an example of anti-government paranoia. For example, in 2013, when it was made public that the CIA, NASA, and NOAA intended to provide funds to the National Academy of Sciences to conduct research into methods to counteract global warming with geoengineering, an article in the International Business Times anticipated that "the idea of any government agency looking at ways to control, or manipulate, the weather will be met with scrutiny and fears of a malign conspiracies" [sic], and mentioned chemtrail conspiracy theories as an example. Robert F. Kennedy Jr, United States Secretary of Health and Human Services since 2025, started supporting the conspiracy theory in 2024.
== Description ==
Proponents of the chemtrail conspiracy theory find support for their theories in their interpretations of sky phenomena, videos posted to the Internet, and reports about government programs; they also have certain beliefs about the goals of the alleged conspiracy and the effects of its alleged efforts and generally take certain actions based on those beliefs.
The term chemtrail is a portmanteau of the words chemical and trail, just as contrail blends condensation and trail.
=== Interpretation of evidence ===
Proponents of the chemtrail conspiracy theory say that chemtrails can be distinguished from contrails by their long duration, asserting that the chemtrails are those trails left by aircraft that persist for as much as a half-day or transform into cirrus-like clouds. The proponents claim that after 1995, contrails had a different chemical composition and lasted a lot longer in the sky; proponents fail to acknowledge evidence of long-lasting contrails shown in World War II–era photographs.
Proponents characterize contrails as streams that persist for hours and that, with their criss-cross, grid-like, or parallel stripe patterns, eventually blend to form large clouds. Proponents view the presence of visible color spectra in the streams, unusual concentrations of sky tracks in a single area, or lingering tracks left by unmarked or military airplanes flying atypical altitudes or locations as markers of chemtrails.
Photographs of barrels installed in the passenger space of an aircraft for flight test purposes have been claimed to show aerosol dispersion systems. The barrels' actual purpose is to simulate the weight of passengers or cargo. The barrels are filled with water, and the water can be pumped from barrel to barrel to test different centers of gravity while the aircraft is in flight.
Former CIA employee and whistleblower Edward Snowden, interviewed on The Joe Rogan Experience, said he had searched through all the secret information of the U.S. government for evidence about (aliens and) chemtrails. According to a CNN report about the webcast, he said: "In case you were wondering: ... Chemtrails are not a thing" and "I had ridiculous access to the networks of the NSA, the CIA, the military, all these groups. I couldn't find anything".
Jim Marrs has cited a 2007 Louisiana television station report as evidence for chemtrails. In the report, the air underneath a crosshatch of supposed chemtrails was measured and apparently found to contain unsafe levels of barium: at 6.8 parts per million, three times the nationally recommended limit. But a subsequent analysis of the footage showed that the equipment had been misused and the reading exaggerated by a factor of 100—the true level of barium measured was both usual and safe.
In 2014, a video that went viral showed a commercial passenger airplane landing on a foggy night, which was described as emitting chemtrails. Discovery News pointed out that passengers sitting behind the wings would clearly see anything being sprayed, which would defeat any intent to be secretive, and that the purported chemical emission was normal air disruption caused by the wings, visible due to the fog. In that same year, several photos of German chancellor Angela Merkel visiting the ILA Berlin Air Show, the water tanks next to her were falsely identified as toxic chemicals.
In October 2014, Englishman Chris Bovey filmed a video of a plane jettisoning fuel on a flight from Buenos Aires to London, which had to dump fuel to lighten its load for an emergency landing in São Paulo. The clip went viral on Facebook, with over three million views and more than 52,000 shares, cited as evidence of chemtrails. He later disclosed that the video post was done as a prank.
In some accounts, the chemicals are described as barium and aluminum salts, polymer fibers, thorium, or silicon carbide.
Chemtrail believers interpret the existence of cloud seeding programs and research into climate engineering as evidence of the conspiracy.
=== Beliefs ===
Various versions of the chemtrail conspiracy theory have been propagated via the Internet and radio programs. There are websites dedicated to the conspiracy theory, and it is particularly favored by far-right groups because it fits well with a deep suspicion of the government.
A 2014 review of 20 chemtrail websites found that believers appeal to science in some of their arguments but do not believe what academic or government-employed scientists say; scientists and federal agencies have consistently denied that chemtrails exist, explaining the sky tracks are simply persistent contrails. The review also found that believers generally hold that chemtrails are evidence of a global conspiracy; they allege various goals which include profit (for example, manipulating futures prices, or making people sick to benefit drug companies), population control, or weapons testing (use of weather as a weapon, or testing bioweapons). One of these ideas is that clouds are being seeded with electrically conductive materials as part of a massive electromagnetic superweapons program based around the High Frequency Active Auroral Research Program (HAARP). Believers say chemtrails are toxic; the 2014 review found that they generally hold that every person is under attack and often express fear, anxiety, sadness, and anger about this. A 2011 study of people from the US, Canada, and the UK found that 2.6% of the sample believed entirely in the conspiracy theory, and 14% believed it partially. An analysis of responses given to the 2016 Cooperative Congressional Election Study showed that 9% of the 36,000 respondents believed it was "completely true" that "the government has a secret program that uses airplanes to put harmful chemicals into the air" while a further 19% believed this was "somewhat true".
Chemtrail conspiracy theorists often describe their experience as being akin to a religious conversion experience. When they "wake up" and become "aware" of chemtrails, the experience motivates them to advocacy of various forms. For example, they often attend events and conferences on geoengineering, and have sent threats to academics working in geoengineering.
Some chemtrail believers adopt the notions of Wilhelm Reich, who devised a "cloudbuster" device from pipework. Reich claimed this device would influence weather and remove harmful energy from the atmosphere. Some chemtrail believers have built cloudbusters filled with crystals and metal filings, which are pointed at the sky in an attempt to clear it of chemtrails.
Chemtrail believers sometimes gather samples and have them tested, rather than rely on reports from government or academic laboratories, but their experiments are usually flawed; for example, collecting samples in jars with metal lids contaminates the sample and is not done in scientific testing.
=== Incidents ===
In 2001, in response to requests from constituents, U.S. Representative Dennis Kucinich introduced (but did not author) H.R. 2977 (107th), the Space Preservation Act of 2001, which would have permanently prohibited basing weapons in space, listing chemtrails as one of a number of "exotic weapons" that would be banned. Proponents have interpreted this explicit reference to chemtrails as official government acknowledgment of their existence. Skeptics noted that the bill in question also mentions "extraterrestrial weapons" and "environmental, climate, or tectonic weapons". The bill received an unfavorable evaluation from the United States Department of Defense and died in committee, with no mention of chemtrails appearing in the text of any of Kucinich's three subsequent failed attempts to enact a Space Preservation Act.
In 2003, in a response to a petition by concerned Canadian citizens that "chemicals used in aerial sprayings are adversely affecting the health of Canadians", the Government House Leader responded: "There is no substantiated evidence, scientific or otherwise, to support the allegation that there is high altitude spraying conducted in Canadian airspace. The term 'chemtrails' is a popularised expression, and there is no scientific evidence to support their existence." The House leader added, "it is our belief that the petitioners are seeing regular airplane condensation trails or contrails."
In 2005 in the United Kingdom, Elliot Morley, a Minister of State for the Department for Environment, Food and Rural Affairs was asked by David Drew, the Labour Party Member of Parliament for Stroud, "what research [the] Department has undertaken into the polluting effects of chemtrails for aircraft", and responded that "the Department is not researching into chemtrails from aircraft as they are not scientifically recognised phenomena", and that work was being conducted to understand "how contrails are formed and what effects they have on the atmosphere."
During the 2011–2017 California drought, some local politicians in Shasta County reacted credulously to conspiracy theories suggesting that weather-modifying chemtrails had caused the unusual weather conditions.
== Contrails ==
Contrails, or condensation trails, are "streaks of condensed water vapor created in the air by an airplane or rocket at high altitudes". Fossil fuel combustion (as in piston and jet engines) produces carbon dioxide and water vapor and soot particulates that act as cloud condensation nuclei. At high altitudes, the air is very cold. Hot humid air from the engine exhaust mixes with the colder surrounding air, causing the water vapor to condense into droplets or ice crystals that form visible clouds. The rate at which contrails dissipate is entirely dependent on weather conditions. If the atmosphere is near saturation, the contrail may exist for some time. Conversely, if the atmosphere is dry, the contrail will dissipate quickly.
It is well established by atmospheric scientists that contrails can persist for hours, and that it is normal for them to spread out into cirrus sheets. The different-sized ice crystals in contrails descend at different rates, which spreads the contrail vertically. Then the differential in wind speeds between altitudes (wind shear) results in the horizontal spreading of the contrail. This mechanism is similar to the formation of cirrus uncinus clouds. Contrails between 25,000 and 40,000 feet (7,600 and 12,200 m) can often merge into an "almost solid" interlaced sheet. Contrails can have a lateral spread of several kilometers, and given sufficient air traffic, it is possible for contrails to create an entirely overcast sky that increases the ice budget of individual contrails and persists for hours.
Experts on atmospheric phenomena say that the characteristics attributed to chemtrails are simply features of contrails responding to diverse conditions in terms of sunlight, temperature, horizontal and vertical wind shear, and humidity levels present at the aircraft's altitude. In the US, the gridlike nature of the National Airspace System's flight lanes tends to cause crosshatched contrails, and in general it is hard to discern from the ground whether overlapping contrails are at similar altitudes or not. The jointly published fact sheet produced by NASA, the EPA, the FAA, and NOAA in 2000 in response to alarms over chemtrails details the science of contrail formation, and outlines both the known and potential impacts of contrails have on temperature and climate. The USAF produced a fact sheet that described these contrail phenomena as observed and analyzed since at least 1953. It also rebutted chemtrail theories more directly by identifying the theories as a hoax and disproving the existence of chemtrails.
Patrick Minnis, an atmospheric scientist with NASA's Langley Research Center, has said that logic does not dissuade most chemtrail proponents: "If you try to pin these people down and refute things, it's, 'Well, you're just part of the conspiracy'".
Analysis of the use of commercial aircraft tracks for climate engineering has shown them to be generally unsuitable.
Astronomer Bob Berman has characterized the chemtrail conspiracy theory as a classic example of failure to apply Occam's razor, writing in 2009 that instead of adopting the long-established "simple solution" that the trails consist of frozen water vapor, "the conspiracy web sites think the phenomenon started only a decade ago and involves an evil scheme in which 40,000 commercial pilots and air traffic controllers are in on the plot to poison their own children."
A 2016 survey of 77 atmospheric scientists concluded that "76 out of 77 (98.7%) of scientists that took part in this study said they had not encountered evidence of a [secret large-scale atmospheric program] (SLAP), and that the data cited as evidence could be explained through other factors, such as typical contrail formation and poor data sampling instructions presented on SLAP websites."
== See also ==
== References ==
== Further reading ==
"'Chemtrails' not real, say leading atmospheric science experts" Archived 20 December 2016 at the Wayback Machine, Carnegie Institution for Science
"Lake Oroville Runoff Enhancement Project" Final Report submitted to California Dept. of Water Resources Division of Operations and Maintenance (September 1995); published by US Department of the Interior's Bureau of Reclamation Technical Service Center, River Systems and Meteorology Group.
Talbot, Margaret (30 August 2002). "The H-Word". The Guardian. London.
Abstract: "Bureau of Reclamation cooperated with the California Department of Water Resources to design and implement a snowpack augmentation program to increase runoff to Oroville Reservoir. The program involves the collection of data to document physical processes leading to increased precipitation. This report summarizes the main results from 3 yr of in-situ physical studies and statistical analysis of precipitation data collected during 87 randomized seeding cases. Liquid propane released from high elevation sites has proven to be a viable, reliable method of seeding wintertime clouds in the Sierra Nevada."
== External links ==
Dunning, Brian (15 February 2007). "Skeptoid #27: Chemtrails: Real or Not?". Skeptoid. | Wikipedia/Chemtrail_conspiracy_theory |
Clinical trials on ayurveda refers to any clinical trials done on ayurvedic treatment. Ayurveda is a traditional medicine system in India and like other cultural medical practices includes both conventional medicine and also complementary and alternative medicine. When there are clinical trials in ayurveda, the focus tends to be on practices in alternative medicine.
A 2017 essay described that in India, ayurveda is inadequately equipped to manage many modern diseases, owing to insufficient research and development. The essay argued that clinical trials in ayurveda should focus on areas outside the scope of modern medicine.
Also, while there is a short history of clinical research on ayurvedic treatments, there is no existing systematic review available which identifies all the studies and interprets them as a whole.
Educational organizations which teach Ayurveda require training if they are to design clinical trials on ayurvedic treatments.
As of 2016 the Clinical Trials Registry – India contained approximately 200 records of clinical trials on ayurvedic treatments.
== List of clinical trials ==
Of all the recorded clinical trials, the following treatments are those for which there are meta-analyses of multiple trials:
Bacopa monnieri for cognitive skill
Withania somnifera for anxiety
treatment for osteoarthritis
Yoga as treatment
== References == | Wikipedia/Clinical_trials_on_Ayurveda |
Bourgeois pseudoscience (Russian: буржуазная лженаука) was a term of condemnation in the Soviet Union for certain scientific disciplines that were deemed unacceptable from an ideological point of view due to their incompatibility with Marxism–Leninism. At various times pronounced "bourgeois pseudosciences" were: Mendelian genetics, cybernetics, quantum physics, theory of relativity, sociology and particular directions in comparative linguistics (the now-debunked Japhetic theory of Nikolay Yakovlevich Marr, which was also refuted by Stalin in "Marxism and Problems of Linguistics").
The term was not used by Stalin himself, who rejected the notion that all sciences must have a class nature. Stalin removed all mention of “bourgeois biology” from Trofim Lysenko’s report, The State of Biology in the Soviet Union, and in the margin next to the statement that “any science is based on class” Stalin wrote, “Ha-ha-ha!! And what about mathematics? Or Darwinism?” The term or its synonyms was used in the 1951 and 1954 editions of the Short Philosophical Dictionary: "Cybernetic is a reactionary pseudoscience originated in the United States... A form of modern mechanicism.", "Eugenics is a bourgeois pseudoscience", "Weismannism-Morganism - bourgeois pseudoscience, designed to justify capitalism". Today, most scholars agree in characterizing eugenics as rooted in pseudoscience, albeit without the "bourgeois" qualifier.
Psychology was declared a "bourgeois pseudoscience" in People's Republic of China during the Cultural Revolution (1966–1976). Furthermore, sociology was banned there in 1952, and it remained banned for until the late 1970s.
== See also ==
Repression of science in the Soviet Union
Cybernetics in the Soviet Union
Censorship in the Soviet Union
Soviet historiography
Politicization of science
== Notes ==
== References == | Wikipedia/Bourgeois_pseudoscience |
In linguistics, the Japhetic hypothesis or Japhetic theory of Soviet linguist Nikolay Yakovlevich Marr (1864–1934) postulated that the Kartvelian languages of the Caucasus area are related to the Semitic languages of the Middle East. The hypothesis gained favor in the 1930s and 1940s among some Soviet linguists for ideological reasons as it was thought to represent "proletarian science" as opposed to "bourgeois science", but also had numerous detractors, most notably Arnold Chikobava. The hypothesis finally fell into disrepute and was largely discarded after 1950, when Joseph Stalin published a scathing critique of the views of Marr and his supporters, titled "Marxism and Problems of Linguistics".
== Term ==
Marr adopted the term "Japhetic" from Japheth, the name of one of the sons of Noah, in order to characterise his hypothesis that the Kartvelian languages of the Caucasus area were related to the Semitic languages of the Middle East (named after Shem, Japheth's brother). Marr postulated a common origin of Caucasian, Semitic-Hamitic, and Basque languages. This initial hypothesis pre-dated the October Revolution (the first reference to it is made in Pan Tadeusz written by Adam Mickiewicz in the 1830s). In 1917, Marr enthusiastically endorsed the revolution, and offered his services to the new Soviet regime. He was soon accepted as the country's leading linguist.
== Hypothesis ==
Under the Soviet government, Marr developed his hypothesis to claim that Japhetic languages had existed across Europe before the advent of the Indo-European languages. They could still be recognised as a substratum over which the Indo-European languages had imposed themselves. Using this model, Marr attempted to apply the Marxist theory of class struggle to linguistics, arguing that these different strata of language corresponded to different social classes. He stated that the same social classes in widely different countries spoke versions of their own languages that were linguistically closer to one another than to the speech of other classes who supposedly spoke “the same” language. This aspect of Marr's thinking was an attempt to extend the Marxist theory of international class consciousness far beyond its original meaning, by trying to apply it to language. Marr also insisted that the notion that a people are united by common language was nothing more than false consciousness created by “bourgeois nationalism”.
To draw support for his speculative doctrine, Marr elaborated a Marxist footing for it. He hypothesized that modern languages tend to fuse into a single language of communist society. This hypothesis was the basis for a mass campaign of "Latinisation" in the 1920s and 1930s to replace the existing Cyrillic alphabets of minority languages with Latin alphabets.
Obtaining recognition of his hypothesis from Soviet officials, Marr was permitted to manage the National Library of Russia from 1926 until 1930 and the Japhetic Institute of the Academy of Sciences from 1921 until his death in 1934. He was elected vice-president of the Soviet Academy of Sciences in 1930.
In 1950, sixteen years after Marr's death, an article titled "Marxism and Problems of Linguistics", written by Joseph Stalin, was published in major Soviet periodicals. It was inspired by the writings of Marr's most energetic opponent, Arnold Chikobava, In the article, Stalin rebuts the Japhetic hypothesis, stating that "N. Ya. Marr introduced into linguistics another and also incorrect and non-Marxist formula, regarding the ‘class character’ of language, and got himself into a muddle and put linguistics into a muddle. Soviet linguistics cannot be advanced on the basis of an incorrect formula which is contrary to the whole course of the history of peoples and languages." Since then, the Japhetic hypothesis has been seen as deeply flawed, both inside and outside the former Soviet Union, but some of Marr's surviving students continued to defend and develop it into the late 1960s.
== See also ==
Georgy Danilov
Dené-Caucasian languages
Khazar theory
Lemurian Tamil
Lysenkoism
Proto-language
Sun Language Theory
== References ==
== External links ==
The Soviet Linguistic Theory (chapter 4 of Roman Smal-Stocki, The Nationality Problem of the Soviet Union): a hostile but thorough exposition of Japhetic hypothesis | Wikipedia/Japhetic_theory |
Chromotherapy, sometimes called color therapy, colorology or cromatherapy, is a pseudoscientific form of alternative medicine which proposes certain diseases can be treated by exposure to certain colors. Its practice is considered to be quackery. Chromotherapists claim to be able to use light in the form of color to balance "energy" lacking from a person's body, whether it be on physical, emotional, spiritual, or mental levels. For example, they thought that shining a colored light on a person would cure constipation. Historically, chromotherapy has been associated with mysticism and occultism.
Color therapy is unrelated to photomedicine, such as phototherapy and blood irradiation therapy, which are scientifically accepted medical treatments for a number of conditions, as well as being unrelated to photobiology, which is the scientific study of the effects of light on living organisms.
== History ==
Avicenna (980–1037), seeing color as of vital importance both in diagnosis and in treatment, discussed chromotherapy in The Canon of Medicine. He wrote that "color is an observable symptom of disease" and also developed a chart that related color to the temperature and physical condition of the body. His view was that red moved the blood, blue or white cooled it, and yellow reduced muscular pain and inflammation.
Pioneer of photography Robert Hunt performed experiments on the effects of different wavelengths of light on the germination and growth of plants, detailed in his 1844 book Researches on Light. Apparently influenced by this work,: 214–215 from 1860 Augustus Pleasonton started to conduct original experiments, and in 1876 published the book The Influence of the Blue Ray of the Sunlight and of the Blue Color of the Sky, detailing how the color blue can improve the growth of crops and livestock and can help heal diseases in humans. This led to the birth of modern chromotherapy, influencing contemporary scientists Dr. Seth Pancoast and Edwin Dwight Babbitt to conduct experiments and publish Blue and Red Light; or, Light and Its Rays as Medicine (1877) and The Principles of Light and Color (1878), respectively.: 214, 222, 229
Pancoast's book has been described by historians as a confusing mix of color therapy, mysticism, and occultism. He held a lifelong interest in the Kabbalah and was a founding member of the Theosophical Society. Pancoast believed that God is light and "the one universal pathological agent" that could cure disease. He would expose medications to colored light before administering them to a patient and also utilized sun-baths fitted with colored panes of glass. Throughout the 19th century, "color healers" claimed colored glass filters could treat many diseases, including constipation and meningitis. In Germany in the late 1890s, Georg von Langsdorff promoted Babbitt's ideas and mixed color therapy with psychometry and spiritualism.
The Buddhist monk Bhante Dharmawara was a notable advocate of color therapy who promoted the use of green, blue, and yellow for health. Other notable advocates include Anthroposophist Theo Gimbel, who authored many books on the subject and founded the Hygeia Institute for Colour Therapy in 1968.
=== Dinshah P. Ghadiali ===
In 1933, Indian scientist Dinshah P. Ghadiali published The Spectro Chromemetry Encyclopaedia, a work on color therapy. Ghadiali claimed to have discovered why and how the different colored rays have various therapeutic effects on organisms. He believed that colors represent chemical potencies in higher octaves of vibration, and for each organism and system of the body, there is a particular color that stimulates and another that inhibits the work of that organ or system. He also thought that, by knowing the action of the different colors upon the different organs and systems of the body, one can apply the correct color that will tend to balance the action of any organ or system that has become abnormal in its function or condition. The American Medical Association published refutations of Ghadiali's color therapy claims. In 1958, the Food and Drug Administration (FDA) facilitated a permanent injunction against Ghadiali's Visible Spectrum Research Institute.
Ghadiali's son, Darius Dinshah, continues to provide information about color therapy via his Dinshah Health Society, a nonprofit organization dedicated to advancing non-pharmaceutical home color therapy, and his book Let There Be Light.
== Conceptual basis ==
Practitioners of ayurvedic medicine believe the body has seven "chakras", which some claim are 'spiritual centers', and are thought to be located along the spine. New Age thought associates each of the chakras with a single color of the visible light spectrum, along with a function and organ or bodily system. According to this view, the chakras can become imbalanced and result in physical and mental diseases, but application of the appropriate color can allegedly correct such imbalances.
== Scientific rejection ==
Chromotherapy is a popular pseudoscience. Its practice is regarded by health experts and historians as a form of quackery.
According to a book published by the American Cancer Society, "available scientific evidence does not support claims that alternative uses of light or color therapy are effective in treating cancer or other illnesses". Regarding Dinshah Ghadiali's work, science writer Martin Gardner had described him as "perhaps the greatest quack of them all". According to Gardner, photographs of Ghadiali at work in his laboratory are "indistinguishable from stills of a grade D movie about a mad scientist".
Historian Deborah Ascher Barnstone has noted that chromotherapy is "distinct from scientifically verified light treatments such as neonatal jaundice treatment. As, unlike chromotherapy, the light used in such therapies, whether scientifically proven or not, was not always colored, their particulars are not relevant in this context."
Photobiology, the term for the scientific study of the effects of light on living tissue, has sometimes been used instead of the term chromotherapy in an effort to distance it from its roots in Victorian mysticism and to strip it of its associations with symbolism and magic. Light therapy is a specific treatment approach using high intensity light to treat specific sleep, skin, and mood disorders.
A review of the existing research on chromotherapy found that there is no evidence to support a causal link between specific colors to health outcomes, there is not enough evidence to support a causal link between specific colors and emotional or mental states, and there is no research to suggest there exists one-to-one relationships between specific colors and emotions.
Chromotherapy has been accused of oversimplifying psychological responses to colors, making sweeping statements based on myths or beliefs that lack empirical support. Guidelines for chromotherapy lack consistency and appear to be subjective judgements that have inconclusive and nonspecific applicability in healthcare systems. While twelve colors have been reported as beneficial for health and well-being, a rigorous definition of each of these colors has yet to be provided, making it impossible to know if all color therapists are using the same wavelengths for these colors.
More recently, concern regarding the theory has questioned the risks associated with the emergence of light-emitting diode (LED) based lamps that have been created for use in chromotherapy. These lamps are classified as low risk for exposure and do not require any warnings to accompany the products. However, certain chromotherapy procedures require the individual to place the lamps near their eyes, which is not the recommended use for these lights and may alter the exposure duration to a level that can cause risk of retinal damage. With no consensus or regulation regarding how these products are to be used and whether eyewear is required, this treatment puts participants at risk for serious eye damage.
== See also ==
Colorpuncture
List of ineffective cancer treatments
List of topics characterized as pseudoscience
== References ==
== Further reading ==
Edwin Dwight Babbitt. (1886). The Principles of Light and Color. East Orange, New Jersey.
Martin Gardner. (1957). Fads and Fallacies in the Name of Science. Dover Publications. ISBN 0-486-20394-8
== External links ==
Color+Therapy at the U.S. National Library of Medicine Medical Subject Headings (MeSH) | Wikipedia/Chromotherapy |
The Skeptic Encyclopedia of Pseudoscience is a two-volume collection of articles that discuss the Skeptics Society's scientific findings of investigations into pseudoscientific and supernatural claims. The editor, Michael Shermer, director of the Skeptics Society, has compiled articles originally published in Skeptic magazine with some conceptual overviews and historical documents to create this encyclopedia. It was published by ABC-CLIO in 2002.
== About the editor ==
Michael Shermer is an American science writer and science historian. He gained Bachelor's and master's degrees in psychology before completing a PhD in the history of science. The author of more than 18 books on skepticism and science, Shermer is the founder of The Skeptics Society—which began in Los Angeles but now has an international membership—and the editor of its magazine Skeptic. Between April 2001 to January 2019, he was a monthly contributor to Scientific American magazine with a column called Skeptic.
Shermer regularly engages in debates on a variety of topics, in which he emphasises the application of scientific skepticism to combat pseudoscience. Shermer was the producer and co-host of the 13-hour Fox Family television series "Exploring the Unknown" which was broadcast in 1999. He is also a scientific advisor to the American Council on Science and Health (ACSH).
== About the contributors ==
Each of the contributing authors is listed alphabetically followed by a paragraph listing which sections of the encyclopedia they have contributed to and their academic expertise and field of interest, as it relates to pseudoscience. Among them are Massimo Pigliucci and James Randi.
== Overview ==
This two-volume work provides a broad introduction to the most prominent pseudoscientific claims made in the name of science. Covering the popular, the academic, and the bizarre, the encyclopedia includes topics from alien abductions to the Bermuda Triangle, crop circles, Feng Shui, and near-death experiences.
It is organised into five sections:
The first is titled ‘Important pseudoscientific concepts’, which is an alphabetically arranged section of 59 subject analyses conducted by scientists and researchers, exploring alternative medicine, astrology, handwriting analysis, hypnosis, reincarnation, séances, spiritualism, UFOs, witchcraft, etc.
The second section is ‘Investigations from the Skeptic magazine’ which as it suggests are deeper analyses of selected subjects, based on 23 investigations from the magazine. More in-depth than the previous section, it includes what Shermer refers to as “…several critical pieces on the pseudoscience often found in psychology and psychotherapy”.
Part three contains case studies: thirteen in-depth analyses of specific studies originally conducted for Skeptic magazine and used as part of the larger phenomena under investigation. For example, three articles are devoted to recovered memory therapy and false memory syndrome. One is from a psychiatrist's perspective, one from a patient's perspective, and one from a father's perspective. The topics of the case studies range from police ‘psychics’ to the ‘medical intuitive’ Carolyn Myss. The aim is to give the reader a complete analysis of a subject. Indeed, in the introduction to the book Shermer says that he expects that this section could be used by students, journalists and science professionals as resource for conducting background research.
In part four, there are 12 articles originally published in Skeptic described as a “debate between experts”, on such topics as ‘memes’ and ‘evolutionary psychology’. Shermer claims that this is “…the most original section ever compiled in an encyclopedia in the form of a “pro and con” debate between experts, allowing readers to judge for themselves by hearing both sides of an issue.”
Part five is titled ‘Historical documents’ and includes five classic works in the history of science and pseudoscience, such as the speech that William Jennings Bryan never delivered in the Scopes trial, and the first scientific and skeptical investigation of a paranormal/spiritual phenomenon (mesmerism) by Benjamin Franklin and Antoine Lavoisier.
== Quotes from the book ==
“If there is an underlying theme in this encyclopedia… it is that science is an exquisite blend of data and theory, facts and hypotheses, observations and views. If we conceive of science as a fluid and dynamic way of thinking instead of a staid and dogmatic body of knowledge, it is clear that the data/theory stratum runs throughout the archaeology of human knowledge and is an inexorable part of the scientific process. We can no more expunge from ourselves all biases and preferences than we can find a truly objective Archimedean point—a god’s-eye view—of the human condition. We are, after all, humans, not gods.”
“What we hope to provide in this encyclopedia is a thorough, objective, and balanced analysis of the most prominent scientific and pseudoscientific controversies made in the name of science, mixing both facts and theory.”
“The encyclopedia entries are written at a level appropriate for high school and college students conducting research in science and pseudoscience, members of the media looking for a balanced treatment of a subject, and those in the general public who desire a highly readable yet trustworthy resource…”
“…members of the media desperately need a reference resource in order to quickly get their minds around a subject, to book guests on both sides of an issue in order to properly set up a debate, and to get “just the facts” needed for the sound-bite story that is often demanded in the hectic world of journalism.”
“…most entries offer a respectable bibliography of the best sources on that subject from both the skeptics’ and the believers’ perspectives, allowing readers to conduct additional research on their own after learning what the encyclopedia’s expert author has had to say on the subject.”
== Reception ==
Tom Gilson in Against the Grain has some positive comments about the encyclopedia:
"[T]he treatment afforded the topics covered in this encyclopedia is serious ... The Skeptic Encyclopedia of Pseudoscience is one of those sets in which the fascination value may equal its reference use ... without a doubt, many people are captivated with the issues discussed in this work." However, he also is of the opinion that the final section is too brief and should be either extended or removed. Gilson questions the price of the volumes, given that “…at least half of the content is reprinted from Skeptic Magazine.” He does however recognise that “The contributors are fully identified and many are academics with advanced degrees.”
The American Reference Books Annual says that: "A careful reading ... should be required of all who wish to get a university degree ... In the Internet age ... people ... should make every effort toward two goals: To spread good scientific methods for evaluating truth claims, and to help nurture enlightened traditional worldviews. ... This set does much in the direction of achieving the first goal."
== See also ==
Scientific skepticism
Skeptic's Dictionary
An Encyclopedia of Claims, Frauds, and Hoaxes of the Occult and Supernatural
== References ==
== External links ==
The Skeptic Encyclopedia of Pseudoscience
ABC-CLIO listing: The Skeptic Encyclopedia of Pseudoscience' | Wikipedia/The_Skeptic_Encyclopedia_of_Pseudoscience |
Uncertainty and Quality in Science for Policy is a 1990 book by Silvio Funtowicz and Jerome Ravetz, in which the authors explain the notational system NUSAP (numeral, unit, spread, assessment, pedigree) and applies it to several examples from the environmental sciences. The work is considered foundational to the development of post-normal science.
== Content ==
This work, written by the fathers of post-normal science, discusses the use of science for policy and its problems. The book emphasizes the need for craft skills with numbers – not only in statistics but also in cost-benefit analysis, and on the need of specific skills for policy-related research. It introduces for the first time NUSAP, a new notational system for the management of uncertainty and quality in quantitative information, and presents examples of its application to radiological hazards, the valuation of ecosystems, and to energy technologies.
This work is one of the most quoted in the field of science and technology studies - see also Science, technology and society (STS), especially relation to the issue of "democratization of expertise". For Carrozza (2015) and Gooday (2006) this work, together with Ravetz's Scientific Knowledge and Its Social Problems (1971) constitutes the bedrock for the conceptualization of post-normal science in the first half of the 1990s.
== References ==
== External links ==
Related material
Book's page at Google books | Wikipedia/Uncertainty_and_Quality_in_Science_for_Policy |
Conspiracy theories alleging that governments are using endocrine disrupting chemical pollutants in the water supply to create an alleged increase in the lesbian, gay, bisexual, transgender or queer (LGBTQ) population were popularized in the 2010s. Most notably, American conspiracy theorist Alex Jones cited research on the effects of atrazine on frogs, which can induce spontaneous sex change or hermaphroditism, to claim that the U.S. government was "putting chemicals in the water that turn the friggin’ frogs gay" as part of a "chemical warfare operation" to increase homosexuality and suppress birth rates. Certain species of frogs however, can spontaneously change sex in non-polluted waterways in response to changes in temperature.
In other animals, exposure to endocrine disruptors during gestation can interfere with prenatal hormones, and consequently the sex differentiation of the brains of their offspring. This has led some researchers to speculate about exposure to endocrine disruptors during human pregnancy, and if it has an effect on later sexual orientation or gender identity of offspring. This hypothesis requires further research.
== History ==
Animal testing in the 2000s suggested that the herbicide atrazine, an endocrine disruptor, may have a feminizing effect on male frogs causing them to become hermaphrodites. Other research failed to reproduce these results in frogs, though reports of reproductive impact has been reported for other animals, and a meta-analysis conducted in 2010 on selected amphibians and freshwater fish showed sublethal reproductive effects at ecologically relevant concentrations. Reviewing 19 studies in total, the United States Environmental Protection Agency concluded in 2013 that atrazine has no consistent effects on development in amphibians.
According to Lambert and Packer:
A direct link between EDCs and sex-reversed frogs has been observed only in the laboratory, not in the wild. What’s causing sex reversal in these wild frog populations is not yet clear, but our latest data suggest that natural temperature variation, occurring independently of urbanization or climate change, may be a catalyst.
In 2015, American conspiracy theorist and radio personality Alex Jones claimed that atrazine had caused a majority of frogs in the US to become homosexual, and that the US government was waging a "chemical warfare operation" to increase rates of homosexuality and decrease birth rates. This claim goes far beyond what was reported in the scientific literature. A quote from Jones's monologue, "I don't like 'em putting chemicals in the water that turn the friggin' frogs gay!" subsequently became an internet meme.
The idea of a link between atrazine and sexual development was later revived by American environmental lawyer and anti-vaccine activist Robert F. Kennedy Jr., during his 2024 presidential campaign. In various podcast appearances, Kennedy claimed that atrazine contamination was causing widespread delayed puberty or precocious puberty in the Midwest, and speculated that it was causing "sexual confusion" and "gender confusion" in children. Kennedy's theory was criticized in various popular media outlets.
Scientific consensus, as summarized in a 2016 review in Psychological Science in the Public Interest, is that there is "no persuasive evidence that the rate of same-sex attraction has varied much across time or place". In contrast to claims about chemicals in the water, the effects of hormones on sexual orientation appear to occur at the prenatal stage, during organization of the brain. Endocrine disruptor exposure during fetal development has been shown to affect sexual differentiation of the brain in animals, however any effect on human sexual orientation or gender identity requires further research.
== See also ==
== References ==
== External links ==
"'They're Turning the Frogs Gay': the Psychology Behind Internet Conspiracy Theories – New Statesman
Weed Killer Makes Male Frogs Lay Eggs - National Geographic | Wikipedia/LGBTQ_chemicals_conspiracy_theory |
Energy medicine is a branch of alternative medicine based on a pseudo-scientific belief that healers can channel "healing energy" into patients and effect positive results. The field is defined by shared beliefs and practices relating to mysticism and esotericism in the wider alternative medicine sphere rather than any unified terminology, leading to terms such as energy healing, vibrational medicine, and similar terms being used synonymously. In most cases, no empirically measurable "energy" is involved: the term refers instead to so-called subtle energy. Practitioners may classify their practice as hands-on, hands-off, or distant, wherein the patient and healer are in different locations. Many approaches to energy healing exist: for example, "biofield energy healing", "spiritual healing", "contact healing", "distant healing", therapeutic touch, Reiki, and Qigong.
Reviews of the scientific literature on energy healing have concluded that no evidence supports its clinical use. The theoretical basis of energy healing has been criticised as implausible; research and reviews supportive of energy medicine have been faulted for containing methodological flaws and selection bias, and positive therapeutic results have been determined to result from known psychological mechanisms, such as the placebo effect. Some claims of those purveying "energy medicine" devices are known to be fraudulent, and their marketing practices have drawn law-enforcement action in the U.S.
== History ==
History records the repeated association or exploitation of scientific inventions by individuals claiming that newly discovered science could help people to heal. In the 19th century, electricity and magnetism were in the "borderlands" of science, and electrical quackery became rife. These concepts continue to inspire writers in the New Age movement. In the early 20th century, health claims for radio-active materials put lives at risk; recently, quantum mechanics and grand unification theory have provided similar opportunities for commercial exploitation. Thousands of devices claiming to heal via putative or veritable energy are used worldwide. Many are illegal or dangerous and are marketed with false or unproven claims. Several of these devices have been banned.
Reliance on spiritual and energetic healing is associated with serious harm or death when patients delay or forego medical treatment.
== Classification ==
The term "energy medicine" has been in general use since the founding of the non-profit International Society for the Study of Subtle Energies and Energy Medicine in the 1980s. Guides are available for practitioners, and other books aim to provide a theoretical basis and evidence for the practice. Energy medicine often proposes that imbalances in the body's "energy field" result in illness, and that by rebalancing the body's energy field, health can be restored. Some modalities describe treatments as ridding the body of negative energies or blockages in 'mind'; illness or episodes of ill health after a treatment are referred to as a 'release' or letting go of a 'contraction' in the body-mind. Usually, a practitioner will then recommend further treatments for complete healing.
The US-based National Center for Complementary and Integrative Health (NCCIH) distinguishes between health care involving scientifically observable energy, which it calls "Veritable Energy Medicine", and health care methods that invoke physically undetectable or unverifiable "energies", which it calls "Putative Energy Medicine":
Types of "veritable energy medicine" include magnet therapy, colorpuncture, and light therapy. Medical techniques involving the use of electromagnetic radiation (e.g., radiation therapy or magnetic resonance imaging) are not considered "energy medicine" in the terms of alternative medicine.
Types of "putative energy medicine" include biofield energy healing therapies that are claimed to direct or modulate "energies" to allow healing in the patient. This includes spiritual healing, psychic healing, therapeutic touch, healing touch, Hands of light, Esoteric healing, Magnetic healing (now a historical term not to be confused with magnet therapy), Qigong healing, Reiki, crystal healing, distant healing, intercessory prayer, and similar modalities. Concepts such as Qi (Chi), Prana, Innate Intelligence, Mana, Pneuma, vital fluid, Odic force, and orgone are among the many terms that have been used to describe these putative energy fields. This category does not include acupuncture, Ayurvedic medicine, chiropractic, moxibustion and other modalities where a physical intervention is used to manipulate a putative energy.
Polarity therapy founded by Randolph Stone is a kind of energy medicine based on the belief that a person's health is subject to positive and negative charges in their electromagnetic field. It has been promoted as capable of curing many human ailments ranging from muscular tightness to cancer; however, according to the American Cancer Society, "available scientific evidence does not support claims that polarity therapy is effective in treating cancer or any other disease."
== Beliefs ==
There are various schools of energy healing, including biofield energy healing, spiritual healing, contact healing, distant healing, Pranic Healing, therapeutic touch, Reiki, and Qigong among others.
Spiritual healing occurs largely among practitioners who do not see traditional religious faith as a prerequisite for effecting cures. Faith healing by contrast takes place within a traditional or non-denominational religious context such as with some televangelists. The Buddha is often quoted by practitioners of energy medicine, but he did not practise "hands on or off" healing.
Energy healing techniques such as therapeutic touch have found recognition in the nursing profession. In 2005–2006, the North American Nursing Diagnosis Association approved the diagnosis of "energy field disturbance" in patients, reflective of what has been variously called a "postmodern" or "anti-scientific" approach to nursing care. This approach has been strongly criticised.
Believers in these techniques have proposed quantum mystical invocations of non-locality to try to explain distant healing. They have also proposed that healers act as a channel passing on a kind of bioelectromagnetism which shares similarities to vitalistic pseudosciences such as orgone or qi. Writing in the Journal of Bodywork and Movement Therapies, James Oschman introduced the concept of healer-sourced electromagnetic fields which change in frequency. Oschman believes that "healing energy" derives from electromagnetic frequencies generated by a medical device, projected from the hands of the healer, or by electrons acting as antioxidants. Beverly Rubik, in an article in the Journal of Alternative and Complementary Medicine, justified her belief with references to biophysical systems theory, bioelectromagnetics, and chaos theory that provide her with a "...scientific foundation for the biofield..." Drew Leder remarked in a paper in the same journal that such ideas were attempts to "make sense of, interpret, and explore 'psi' and distant healing." and that "such physics-based models are not presented as explanatory but rather as suggestive."
Physicists and sceptics criticise these explanations as pseudophysics – a branch of pseudoscience which explains magical thinking by using irrelevant jargon from modern physics to exploit scientific illiteracy and to impress the unsophisticated.
Indeed, even enthusiastic supporters of energy healing say that "there are only very tenuous theoretical foundations underlying [spiritual] healing".
== Scientific investigations ==
=== Distant healing ===
A systematic review of 23 trials of distant healing published in 2000 did not draw definitive conclusions because of the methodological limitations among the studies. In 2001 the lead author of that study, Edzard Ernst, published a primer on complementary therapies in cancer care in which he explained that though "about half of these trials suggested that healing is effective", the evidence was "highly conflicting" and that "methodological shortcomings prevented firm conclusions." He concluded that "as long as it is not used as an alternative to effective therapies, spiritual healing should be virtually devoid of risks." A 2001 randomised clinical trial by the same group found no statistically significant difference on chronic pain between distance healers and "simulated healers". A 2003 review by Ernst updating previous work concluded that the weight of evidence had shifted against the use of distant healing, and that it can be associated with adverse effects."
=== Contact healing ===
A 2001 randomised clinical trial randomly assigned 120 patients with chronic pain to either healers or "simulated healers", but could not demonstrate efficacy for either distance or face-to-face healing. A systematic review in 2008 concluded that the evidence for a specific effect of spiritual healing on relieving neuropathic or neuralgic pain was not convincing. In their 2008 book Trick or Treatment, Simon Singh and Edzard Ernst concluded that "spiritual healing is biologically implausible and its effects rely on a placebo response. At best, it may offer comfort; at worst, it can result in charlatans taking money from patients with serious conditions who require urgent conventional medicine."
=== Evidence base ===
Alternative medicine researcher Edzard Ernst has said that although an initial review of pre-1999 distant healing trials highlighted 57% of trials as showing positive results. Later reviews of non-randomised and randomised clinical trials conducted between 2000 and 2002 led to the conclusion that "the majority of the rigorous trials do not support the hypothesis that distant healing has specific therapeutic effects." Ernst described the evidence base for healing practices to be "increasingly negative". Many of the reviews were also under suspicion for fabricated data, lack of transparency, and scientific misconduct. He concluded that "[s]piritual healing continues to be promoted despite the absence of biological plausibility or convincing clinical evidence ... that these methods work therapeutically and plenty to demonstrate that they do not." A 2014 study of energy healing for colorectal cancer patients showed no improvement in quality of life, depressive symptoms, mood, or sleep quality.
== Earthing ==
The Earthing Institute gathers researchers and therapists who believe that to maintain or regain good health, direct contact with Earth by removing floors, carpets, and especially shoes is necessary. Walking barefoot and sleeping on the ground are conceived as useful tools for achieving the "earthing" (or "grounding") of the body. It is claimed that thanks to earthing one would benefit from the "extraordinary healing power" of Nature through the transferral of electrons from the Earth's surface to the body: "a primordial and naturally stabilized electric reference point for all body biological circuits is created". According to its practitioners, Earthing has preventive and curative effects on chronic inflammation, aging-related disorders, cardiovascular diseases, diabetes, arthritis, autoimmune disorders, cancer, and even depression and autism spectrum disorders.
The concept of earthing has been criticized as pseudoscience by skeptics and the medical community. A review of the available literature on the subject was written by several people that are financially tied to the company espousing the practice of earthing. Steven Novella referred to the work as "typical of the kind of worthless studies designed to generate false positives—the kind of in-house studies that companies sometimes use so that they can claim their products are clinically proven."
== Bioresonance therapy ==
Bioresonance therapy (including MORA therapy and BICOM) is a pseudoscientific medical practice in which it is proposed that electromagnetic waves can be used to diagnose and treat human illness.
=== History and method ===
Bioresonance therapy was invented (in Germany) in 1977 by Franz Morell and his son-in-law, engineer Erich Rasche. Initially, they marketed it as "MORA-Therapie", for MOrell and RAsche. Some of the machines contain an electronic circuit measuring skin-resistance, akin to the E-meter used by Scientology, which the bioresonance creators sought to improve; Franz Morell had links with Scientology.
Practitioners claim to be able to detect a variety of diseases and addictions. Some practitioners also claim they can treat diseases using this therapy without drugs, by stimulating a change of "bioresonance" in the cells, and reversing the change caused by the disease. The devices would need to isolate and pinpoint pathogens' responses from the mixture of responses the device receives via the electrodes. These transformed signals transmitted over the same electrodes has a healing effect, claim practitioners.
=== Scientific evaluation ===
Lacking any scientific explanation of how bioresonance therapy might work, researchers have classified bioresonance therapy as pseudoscience. Some studies did not show effects above that of the placebo effect. WebMD states: "There is no reliable scientific evidence that bioresonance is an accurate indicator of medical conditions or disease or an effective treatment for any condition."
Proven cases of online fraud have occurred, with a practitioner making false claims that he could cure cancer, and that his clients did not need to follow the chemotherapy or surgery recommended by medical doctors, which can be life-saving. Ben Goldacre ridiculed the BBC when it reported as fact a clinic's claim that the treatment could stop 70% of clients smoking, a better result than any conventional therapy.
In the United States of America, the U.S. Food and Drug Administration (FDA) classifies "devices that use resistance measurements to diagnose and treat various diseases" as Class III devices, which require FDA approval before marketing. The FDA has banned some of these devices from the US market, and has prosecuted many sellers of electrical devices for making false claims of health benefits.
According to Quackwatch, the therapy is completely nonsensical and the proposed mechanism of action impossible.
== Explanations for positive reports ==
There are several, primarily psychological, explanations for positive reports after energy therapy, including placebo effects, spontaneous remission, and cognitive dissonance. A 2009 review found that the "small successes" reported for two therapies collectively marketed as "energy psychology" (Emotional Freedom Techniques and Tapas Acupressure Technique) "are potentially attributable to well-known cognitive and behavioral techniques that are included with the energy manipulation." The report concluded that "[p]sychologists and researchers should be wary of using such techniques, and make efforts to inform the public about the ill effects of therapies that advertise miraculous claims."
There are primarily two explanations for anecdotes of cures or improvements, relieving any need to appeal to the supernatural. The first is post hoc ergo propter hoc, meaning that a genuine improvement or spontaneous remission may have been experienced coincidental with but independent from anything the healer or patient did or said. These patients would have improved just as well even had they done nothing. The second is the placebo effect, through which a person may experience genuine pain relief and other symptomatic alleviation. In this case, the patient genuinely has been helped by the healer – not through any mysterious or numinous function, but by the power of their own belief that they would be healed. In both cases, the patient may experience a real reduction in symptoms, though in neither case has anything miraculous or inexplicable occurred. Both cases are strictly limited to the body's natural abilities.
Positive findings from research studies can also result from such psychological mechanisms, or as a result of experimenter bias, methodological flaws such as lack of blinding, or publication bias; positive reviews of the scientific literature may show selection bias, in that they omit key studies that do not agree with the author's position. All of these factors must be considered when evaluating claims.
== See also ==
== References ==
== Further reading ==
Bioresonance therapy
Hörner M, Bioresonanz: "Anspruch einer Methode und Ergebnis einer technischen Überprüfung", Allergologie, 1995, 18 S. 302
Kofler H, "Bioresonanz bei Pollinose. Eine vergleichende Untersuchung zur diagnostischen und therapeutischen Wertigkeit", Allergologie 1996, 19, p. 114
Niggemann B, "Unkonventionelle Verfahren in der Allergologie. Kontroverse oder Alternative?" Allergologie 2002, 25, p. 34
oracknows (May 16, 2008). "Your Friday Dose of Woo: MORA the same ol' same ol' woo". ScienceBlogs. Retrieved February 22, 2014.
Schultze-Werninghaus, "paramedizinische Verfahren: Bioresonanzdiagnostik und -Therapie", Allergo J, 1993, 2, pp. 40–2
Wandtke F, "Bioresonanz-Allergietest versus pricktest und RAST", Allergologie 1993, 16, p. 144
Wille A, "Bioresonance therapy (biophysical information therapy) in stuttering children", Forsch Komplementärmed, 1999 Feb; 6 Suppl 1:50–2
== External links ==
NIH Energy medicine: overview. Archived May 22, 2016, at the Portuguese Web Archive
Miracle Machines: The 21st-Century Snake Oil: a Seattle Times series on fraudulent energy medicine devices
What Is Complementary and Alternative Medicine? "biofield".
An overview of the pseudoscience behind "bioresonance therapy": "Electrodiagnostic" Devices | Wikipedia/Energy_medicine |
A polygraph, often incorrectly referred to as a lie detector test, is a pseudoscientific device or procedure that measures and records several physiological indicators such as blood pressure, pulse, respiration, and skin conductivity while a person is asked and answers a series of questions. The belief underpinning the use of the polygraph is that deceptive answers will produce physiological responses that can be differentiated from those associated with non-deceptive answers; however, there are no specific physiological reactions associated with lying, making it difficult to identify factors that separate those who are lying from those who are telling the truth.
In some countries, polygraphs are used as an interrogation tool with criminal suspects or candidates for sensitive public or private sector employment. Some United States law enforcement and federal government agencies, as well as many police departments, use polygraph examinations to interrogate suspects and screen new employees. Within the US federal government, a polygraph examination is also referred to as a psychophysiological detection of deception examination.
Assessments of polygraphy by scientific and government bodies generally suggest that polygraphs are highly inaccurate, may easily be defeated by countermeasures, and are an imperfect or invalid means of assessing truthfulness. A comprehensive 2003 review by the National Academy of Sciences of existing research concluded that there was "little basis for the expectation that a polygraph test could have extremely high accuracy." The American Psychological Association states that "most psychologists agree that there is little evidence that polygraph tests can accurately detect lies." For this reason, the use of polygraphs to detect lies is considered a form of pseudoscience, or junk science.
== Testing procedure ==
The examiner typically begins polygraph test sessions with a pre-test interview to gain some preliminary information which will later be used to develop diagnostic questions. Then the tester will explain how the polygraph is supposed to work, emphasizing that it can detect lies and that it is important to answer truthfully. Then a "stim test" is often conducted: the subject is asked to deliberately lie and then the tester reports that he was able to detect this lie. Guilty subjects are likely to become more anxious when they are reminded of the test's validity. However, there are risks of innocent subjects being equally or more anxious than the guilty. Then the actual test starts. Some of the questions asked are "irrelevant" ("Is your name Fred?"), others are "diagnostic" questions, and the remainder are the "relevant questions" that the tester is really interested in. The different types of questions alternate. The test is passed if the physiological responses to the diagnostic questions are larger than those during the relevant questions.
Criticisms have been given regarding the validity of the administration of the Control Question Technique. The CQT may be vulnerable to being conducted in an interrogation-like fashion. This kind of interrogation style would elicit a nervous response from innocent and guilty suspects alike. There are several other ways of administering the questions.
An alternative is the Guilty Knowledge Test (GKT), or the Concealed Information Test, which is used in Japan. The administration of this test is given to prevent potential errors that may arise from the questioning style. The test is usually conducted by a tester with no knowledge of the crime or circumstances in question. The administrator tests the participant on their knowledge of the crime that would not be known to an innocent person. For example: "Was the crime committed with a .45 or a 9 mm?" The questions are in multiple choice and the participant is rated on how they react to the correct answer. If they react strongly to the guilty information, then proponents of the test believe that it is likely that they know facts relevant to the case. This administration is considered more valid by supporters of the test because it contains many safeguards to avoid the risk of the administrator influencing the results.
== Effectiveness ==
Assessments of polygraphy by scientific and government bodies generally suggest that polygraphs are inaccurate, may be defeated by countermeasures, and are an imperfect or invalid means of assessing truthfulness. Despite claims that polygraph tests are between 80% and 90% accurate by advocates, the National Research Council has found no evidence of effectiveness. In particular, studies have indicated that the relevant–irrelevant questioning technique is not ideal, as many innocent subjects exert a heightened physiological reaction to the crime-relevant questions. The American Psychological Association states "Most psychologists agree that there is little evidence that polygraph tests can accurately detect lies."
In 2002, a review by the National Research Council found that, in populations "untrained in countermeasures, specific-incident polygraph tests can discriminate lying from truth telling at rates well above chance, though well below perfection". The review also warns against generalization from these findings to justify the use of polygraphs—"polygraph accuracy for screening purposes is almost certainly lower than what can be achieved by specific-incident polygraph tests in the field"—and notes some examinees may be able to take countermeasures to produce deceptive results.
In the 1998 US Supreme Court case United States v. Scheffer, the majority stated that "There is simply no consensus that polygraph evidence is reliable [...] Unlike other expert witnesses who testify about factual matters outside the jurors' knowledge, such as the analysis of fingerprints, ballistics, or DNA found at a crime scene, a polygraph expert can supply the jury only with another opinion." The Supreme Court summarized their findings by stating that the use of polygraph was "little better than could be obtained by the toss of a coin." In 2005, the 11th Circuit Court of Appeals stated that "polygraphy did not enjoy general acceptance from the scientific community". In 2001, William Iacono, Professor of Psychology and Neuroscience at the University of Minnesota, concluded:
Although the CQT [Control Question Test] may be useful as an investigative aid and tool to induce confessions, it does not pass muster as a scientifically credible test. CQT theory is based on naive, implausible assumptions indicating (a) that it is biased against innocent individuals and (b) that it can be beaten simply by artificially augmenting responses to control questions. Although it is not possible to adequately assess the error rate of the CQT, both of these conclusions are supported by published research findings in the best social science journals (Honts et al., 1994; Horvath, 1977; Kleinmuntz & Szucko, 1984; Patrick & Iacono, 1991). Although defense attorneys often attempt to have the results of friendly CQTs admitted as evidence in court, there is no evidence supporting their validity and ample reason to doubt it. Members of scientific organizations who have the requisite background to evaluate the CQT are overwhelmingly skeptical of the claims made by polygraph proponents.
Polygraphs measure arousal, which can be affected by anxiety, anxiety disorders such as post-traumatic stress disorder (PTSD), nervousness, fear, confusion, hypoglycemia, psychosis, depression, substance-induced states (nicotine, stimulants), substance-withdrawal state (alcohol withdrawal) or other emotions; polygraphs do not measure "lies". A polygraph cannot differentiate anxiety caused by dishonesty and anxiety caused by something else.
Since the polygraph does not measure lying, the Silent Talker Lie Detector inventors expected that adding a camera to film microexpressions would improve the accuracy of the evaluators. This did not happen in practice according to an article in the Intercept.
=== US Congress Office of Technology Assessment ===
In 1983, the US Congress Office of Technology Assessment published a review of the technology and found that
there is at present only limited scientific evidence for establishing the validity of polygraph testing. Even where the evidence seems to indicate that polygraph testing detects deceptive subjects better than chance, significant error rates are possible, and examiner and examinee differences and the use of countermeasures may further affect validity.
=== National Academy of Sciences ===
In 2003, the National Academy of Sciences (NAS) issued a report entitled "The Polygraph and Lie Detection". The NAS found that "overall, the evidence is scanty and scientifically weak", concluding that 57 of the approximately 80 research studies that the American Polygraph Association relied on to reach their conclusions were significantly flawed. These studies did show that specific-incident polygraph testing, in a person untrained in counter-measures, could discern the truth at "a level greater than chance, yet short of perfection". However, due to several flaws, the levels of accuracy shown in these studies "are almost certainly higher than actual polygraph accuracy of specific-incident testing in the field". By adding a camera, the Silent Talker Lie Detector attempted to give more data to the evaluator by providing information about microexpressions. However adding the Silent Talker camera did not improve lie detection and was very expensive and cumbersome to include according to an article in the Intercept.
When polygraphs are used as a screening tool (in national security matters and for law enforcement agencies for example) the level of accuracy drops to such a level that "Its accuracy in distinguishing actual or potential security violators from innocent test takers is insufficient to justify reliance on its use in employee security screening in federal agencies." The NAS concluded that the polygraph "may have some utility but that there is "little basis for the expectation that a polygraph test could have extremely high accuracy".
The NAS conclusions paralleled those of the earlier United States Congress Office of Technology Assessment report "Scientific Validity of Polygraph Testing: A Research Review and Evaluation". Similarly, a report to Congress by the Moynihan Commission on Government Secrecy concluded that "The few Government-sponsored scientific research reports on polygraph validity (as opposed to its utility), especially those focusing on the screening of applicants for employment, indicate that the polygraph is neither scientifically valid nor especially effective beyond its ability to generate admissions".
Despite the NAS finding of a "high rate of false positives," failures to expose individuals such as Aldrich Ames and Larry Wu-Tai Chin, and other inabilities to show a scientific justification for the use of the polygraph, it continues to be employed.
== Countermeasures ==
Several proposed countermeasures designed to pass polygraph tests have been described. There are two major types of countermeasures: "general state" (intending to alter the physiological or psychological state of the subject during the test), and "specific point" (intending to alter the physiological or psychological state of the subject at specific periods during the examination, either to increase or decrease responses during critical examination periods).
General state: asked how he passed the polygraph test, Central Intelligence Agency officer turned KGB mole Aldrich Ames explained that he sought advice from his Soviet handler and received the simple instruction to: "Get a good night's sleep, and rest, and go into the test rested and relaxed. Be nice to the polygraph examiner, develop a rapport, and be cooperative and try to maintain your calm". Additionally, Ames explained, "There's no special magic... Confidence is what does it. Confidence and a friendly relationship with the examiner... rapport, where you smile and you make him think that you like him".
Specific point: other suggestions for countermeasures include for the subject to mentally record the control and relevant questions as the examiner reviews them before the interrogation begins. During the interrogation the subject is supposed to carefully control their breathing while answering the relevant questions, and to try to artificially increase their heart rate during the control questions, for example by thinking of something scary or exciting, or by pricking themselves with a pointed object concealed somewhere on the body. In this way the results will not show a significant reaction to any of the relevant questions.
== Use ==
Law enforcement agencies and intelligence agencies in the United States are by far the biggest users of polygraph technology. In the United States alone most federal law enforcement agencies either employ their own polygraph examiners or use the services of examiners employed in other agencies. In 1978 Richard Helms, the eighth Director of Central Intelligence, stated:
We discovered there were some Eastern Europeans who could defeat the polygraph at any time. Americans are not very good at it, because we are raised to tell the truth and when we lie it is easy to tell we are lying. But we find a lot of Europeans and Asiatics can handle that polygraph without a blip, and you know they are lying and you have evidence that they are lying.
Susan McCarthy of Salon said in 2000 that "The polygraph is an American phenomenon, with limited use in a few countries, such as Canada, Israel and Japan."
=== Armenia ===
In Armenia, government administered polygraphs are legal, at least for use in national security investigations. The National Security Service (NSS), Armenia's primary intelligence service, requires polygraph examinations of all new applicants.
=== Australia ===
Polygraph evidence became inadmissible in New South Wales courts under the Lie Detectors Act 1983. Under the same act, it is also illegal to use polygraphs for the purpose of granting employment, insurance, financial accommodation, and several other purposes for which polygraphs may be used in other jurisdictions.
=== Canada ===
In Canada, the 1987 decision of R v Béland, the Supreme Court of Canada rejected the use of polygraph results as evidence in court, finding that they were inadmissible. The polygraph is still used as a tool in the investigation of criminal acts and sometimes employed in the screening of employees for government organizations.
In the province of Ontario, the Employment Standards Act, 2000 prohibits employers from asking or requiring employees to undergo a polygraph test. Police services are permitted use polygraph tests as part of an investigation if the person consents.
=== Europe ===
In a majority of European jurisdictions, polygraphs are generally considered to be unreliable for gathering evidence, and are usually not used by local law enforcement agencies. Polygraph testing is widely seen in Europe to violate the right to remain silent.: 62ff
In England and Wales a polygraph test can be taken, but the results cannot be used in a court of law to prove a case. However, the Offender Management Act 2007 put in place an option to use polygraph tests to monitor serious sex offenders on parole in England and Wales; these tests became compulsory in 2014 for high risk sexual offenders currently on parole in England and Wales.
The Supreme Court of Poland declared on January 29, 2015, that the use of polygraph in interrogation of suspects is forbidden by the Polish Code of Criminal Procedure. Its use might be allowed though if the suspect has been already accused of a crime and if the interrogated person consents of the use of a polygraph. Even then, the use of polygraph can never be used as a substitute of actual evidence.
As of 2017, the justice ministry and Supreme Court of both of the Netherlands and Germany had rejected use of polygraphs.: 62ff
According to the 2017 book Psychology and Law: Bridging the Gap by psychologists David Canter and Rita Žukauskienė Belgium was the European country with the most prevalent use of polygraph testing by police, with about 300 polygraphs carried out each year in the course of police investigations. The results are not considered viable evidence in bench trials, but have been used in jury trials.: 62ff
In Lithuania, "polygraphs have been in use since 1992", with law enforcement utilizing the Event Knowledge Test (a "modification" of the Concealed Information Test) in criminal investigations.
=== India ===
In 2008, an Indian court adopted the Brain Electrical Oscillation Signature Profiling test as evidence to convict a woman who was accused of murdering her fiancé. It was the first time that the result of polygraph was used as evidence in court.
On May 5, 2010, The Supreme Court of India declared use of narcoanalysis, brain mapping and polygraph tests on suspects as illegal and against the constitution if consent is not obtained and forced. Article 20(3) of the Indian Constitution states: "No person accused of any offence shall be compelled to be a witness against himself." Polygraph tests are still legal if the defendant requests one.
=== Israel ===
The Supreme Court of Israel, in Civil Appeal 551/89 (Menora Insurance v. Jacob Sdovnik), ruled that the polygraph has not been recognized as a reliable device. In other decisions, polygraph results were ruled inadmissible in criminal trials. Polygraph results are only admissible in civil trials if the person being tested agrees to it in advance.
=== Philippines ===
The results of polygraph tests are inadmissible in court in the Philippines. The National Bureau of Investigation, however, uses polygraphs in aid of investigation.
=== United States ===
In 2018, Wired magazine reported that an estimated 2.5 million polygraph tests were given each year in the United States, with the majority administered to paramedics, police officers, firefighters, and state troopers. The average cost to administer the test is more than $700 and is part of a $2 billion industry.
In 2007, polygraph testimony was admitted by stipulation in 19 states, and was subject to the discretion of the trial judge in federal court. The use of polygraph in court testimony remains controversial, although it is used extensively in post-conviction supervision, particularly of sex offenders. In Daubert v. Merrell Dow Pharmaceuticals, Inc. (1993), the old Frye standard was lifted and all forensic evidence, including polygraph, had to meet the new Daubert standard in which "underlying reasoning or methodology is scientifically valid and properly can be applied to the facts at issue." While polygraph tests are commonly used in police investigations in the US, no defendant or witness can be forced to undergo the test unless they are under the supervision of the courts. In United States v. Scheffer (1998), the US Supreme Court left it up to individual jurisdictions whether polygraph results could be admitted as evidence in court cases. Nevertheless, it is used extensively by prosecutors, defense attorneys, and law enforcement agencies. In the states of Rhode Island, Massachusetts, Maryland, New Jersey, Oregon, Delaware and Iowa it is illegal for any employer to order a polygraph either as conditions to gain employment, or if an employee has been suspected of wrongdoing. The Employee Polygraph Protection Act of 1988 (EPPA) generally prevents employers from using lie detector tests, either for pre-employment screening or during the course of employment, with certain exemptions. As of 2013, about 70,000 job applicants are polygraphed by the federal government on an annual basis. In the United States, the State of New Mexico admits polygraph testing in front of juries under certain circumstances.
In 2010 the NSA produced a video explaining its polygraph process. The video, ten minutes long, is titled "The Truth About the Polygraph" and was posted to the website of the Defense Security Service. Jeff Stein of The Washington Post said that the video portrays "various applicants, or actors playing them—it’s not clear—describing everything bad they had heard about the test, the implication being that none of it is true." AntiPolygraph.org argues that the NSA-produced video omits some information about the polygraph process; it produced a video responding to the NSA video. George Maschke, the founder of the website, accused the NSA polygraph video of being "Orwellian".
The polygraph was invented in 1921 by John Augustus Larson, a medical student at the University of California, Berkeley and a police officer of the Berkeley Police Department in Berkeley, California. The polygraph was on the Encyclopædia Britannica 2003 list of greatest inventions, described as inventions that "have had profound effects on human life for better or worse." In 2013, the US federal government had begun indicting individuals who stated that they were teaching methods on how to defeat a polygraph test. During one of those investigations, upwards of 30 federal agencies were involved in investigations of almost 5000 people who had various degrees of contact with those being prosecuted or who had purchased books or DVDs on the topic of beating polygraph tests.
== Security clearances ==
In 1995, Harold James Nicholson, a Central Intelligence Agency (CIA) employee later convicted of spying for Russia, had undergone his periodic five-year reinvestigation, in which he showed a strong probability of deception on questions regarding relationships with a foreign intelligence unit. This polygraph test later led to an investigation which resulted in his eventual arrest and conviction. In most cases, however, polygraphs are more of a tool to "scare straight" those who would consider espionage. Jonathan Pollard was advised by his Israeli handlers that he was to resign his job from American intelligence if he was ever told he was subject to a polygraph test. Likewise, John Anthony Walker was advised by his handlers not to engage in espionage until he had been promoted to the highest position for which a polygraph test was not required, to refuse promotion to higher positions for which polygraph tests were required, and to retire when promotion was mandated.
In 1983, CIA employee Edward Lee Howard was dismissed when, during a polygraph screening, he truthfully answered a series of questions admitting to minor crimes such as petty theft and drug abuse. In retaliation for his perceived unjust punishment for minor offenses, he later sold his knowledge of CIA operations to the Soviet Union.
Polygraph tests may not deter espionage. From 1945 to the present, at least six Americans have committed espionage while successfully passing polygraph tests. Notable cases of two men who created a false negative result with the polygraphs were Larry Wu-Tai Chin, who spied for China, and Aldrich Ames, who was given two polygraph examinations while with the CIA, the first in 1986 and the second in 1991, while spying for the Soviet Union/Russia. The CIA reported that he passed both examinations after experiencing initial indications of deception. According to a Senate investigation, an FBI review of the first examination concluded that the indications of deception were never resolved.
Ana Belen Montes, a Cuban spy, passed a counterintelligence scope polygraph test administered by the US Defense Intelligence Agency (DIA) in 1994.
Despite these errors, in August 2008, the DIA announced that it would subject each of its 5,700 prospective and current employees to polygraph testing at least once annually. This expansion of polygraph screening at DIA occurred while DIA polygraph managers ignored documented technical problems discovered in the Lafayette computerized polygraph system. The DIA uses computerized Lafayette polygraph systems for routine counterintelligence testing. The impact of the technical flaws within the Lafayette system on the analysis of recorded physiology and on the final polygraph test evaluation is currently unknown.
In 2012, a McClatchy investigation found that the National Reconnaissance Office was possibly breaching ethical and legal boundaries by encouraging its polygraph examiners to extract personal and private information from US Department of Defense personnel during polygraph tests that purported to be limited in scope to counterintelligence matters. Allegations of abusive polygraph practices were brought forward by former NRO polygraph examiners.
== Alternative tests ==
Most polygraph researchers have focused more on the exam's predictive value on a subject's guilt. However, there have been no empirical theories established to explain how a polygraph measures deception. A 2010 study indicated that functional magnetic resonance imaging (fMRI) may benefit in explaining the psychological correlations of polygraph exams. It could also explain which parts of the brain are active when subjects use artificial memories. Most brain activity occurs in both sides of the prefrontal cortex, which is linked to response inhibition. This indicates that deception may involve inhibition of truthful responses. Some researchers believe that reaction time (RT) based tests may replace polygraphs in concealed information detection. RT based tests differ from polygraphs in stimulus presentation duration and can be conducted without physiological recording as subject response time is measured via computer. However, researchers have found limitations to these tests as subjects voluntarily control their reaction time, deception can still occur within the response deadline, and the test itself lacks physiological recording.
== History ==
Earlier societies utilized elaborate methods of lie detection which mainly involved torture. For instance, in the Middle Ages, boiling water was used to detect liars, as it was believed honest men would withstand it better than liars. Early devices for lie detection include an 1895 invention of Cesare Lombroso used to measure changes in blood pressure for police cases, a 1904 device by Vittorio Benussi used to measure breathing, the Mackenzie-Lewis Polygraph first developed by James Mackenzie in 1906 and an abandoned project by American William Moulton Marston which used blood pressure to examine German prisoners of war (POWs). Marston said he found a strong positive correlation between systolic blood pressure and lying.
Marston wrote a second paper on the concept in 1915, when finishing his undergraduate studies. He entered Harvard Law School and graduated in 1918, re-publishing his earlier work in 1917. Marston's main inspiration for the device was his wife, Elizabeth Holloway Marston. "According to Marston’s son, it was his mother Elizabeth, Marston's wife, who suggested to him that 'When she got mad or excited, her blood pressure seemed to climb'" (Lamb, 2001). Although Elizabeth is not listed as Marston’s collaborator in his early work, Lamb, Matte (1996), and others refer directly and indirectly to Elizabeth's work on her husband's deception research. She also appears in a picture taken in his polygraph laboratory in the 1920s (reproduced in Marston, 1938).
Despite his predecessors' contributions, Marston styled himself the "father of the polygraph". (Today he is often equally or more noted as the creator of the comic book character Wonder Woman and her Lasso of Truth, which can force people to tell the truth.) Marston remained the device's primary advocate, lobbying for its use in the courts. In 1938 he published a book, The Lie Detector Test, wherein he documented the theory and use of the device. In 1938 he appeared in advertising by the Gillette company claiming that the polygraph showed Gillette razors were better than the competition.
A device recording both blood pressure and breathing was invented in 1921 by John Augustus Larson of the University of California and first applied in law enforcement work by the Berkeley Police Department under its nationally renowned police chief August Vollmer. Further work on this device was done by Leonarde Keeler. As Larson's protege, Keeler updated the device by making it portable and added the galvanic skin response to it in 1939. His device was then purchased by the FBI, and served as the prototype of the modern polygraph.
Several devices similar to Keeler's polygraph version included the Berkeley Psychograph, a blood pressure-pulse-respiration recorder developed by C. D. Lee in 1936 and the Darrow Behavior Research Photopolygraph, which was developed and intended solely for behavior research experiments.
A device which recorded muscular activity accompanying changes in blood pressure was developed in 1945 by John E. Reid, who claimed that greater accuracy could be obtained by making these recordings simultaneously with standard blood pressure-pulse-respiration recordings.
== Society and culture ==
=== Portrayals in media ===
Lie detection has a long history in mythology and fairy tales; the polygraph has allowed modern fiction to use a device more easily seen as scientific and plausible. Notable instances of polygraph usage include uses in crime and espionage themed television shows and some daytime television talk shows, cartoons and films. Numerous TV shows have been called Lie Detector or featured the device. The first Lie Detector TV show aired in the 1950s, created and hosted by Ralph Andrews. In the 1960s Andrews produced a series of specials hosted by Melvin Belli. In the 1970s the show was hosted by Jack Anderson. In early 1983 Columbia Pictures Television put on a syndicated series hosted by F. Lee Bailey. In 1998 TV producer Mark Phillips with his Mark Phillips Philms & Telephision put Lie Detector back on the air on the FOX Network—on that program Ed Gelb with host Marcia Clark questioned Mark Fuhrman about the allegation that he "planted the bloody glove". In 2005 Phillips produced Lie Detector as a series for PAX/ION; some of the guests included Paula Jones, Reverend Paul Crouch accuser Lonny Ford, Ben Rowling, Jeff Gannon and Swift Boat Vet, Steve Garner.
In the UK, shows such as The Jeremy Kyle Show used polygraph tests extensively. The show was ultimately canceled when a participant committed suicide shortly after being polygraphed. The guest was slated by Kyle on the show for failing the polygraph, but no other evidence has come forward to prove any guilt. Producers later admitted in the inquiry that they were unsure on how accurate the tests performed were.
In the Fox game show The Moment of Truth, contestants are privately asked personal questions a few days before the show while hooked to a polygraph. On the show they asked the same questions in front of a studio audience and members of their family. In order to advance in the game they must give a "truthful" answer as determined by the previous polygraph exam.
Daytime talk shows, such as Maury Povich and Steve Wilkos, have used polygraphs to supposedly detect deception in interview subjects on their programs that pertain to cheating, child abuse, and theft.
In episode 93 of the US science show MythBusters, the hosts attempted to fool the polygraph by using pain when answering truthfully, in order to test the notion that polygraphs interpret truthful and non-truthful answers as the same. They also attempted to fool the polygraph by thinking pleasant thoughts when lying and thinking stressful thoughts when telling the truth, to try to confuse the machine. However, neither technique was successful for a number of reasons. Michael Martin correctly identified each guilty and innocent subject. Martin suggested that when conducted properly, polygraphs are correct 98% of the time, but no scientific evidence has been offered for this.
The history of the polygraph is the subject of the documentary film The Lie Detector, which first aired on American Experience on January 3, 2023.
=== Hand-held lie detector for US military ===
A hand-held lie detector is being deployed by the US Department of Defense according to a report in 2008 by investigative reporter Bill Dedman of NBC News. The Preliminary Credibility Assessment Screening System, or PCASS, captures less physiological information than a polygraph, and uses an algorithm, not the judgment of a polygraph examiner, to render a decision whether it believes the person is being deceptive or not. The device was first used in Afghanistan by US Army troops. The Department of Defense ordered its use be limited to non-US persons, in overseas locations only.
=== Notable cases ===
Polygraphy has been faulted for failing to trap known spies such as double-agent Aldrich Ames, who passed two polygraph tests while spying for the Soviet Union. Ames failed several tests while at the CIA that were never acted on. Other spies who passed the polygraph include Karl Koecher, Ana Montes, and Leandro Aragoncillo. CIA spy Harold James Nicholson failed his polygraph examinations, which aroused suspicions that led to his eventual arrest. Polygraph examination and background checks failed to detect Nada Nadim Prouty, who was not a spy but was convicted for improperly obtaining US citizenship and using it to obtain a restricted position at the FBI.
The polygraph also failed to catch Gary Ridgway, the "Green River Killer". Another suspect allegedly failed a given lie detector test, whereas Ridgway passed. Ridgway passed a polygraph in 1984; he confessed almost 20 years later when confronted with DNA evidence. Conversely, innocent people have been known to fail polygraph tests. In Wichita, Kansas in 1986, Bill Wegerle was suspected of murdering his wife Vicki Wegerle because he failed two polygraph tests (one administered by the police, the other conducted by an expert that Wegerle had hired), although he was neither arrested nor convicted of her death. In March 2004, evidence surfaced connecting her death to the serial killer known as BTK, and in 2005 DNA evidence from the Wegerle murder confirmed that BTK was Dennis Rader, exonerating Wegerle.
Prolonged polygraph examinations are sometimes used as a tool by which confessions are extracted from a defendant, as in the case of Richard Miller, who was persuaded to confess largely by polygraph results combined with appeals from a religious leader. In the Watts family murders, Christopher Watts failed one such polygraph test and subsequently confessed to murdering his wife. In the 2002 disappearance of seven-year-old Danielle van Dam of San Diego, police suspected neighbor David Westerfield; he became the prime suspect when he allegedly failed a polygraph test.
== See also ==
Bogus pipeline
Cleve Backster
Doug Williams (polygraph critic)
Ecological fallacy
Ronald Pelton
Voice stress analysis
P300 (neuroscience)#Applications
== References ==
== Further reading ==
Aftergood, Steven (2000). "Essays on Science and Society: Polygraph Testing and the DOE National Laboratories". Science. 290 (5493): 939–940. doi:10.1126/science.290.5493.939. PMID 17749189. S2CID 153185280.
Alder, Ken (2007). The Lie Detectors. New York: Free Press. ISBN 978-0-7432-5988-0.
Bunn, Geoffrey C. The Truth Machine: A Social History of the Lie Detector (Johns Hopkins University Press; 2012) 256 pages
Blinkhorn, S. (1988) "Lie Detection as a psychometric procedure" In "The Polygraph Test" (Gale, A. ed. 1988) 29–39.
Cumming, Alfred (Specialist in Intelligence and National Security). "Polygraph Use by the Department of Energy: Issues for Congress." (Archive) Congressional Research Service. February 9, 2009.
Harris, Mark (October 1, 2018). "The Lie Generator: Inside the Black Mirror World of Polygraph Job Screenings". Wired.
Jones, Ishmael (2008). The Human Factor: Inside the CIA's Dysfunctional Intelligence Culture. New York: Encounter Books. ISBN 978-1-59403-382-7.
Lykken, David (1998). A Tremor in the Blood. New York: Plenum Trade. ISBN 978-0-306-45782-1.
Maschke, G.W. & Scalabrini, G.J. (2018) The Lie Behind the Lie Detector. 5th ed. Available on-line at Learn How to Pass (or Beat) a Polygraph Test.
McCarthy, Susan. "Passing the polygraph." Salon. March 2, 2000.
Roese, N. J.; Jamieson, D. W. (1993). "Twenty years of bogus pipeline research: A critical review and meta-analysis". Psychological Bulletin. 114 (2): 363–375. doi:10.1037/0033-2909.114.2.363.
Sullivan, John (2007). Gatekeeper. Potomac Books Inc. ISBN 978-1-59797-045-7.
Taylor, Marisa (Tish Wells contributed). "Feds expand polygraph screening, often seeking intimate facts." McClatchy. December 6, 2012.
Woodrow, Michael J. "The Truth about the Psychophysiological Detection of Deception Examination 3rd Edition" Lulu Press. New York ISBN 978-1-105-89546-3
== External links ==
AntiPolygraph.org Archived 2019-09-05 at the Wayback Machine, a website critical of polygraph
The Polygraph Museum Historical photographs and descriptions of polygraph instruments.
The North American Polygraph and Psychophysiology: Disinterested, Uninterested, and Interested Perspectives by John J. Furedy, International Journal of Psychophysiology, Spring/Summer 1996
Trial By Ordeal? Polygraph Testing In Australia
"Thought Wave Lie Detector Measures Current in Nerves" Popular Mechanics, July 1937
Mikkelson, David (July 11, 2011). "Next case on the Legal Colander". Snopes. | Wikipedia/Polygraph |
A fringe theory is an idea or a viewpoint that differs significantly from the accepted scholarship of the time within its field. Fringe theories include the models and proposals of fringe science, as well as similar ideas in other areas of scholarship, such as the humanities. In a narrower sense, the term fringe theory is commonly used as a pejorative, roughly synonymous with the terms pseudo-scholarship and conspiracy theory. Precise definitions distinguishing widely held viewpoints and unaccepted theories are difficult to construct. Issues of false balance or false equivalence can occur when fringe theories are presented as being equal to widely accepted theories.
== Definitions ==
Fringe theories are ideas which depart significantly from a prevailing or mainstream theory. A fringe theory is neither a majority opinion nor that of a respected minority. In general, the term fringe theory is closer to the popular understanding of the word theory—a hypothesis or a guess or an uncertain idea—than to the concept of an established scientific theory. Although often used in the context of fringe science, fringe theories have been discussed in fields of scholarship, such as Biblical criticism, history, finance, law, medicine, and politics. They even exist in fields of study which are themselves outside the mainstream, such as cryptozoology and parapsychology.
Fringe theories meet with varying levels of academic acceptance. Financial journalist Alexander Davidson characterized fringe theories as "peddled by a small band of staunch supporters," but not necessarily without merit. Daniel N. Robinson described them as occupying "a limbo between the decisive dead end and the ultimately credible productive theory." However, the term is also used pejoratively; advocates of fringe theories are dismissed as cranks or crackpots who are out of touch with reality. In this sense, there is some overlap with other dismissive labels, such as pseudoarchaeology, pseudohistory, and pseudoscience. Describing ideas as fringe theories may be less pejorative than describing them as pseudoscholarship; while it is unlikely that anyone would identify their own work as pseudoscience, astrologer David Cochrane is "proud to be a fringe theorist."
The term is also used to describe conspiracy theories. Such theories "explain" historical or political events as the work of a powerful secret organization — "a vast, insidious, preternaturally effective international conspiratorial network," according to Richard Hofstadter. The conspirators are possessed of "almost superhuman power and cunning," as described by historian Esther Webman.
Margaret Wertheim suggested that fringe theories should be treated in a manner similar to outsider art. In 2003 she curated an exhibit at the Santa Monica Museum of Art which was dedicated to the work of pseudoscientist Jim Carter.
=== Demarcation problem ===
Wertheim wrote that a "credentialed physicist ... can generally recognize a fringe theory by sight" when it comes in the form of an eccentrically formatted manuscript. However, it is difficult to distinguish between fringe theories and respected minority theories. A workable definition of what constitutes a fringe theory may not actually be possible. This is an aspect of the demarcation problem that occurs within both science and the humanities.
Geologist Steven Dutch approached the demarcation problem by dividing scientific ideas into three categories: fringe, frontier, and center, based upon their adherence to scientific methodology and their level of acceptance. Later authors, including Richard Duschl, expanded these categories. Under Duschl's system, a fringe theory is a mix of legitimate new ideas and pseudoscience; it awaits analysis to determine whether it will pass into the "frontier" or be rejected entirely.
== Mainstream acceptance of fringe theories ==
Most fringe theories never become part of established scholarship. Rejected ideas may help to refine mainstream thought, but most outside theories are simply incorrect and have no wider impact. Nevertheless, some ideas gradually receive wider acceptance until they are no longer viewed as fringe theories, and occasionally, such theories even become the mainstream view.
A widely known example is Alfred Wegener's theory of continental drift, which eventually served as the basis for the accepted model of plate tectonics. Other ideas that have made the transition include the germ theory of disease, Birkeland's explanation of the aurora, prions, and complexity theory in project management. Behavioral finance was described in a 2002 journal article as "at the fringe of ... modern financial theory", but it has since been widely applied in many fields of business.
Sometimes, the change is not gradual but represents a paradigm shift. Writing for the New York Law Journal, Andrew Bluestone described how a single court case in New York changed the use of an obscure common law statute regarding attorney misconduct from a "fringe theory of law" to an accepted, mainstream cause for legal action in the state.
Conversely, former mainstream theories such as phlogiston and luminiferous aether may be superseded and relegated to the fringe.
Such shifts between fringe theory and accepted theories are not always clear-cut. In 1963, Reuben Fine wrote that mainstream psychology had adopted aspects of Sigmund Freud's psychoanalysis but that many students of the discipline believed psychoanalysis to be a "lunatic fringe theory which has little to do with scientific psychology," and psychoanalysis is now generally considered discredited, according to author Frederick Crews who stated, "if you consult psychology faculties in top American universities, you will find almost no one now who believes in the Freudian system of thought. As a research paradigm it's pretty much dead."
== False balance ==
The news media may play a role in the dissemination and popularization of fringe theories. The media sometimes reduce complex topics to two sides and frame issues in terms of an underdog challenger fighting the mainstream theory. Biblical scholar Matthew Collins wrote that this simplification can be "both misrepresentative and misleading, especially when a far-fetched fringe theory is, in the name of neutrality and fairness, elevated to the role of equally legitimate contender." This false equivalence can become the expected media behavior. When The New York Times published an article strongly supporting the mainstream scientific stance on thiomersal and vaccines, others in the media condemned the Times for portraying the alleged vaccine-autism connection as a fringe theory, calling the article a "hit piece".
Issues of false balance also arise in education, especially in the context of the creation–evolution controversy. Creationism has been discredited as a fringe theory akin to Lamarckism or the cosmology of Immanuel Velikovsky's Worlds in Collision. Because advocates of creationism want schools to present only their preferred alternative, not the entire variety of minority views, they have attempted to portray scholarship on the issue as being equally divided between only two models.
== References ==
== Bibliography ==
Batt, Sharon (1996) [1994]. Patient No More: The Politics of Breast Cancer (Australian ed.). Spinifex Press. ISBN 978-1-875559-39-8.
Bell, David (2005). Science, Technology, and Culture. Issues in Cultural and Media Studies. Open University Press. ISBN 978-0-335-21326-9.
Curlee, Wanda; Gordon, Robert Lee (2013). Successful Program Management: Complexity Theory, Communication, and Leadership. Best Practices and Advances in Program Management Series. Auerbach. ISBN 978-1-4665-6879-2.
Davidson, Alexander (2002). How to Win in a Volatile Stock Market: The Definitive Guide to Investment Bargain Hunting (2nd ed.). Kogan Page. ISBN 978-0-7494-3803-6.
Erduran, Sibel; Dagher, Zoubeida (2013). Reconceptualizing the Nature of Science for Science Education: Scientific Knowledge, Practices and Other Family Categories. Contemporary Trends and Issues in Science Education. Springer. ISBN 978-94-017-9056-7.
Fine, Reuben (2013) [1963]. Freud: A Critical Re-evaluation of his Theories (Reprint ed.). Routledge. ISBN 978-0-415-71708-3.
Fritze, Ronald H. (2009). Invented Knowledge: False History, Fake Science and Pseudo-religions. Reaktion Books. ISBN 978-1-86189-430-4.
Hansson, Sven Ove (2013). "Defining Pseudoscience and Science". In Pigliucci, Massimo; Boudry, Maarten (eds.). Philosophy of Pseudoscience: Reconsidering the Demarcation Problem. University of Chicago Press. pp. 61–78. ISBN 978-0-226-05196-3.
Jago, Lucy (2002) [2001]. The Northern Lights (Reprint ed.). Vintage. ISBN 978-0-375-70882-4.
Offit, Paul A. (2010). Autism's False Prophets: Bad Science, Risky Medicine, and the Search for a Cure. Columbia University Press. ISBN 978-0-231-14637-1.
Quinn, Paul (2012). "Anti-Catholicism, Islamophobia, and Modern Christian Multi-Media". In Ansari, Humayun; Hafez, Farid (eds.). From the Far Right to the Mainstream: Islamophobia in Party Politics and the Media. Campus Verlag. pp. 130–153. ISBN 978-3-593-39648-4.
Rundlett, Ellsworth T. III (2013) [1991]. Maximizing Damages in Small Personal Injury Cases (Revision ed.). James Publishing. ISBN 978-0-938065-55-5.
Shermer, Michael (2013). "Science and Pseudoscience". In Pigliucci, Massimo; Boudry, Maarten (eds.). Philosophy of Pseudoscience: Reconsidering the Demarcation Problem. University of Chicago Press. pp. 203–224. ISBN 978-0-226-05196-3.
Shiel, Lisa A. (2013). Forbidden Bigfoot: Exposing the Controversial Truth about Sasquatch, Stick Signs, UFOs, Human Origins, and the Strange Phenomena in Our Own Backyards. Jacobsville Books. ISBN 978-1-934631-29-4.
Thurs, Daniel L.; Numbers, Ronald L. (2013). "Science, Pseudoscience, and Science Falsely So-Called". In Pigliucci, Massimo; Boudry, Maarten (eds.). Philosophy of Pseudoscience: Reconsidering the Demarcation Problem. University of Chicago Press. pp. 121–144. ISBN 978-0-226-05196-3.
Ullmann-Margalit, Edna (2006). Out of the Cave: A Philosophical Inquiry into the Dead Sea Scrolls Research. Harvard University Press. ISBN 978-0-674-02223-2.
Velasquez-Manoff, Moises (2013) [2012]. An Epidemic of Absence: A New Way of Understanding Allergies and Autoimmune Diseases (Reprint ed.). Scribner. ISBN 978-1-4391-9939-8.
Webman, Esther (2011). "Introduction—hate and absurdity: the impact of The Protocols of the Elders of Zion". In Webman, Esther (ed.). The Global Impact of the Protocols of the Elders of Zion: A Century-Old Myth. Routledge Jewish Studies Series. Routledge. pp. 1–24. ISBN 978-0-415-59892-7.
Wertheim, Margaret (2011). Physics on the Fringe: Smoke Rings, Circlons, and Alternative Theories of Everything. Walker Books. ISBN 978-0-8027-7872-7.
== External links ==
Media related to Fringe theory at Wikimedia Commons | Wikipedia/Fringe_theory |
Why People Believe Weird Things: Pseudoscience, Superstition, and Other Confusions of Our Time is a 1997 book by science writer Michael Shermer. The foreword was written by Stephen Jay Gould.
== Summary ==
In the first section, Shermer discusses the ideas that he has towards racism. He also explains his conversion to Deism from New Age mysticism (to which he had converted from being a Fundamentalist Christian Baptist).
In part two Shermer explains paranormal thinking and how one comes to believe in things without evidence. He uses Edgar Cayce as an example, and while he agrees with parts of Ayn Rand's Objectivism, he criticizes its moral absolutism and argues that many follow her philosophy unquestioningly, which he believes contradicts free thinking.
Part three begins with Shermer describing several debates he had with Duane Gish. He lays out some creationist arguments in 25 separate claims, and attempts to debunk each one with his own evidence. He closes retelling how a constitutional ban on teaching creationism in public schools was narrowly upheld at the Supreme Court of the United States in 1987.
Shermer shows that the Holocaust deniers reject proven facts for, as he states, ideological reasons. Like the creationists, he asserted, many Holocaust deniers believe that the evidence sides with them. He describes meeting and arguing with the deniers and lays out their arguments then shows evidence to support his own statements.
In part five Shermer relates Frank J. Tipler to Voltaire's character Pangloss to show how smart people deceive themselves. Shermer explores the psychology of scholars and business men who give up their careers in their pursuit to broadcast their paranormal beliefs. In his last chapter, added to the revised version, Shermer explains why he believes that "intelligent people" can be more susceptible to believing in weird things than others.
== Reception ==
According to Reason, "Shermer's episodic book covers a wide range of subjects, in a wide range of manners. He takes ritual jabs at such old debunker punching bags as ESP and UFOs (through UFOlogy's newest twist, alien abduction of humans). You'll also find cogent debunkings of strange phenomena such as fire walking and psychics who can discover "unknowable" facts about strangers. The longest sections of the book take on the more-substantive issues of creationism and Holocaust denial." It was given 4 out of 5 stars by popularscience.co.uk, which said "In this classic, originally published in 1997 but reviewed in a new UK edition, he gives a powerful argument for taking the sceptical viewpoint". According to the Los Angeles Times, "Shermer's directly written book is the perfect handbook to thrust on anyone you know who has been lured into conforming paranoias that circulate amid the premillennial jitters."
The Independent Thinking Review wrote, "This is a book that deserves to be widely read. Skeptics and critical thinkers can learn from it, but more importantly, it's a book to give those who maybe aren't as skeptical as you, those who need some clear and reasonable arguments to gently push them in a more critical direction. Read this book yourself: buy it for someone whose mind you care about."
== See also ==
Skepticism
The Psychology of the Occult
== References ==
== External links ==
Why People Believe Weird Things excerpt of the book of author's website
Why People Believe Weird Things review from The Skeptic's Dictionary
Why People Believe Weird Things review from Reason magazine | Wikipedia/Why_People_Believe_Weird_Things:_Pseudoscience,_Superstition,_and_Other_Confusions_of_Our_Time |
Recovered-memory therapy (RMT) is a catch-all term for a controversial and scientifically discredited form of psychotherapy that critics say utilizes one or more unproven therapeutic techniques (such as some forms of psychoanalysis, hypnosis, journaling, past life regression, guided imagery, and the use of sodium amytal interviews) to purportedly help patients recall previously forgotten memories. Proponents of recovered memory therapy claim, contrary to evidence, that traumatic memories can be buried in the subconscious and thereby affect current behavior, and that these memories can be recovered through the use of RMT techniques. RMT is not recommended by professional mental health associations. RMT can result in patients developing false memories of sexual abuse from their childhood and events such as alien abduction which had not actually occurred.
== Terminology ==
A 2018 online survey found that although 5% of a U.S. public sample reported recovering memories of abuse during therapy (abuse they reported having no previous memory of), none of them used the terminology "recovered memory therapy"—instead those recovering memories reported using a variety of other therapy types (e.g., behavioral therapy, EMDR, etc.). Practitioners of RMT generally utilize methods (such as hypnosis, age regression, guided visualization, and/or the use of substances such as sodium amytal) that are intended to recover true memories, yet known to support the creation of false memories.
== Research ==
The belief that a child can suffer horrific abuse, but immediately bury the memory deep in their psyche, remembering nothing of what had just happened, and grow up to be deeply psychologically scarred by this disassociation, while now commonplace in popular culture, is not supported by evidence.
A review article on potentially harmful therapies listed RMT as a treatment that will probably produce harm in some who receive it. Richard Ofshe, an American sociologist and expert on coerced and suggested testimony, describes the practice of "recovering" memories as fraudulent and dangerous. An inquiry by the Australian government into the practice found little support for or use of memory recovery therapies among health professionals, and warned that professionals had to be trained to avoid the creation of false memories. As part of its Crime Victims Compensation Program the state of Washington issued a report on the efficacy of RMT. It noted that the therapy had no positive benefits in the case studies analyzed and that "the ability of repressed memory patients to function in the activities of daily living is significantly and possibly irrevocably impaired as a direct result of the controversial therapy modalities.” Moreover, it recognized the potential for legal action from participants due to negative effects sustained from the program.
Studies by Elizabeth Loftus and others have concluded that it is possible to produce false memories of childhood incidents. The experiments involved manipulating subjects into believing that they had some fictitious experience in childhood, such as being lost in a shopping mall at age 6. This involved using a suggestive technique called "familial informant false narrative procedure," in which the experimenter claims the validity of the false event is supported by a family member of the subject. The study has been used to support the theory that false memories of traumatic sexual abuse can be implanted in a patient by therapists. Critics of these studies argue that the techniques do not resemble any approved or mainstream treatment modality, and there are criticisms that the implanted events used are not emotionally comparable to sexual abuse. Critics contend that Loftus's conclusions overreach the evidence. Loftus has rebutted these criticisms.
Some patients later retract memories they had previously believed to be recovered through RMT upon encountering critical literature regarding recovered memory therapy. This literature often highlights the therapy's dangerous and pseudoscientific aspects, thereby exposing them to scientific facts that prompt reconsideration. Patients have reported significant harmful effects due to the use of RMT.
A 2018 US study is the largest study known that surveys the general public about memory recovery in therapy. The study was presented to participants aged 50 years or older as a "Life Experience" survey and found that 8% of the 2,326 adults had reported seeing therapists, mostly starting in the 1990s, that discussed the possibility of repressed memories of abuse. 4% of adults had reported recovering memories of abuse in therapy for which they had no previous memory. Recovered memories of abuse were associated with most therapy types. A 1994 survey of 1000 therapists by Michael D. Yapko found that 19% of the therapists knew of a case in which a client's memory had been suggested by therapy but was in fact false.
== Professional guidelines ==
There are several individuals and groups that have published guidelines, criticisms or cautions about recovered memory therapy and techniques to stimulate recall:
In the Brandon Report, a set of training, practice, research and professional development recommendations, the United Kingdom's Royal College of Psychiatrists advised psychiatrists to avoid use of RMT or any "memory recovery techniques", citing a lack of evidence to support the accuracy of memories recovered in this way.
In 2004, the government of the Health Council of the Netherlands issued a report in response to inquiries from professionals regarding RMT and memories of traumatic child sexual abuse. The Health Council stated that while traumatic childhood experiences were major risk factors for psychological problems in adulthood, the fact that most traumatic memories are well-remembered but can be forgotten or become inaccessible though the influence of specific circumstances precludes a simple description of the relationship between memory and trauma. The report also notes that memories can be confabulated, re-interpreted and even apparently vivid or dramatic memories can be false, a risk that is increased when therapists use suggestive techniques, attempt to link symptoms to past trauma, with certain patients and through the use of methods to stimulate memories.
The Australian Hypnotherapists Association (AHA) issued a similar statement, for contexts where false memories of child sexual abuse may arise. The AHA acknowledges that child sexual abuse is serious, damaging and at least some memories are genuine, while cautioning that some questioning techniques and interventions may lead to illusory memories leading to false beliefs about abuse.
The Canadian Psychological Association has issued guidelines for psychologists addressing recovered memories. Psychologists are urged to be aware of their limitations in knowledge and training regarding memory, trauma and development and "that there is no constellation of symptoms which is diagnostic of child sexual abuse". The guidelines also urge caution and awareness of the benefits and limitations of "relaxation, hypnosis, guided imagery, free associations, inner child exercises, age regression, body memory interpretation, body massage, dream interpretation, and the use of projective techniques" and special caution regarding any legal involvement of memories, abuse and therapy.
== Legal issues ==
In Ramona v. Isabella, Gary Ramona sued his daughter's therapist for implanting false memories of his abuse of her. In the first case putting recovered memory therapy, itself, on trial, he eventually was awarded $500,000 in 1994.
Discussing RMT in the New South Wales Parliament in 1995, the state Minister for Health, Andrew Refshauge – a medical practitioner – stated that the general issue of admissibility of evidence based on recovered memories was one for the Attorney General. In 2004 Australian Counselling Association issued a draft position statement regarding recovered memories in which it informed its membership of possible legal difficulties if they affirm accusations as true based solely upon discussion of a patient's recovered memories, without adequate corroborating evidence.
A degree of controversy does remain within legal circles, with some holding the view that therapists and courts should consider repressed memories the same as they consider regular memories. Three relevant studies state that repressed memories are "no more and no less accurate than continuous memories."
Recovered memory therapy was an issue in the criminal trials of some Catholic priests accused of fondling or sexually assaulting juvenile-turned-adult parishioners.
In a 2017 criminal case in Canada, a Nova Scotian clergyman, the Reverend Brent Hawkes, was acquitted in a case involving recovered memories of alleged historical sexual abuse when Justice Alan Tufts described in his ruling that the complainant's method of re-constructing his memory of alleged events after joining a men's group and hearing similar accounts from other "survivors" his evidence could not be reliable.
Several court cases awarded multimillion-dollar verdicts against Minnesota psychiatrist Diane Bay Humenansky, who used hypnosis and other suggestive techniques associated with RMT, resulting in accusations by several patients against family members that were later found to be false.
In 1999, the Netherlands Board of Prosecutors General formed The National Expert Group on Special Sexual Matters, in Dutch - Landelijke Expertisegroep Bijzondere Zedenzaken (LEBZ). LEBZ consists of a multidisciplinary group of experts whom investigating police officers and prosecutors are mandated to consult before considering arresting or prosecuting a person accused of sexual crimes involving repressed memories or recovered memory therapy. The LEBZ released a report for the period of 2003–2007 stating that 90% of the cases they consulted on were stopped due to their recommendations that the allegations were not based on reliable evidence.
== See also ==
Amnesia
Emotion and memory
Gaslighting
Memory inhibition
Repressed memory
Psychological trauma
Satanic ritual abuse
Spectral evidence
== References ==
== Further reading ==
Freyd, Jennifer J. (1996). Betrayal Trauma – The Logic of Forgetting Childhood Abuse. Cambridge, MA: Harvard University Press. ISBN 978-0-674-06805-6.
Ofshe, Richard and Watters, Ethan. Making Monsters: False Memories, Psychotherapy, And Sexual Hysteria. University of California Press; Reprint edition, 1996, ISBN 0-520-20583-9.
Loftus, Elizabeth and Ketcham, Katherine. The Myth of Repressed Memory: False Memories and Allegations of Sexual Abuse. St. Martin's Griffin 1st edition, 1996.
Lilienfeld, Scott. "Psychological treatments that cause harm." Perspectives on Psychological Science, Volume 2(1), pp. 53–70, 2007.
Knopp, Fay Honey (1996). A Primer on the Complexities of Traumatic Memory of Childhood Sexual Abuse – A Psychobiological Approach. Brandon, VT: Safer Society Press. ISBN 978-1-884444-20-3.
Pope, Kenneth S., KS (1996). "Memory, Abuse, & Science: Questioning Claims about the False Memory Syndrome Epidemic". American Psychologist. 51 (9): 957–974. doi:10.1037/0003-066X.51.9.957. PMID 8819364. Retrieved 2007-12-28.
Pendergrast, Mark, Victims of Memory (1993), ISBN 0-942679-18-0
== External links ==
Answers to questions about recovered memory by the American Psychological Association | Wikipedia/Recovered-memory_therapy |
The Bates method is an ineffective and potentially dangerous alternative therapy aimed at improving eyesight. Eye-care physician William Horatio Bates (1860–1931) held the erroneous belief that the extraocular muscles caused changes in focus and that "mental strain" caused abnormal action of these muscles; hence he believed that relieving such "strain" would cure defective vision. In 1952, optometry professor Elwin Marg wrote of Bates, "Most of his claims and almost all of his theories have been considered false by practically all visual scientists."
No type of training has been shown to change the refractive power of the eye. Moreover, certain aspects of the Bates method can put its followers at risk: They may damage their eyes through overexposure to sunlight, not wear their corrective lenses when they need them (e.g., while driving), or neglect conventional eye care, possibly allowing serious conditions to develop.
== Early history ==
In 1891, Bates published an article in the New York Medical Journal claiming to have successfully reversed seven cases of nearsightedness, or myopia. In 1911, Bates published an article claiming to have taught myopic schoolchildren how to correctly focus in the distance. He recommended that schools post a Snellen chart in each classroom and encourage students to read it daily.
In 1917, Bates teamed up with "'physical culture' faddist" Bernarr Macfadden on a "New Course of Eye Training" which was heavily advertised in the Physical Culture magazine. Bates' name was later dropped from the advertising, but Macfadden continued to market this correspondence course, which was renamed "Strengthening the Eyes". This course was criticized by the American Medical Association's Bureau of Investigation as dangerous quackery. In July 1919, Bates began publishing Better Eyesight, "A Monthly Magazine Devoted to the Prevention and Cure of Imperfect Sight Without Glasses". This was also criticized "as it were the product of a psychopathic ward".
In 1920, Bates self-published a book, The Cure of Imperfect Sight by Treatment Without Glasses (or Perfect Sight Without Glasses). In 1926, articles by his assistant Emily Lierman were re-printed in a book titled Stories From the Clinic; some of these stories claimed that such methods had cured glaucoma and cataracts as well as refractive errors. In 1929, the Federal Trade Commission lodged a complaint against Bates for advertising "falsely or misleadingly".
== Underlying concepts ==
=== Accommodation ===
Accommodation is the process by which the vertebrate eye adjusts optical power to maintain focus on the retina while the eye's gaze shifts to a point either closer or farther away. The long-standing medical consensus is that this is accomplished by action of the ciliary muscle, a muscle within the eye, which adjusts the curvature of the eye's crystalline lens. This explanation is based in the observed effect of atropine temporarily preventing accommodation when applied to the ciliary muscle, as well as images reflected on the crystalline lens becoming smaller as the eye shifts focus to a closer point, indicating a change in the lens' shape. Bates rejected this explanation, and in his 1920 book presented photographs that he said showed that the image remained the same size even as the eye shifted focus, concluding from this that the lens was not a factor in accommodation. However, optometrist Philip Pollack in a 1956 work characterized these photographs as "so blurred that it is impossible to tell whether one image is larger than the other", in contrast to later photographs that clearly showed a change in the size of the reflected images, just as had been observed since the late 19th century.
Bates adhered to a different explanation of accommodation that had already been generally disregarded by the medical community of his time. Bates' model had the muscles surrounding the eyeball controlling its focus. In addition to their known function of turning the eye, Bates maintained, they also affect its shape, elongating the eyeball to focus at the near-point or shortening it to focus at a distance. Science author John Grant writes that many animals, such as fishes, accommodate by elongation of the eyeball, "it's just that humans aren't one of those animals."
Laboratory tests have shown that the human eyeball is far too rigid to spontaneously change shape to a degree that would be necessary to accomplish what Bates described. Exceedingly small changes in axial length of the eyeball (18.6–19.2 μm) are caused by the action of the ciliary muscle during accommodation. However, these changes are far too small to account for the necessary changes in focus, producing changes of only −0.036 dioptres.
=== Causes of sight problems ===
Medical professionals characterize refractive errors as consequences of the eye's shape and other basic anatomy, which no evidence shows any exercise can alter. Bates, however, believed that these conditions are caused by tension of the muscles surrounding the eyeball, which he believed prevents the eyeball from sufficiently changing shape (per his explanation of accommodation) when gaze is shifted nearer or farther. Bates characterized this supposed muscular tension as the consequence of a "mental strain" to see, the relief of which he claimed would instantly improve sight. He also linked disturbances in the circulation of blood, which he said is "very largely influenced by thought", not only to refractive errors, but also to double vision, crossed-eye, lazy eye, and to more serious eye conditions such as cataracts and glaucoma. His therapies were based on these assumptions.
Bates felt that corrective lenses, which he characterized as "eye crutches", are an impediment to curing poor vision. In his view, "strain" would increase as the eyes adjust to the correction in front of them. He thus recommended that glasses be discarded by anyone applying his method.
== Treatments ==
In his writings, Bates discussed several techniques that he claimed helped patients to improve their sight. These techniques were all supposed to relieve "strain" to which Bates attributed sight problems.
=== Palming ===
Bates suggested closing the eyes for minutes at a time to help bring about relaxation. He asserted that the relaxation could be deepened in most cases by "palming", or covering the closed eyes with the palms of the hands, without putting pressure on the eyeballs. If the covered eyes did not strain, he said, they would see "a field so black that it is impossible to remember, imagine, or see anything blacker", since light was excluded by the palms. However, he reported that some of his patients experienced "illusions of lights and colors" sometimes amounting to "kaleidoscopic appearances" as they "palmed", occurrences he attributed to his ubiquitous "strain" and that he claimed disappeared when one truly relaxed. This phenomenon, however, was almost certainly caused by Eigengrau or "dark light". In fact, even in conditions of perfect darkness, as inside a cave, neurons at every level of the visual system produce random background activity that is interpreted by the brain as patterns of light and color.
If while palming one ends up applying pressure to the eyes, this may increase the risk of glaucoma.
=== Visualization ===
Bates placed importance on mental images, as he felt relaxation was the key to clarity of imagination as well as of actual sight. He claimed that one's poise could be gauged by the visual memory of black; that the darker it appeared in the mind, and the smaller the area of black that could be imagined, the more relaxed one was at the moment. He recommended that patients think of the top letter from an eye chart and then visualize progressively smaller black letters, and eventually a period or comma. He cautioned against "concentrating" on such images, as he regarded an attempt to "think of one thing only" as a strain.
While Bates preferred to have patients imagine something black, he also reported that some found objects of other colors easiest to visualize, thus were benefited most by remembering those, because, he asserted, "the memory can never be perfect unless it is easy." Skeptics reason that the only benefit to eyesight gained from such techniques is itself imagined, and point out that familiar objects, including letters on an eye chart, can be recognized even when they appear less than clear.
=== Movement ===
Bates thought that the manner of eye movement affected the sight. He suggested "shifting", or moving the eyes back and forth to get an illusion of objects "swinging" in the opposite direction. He believed that the smaller the area over which the "swing" was experienced, the greater was the benefit to sight. He combined this with visualization, advocating that patients close their eyes and imagine movement of objects. By alternating actual and mental shifting over an image, Bates wrote, many patients were quickly able to shorten the "shift" to a point where they could "conceive and swing a letter the size of a period in a newspaper".
Perhaps finding Bates' concepts of "shifting" and "swinging" too complicated, Bernarr Macfadden suggested simply moving the eyes up and down, from side to side, and shifting one's gaze between a near-point and a far-point.
=== Sunning ===
Bates advocated sungazing, characterizing ill effects as "always temporary". This is at odds with the well-known risk of eye damage that can result from direct sunlight observation.
In his magazine, Bates later suggested exposing only the white part of the eyeball to direct sunlight, and only for seconds at a time, after allowing the sun to shine on closed eyelids for a longer period. Posthumous publications of Bates' book omitted mention of the supposed benefits from direct sunlight shining on open eyes. Even on closed eyes, direct sunlight exposure poses a risk of damage to the eyelids, including skin cancer.
== After Bates ==
After Bates died in 1931, his methods of treatment were continued by his widow Emily and other associates. In 1932, Gayelord Hauser published a book endorsing the Bates method but also adding new exercises and recommendations for his own dietary products. Most subsequent proponents did not stand by Bates' explanation of how the eye focused mechanically, but nonetheless maintained that relieving habitual "strain" was the key to improving sight.
=== Margaret Darst Corbett ===
Margaret Darst Corbett first met Bates when she consulted him about her husband's eyesight. She became his pupil, and eventually taught his method at her School of Eye Education in Los Angeles. She was of the stated belief that "the optic nerve is really part of the brain, and vision is nine-tenths mental and one-tenth only physical."
In late 1940, Corbett and her assistant were charged with violations of the Medical Practice Act of California for treating eyes without a license. At the trial, many of her students testified on her behalf, describing in detail how she had enabled them to discard their glasses. One witness testified that he had been almost blind from cataracts, but that after working with Corbett, his vision had improved to such an extent that for the first time he could read for eight hours at a stretch without glasses. Corbett explained in court that she was practicing neither optometry nor ophthalmology and represented herself not as a doctor, but only as an "instructor of eye training". Describing her method, she said, "We turn vision on by teaching the eyes to shift. We want the sense of motion to relieve staring, to end the fixed look. We use light to relax the eyes and to accustom them to the sun."
The trial attracted widespread interest, as did the "not guilty" verdict. The case spurred a bill in the Californian State Legislature that would have then made such vision "education" illegal without an optometric or medical license. After a lively campaign in the media, the bill was rejected.
=== Aldous Huxley ===
Perhaps the most famous proponent of the Bates method was the British writer Aldous Huxley. At the age of 16, Huxley had an attack of keratitis, which, after an 18-month period of near-blindness, left him with one eye just capable of light perception and the other with an unaided Snellen fraction of 10/200. This was mainly due to opacities in both corneas, complicated by hyperopia and astigmatism. He was able to read only if he wore thick glasses and dilated his better pupil with atropine, to allow that eye to see around an opacity in the center of the cornea.
In 1939, at the age of 45 and with eyesight that continued to deteriorate, he happened to hear of the Bates method and sought the help of Margaret Corbett, who gave him regular lessons. Three years later, he wrote The Art of Seeing, in which he related: "Within a couple of months, I was reading without spectacles, and what was better still, without strain and fatigue.... At the present time, my vision, though very far from normal, is about twice as good as it used to be when I wore spectacles." Describing the process, Huxley wrote, "Vision is not won by making an effort to get it: it comes to those who have learned to put their minds and eyes into a state of alert passivity, of dynamic relaxation." He expressed indifference regarding the veracity of Bates' explanation of how the eye focuses, stating, "my concern is not with the anatomical mechanism of accommodation, but with the art of seeing."
His case generated wide publicity, as well as scrutiny. Ophthalmologist Walter B. Lancaster, for example, suggested in 1944 that Huxley had "learned how to use what he has to better advantage" by training the "cerebral part of seeing", rather than actually improving the quality of the image on the retina.
In 1952, 10 years after writing The Art of Seeing, Huxley spoke at a Hollywood banquet, wearing no glasses, and according to Bennett Cerf, apparently reading his paper from the lectern without difficulty. In Cerf's words:
Then suddenly he faltered—and the disturbing truth became obvious. He wasn't reading his address at all. He had learned it by heart. To refresh his memory, he brought the paper closer and closer to his eyes. When it was only an inch or so away, he still couldn't read it, and had to fish for a magnifying glass in his pocket to make the typing visible to him. It was an agonizing moment.
In response to this, Huxley wrote, "I often do use magnifying glasses where conditions of light are bad, and have never claimed to be able to read except under very good conditions." This underscored that he had not regained anything close to normal vision, and in fact never claimed that he had.
=== Modern variants ===
"Natural vision correction" or "natural vision improvement" continues to be marketed by practitioners offering individual instruction, many of whom have no medical or optometric credentials. Most base their approach in the Bates method, though some also integrate vision therapy techniques. Also, many self-help books and programs, which have not been subjected to randomized controlled trials, are aimed at improving eyesight naturally. Purveyors of such approaches argue that they lack the funds to formally test them.
The heavily advertised "See Clearly Method" (of which sales were halted by a court order in November 2006, in response to what were found to be dishonest marketing practices) included "palming" and "light therapy", both adapted from Bates. The creators of the program, however, emphasized that they did not endorse Bates' approach overall.
In his 1992 book The Bates Method, A Complete Guide to Improving Eyesight—Naturally, "Bates method teacher" Peter Mansfield was very critical of eye care professionals for prescribing corrective lenses. The book included accounts of 12 "real cases", but did not report any information about refractive error.
Czech native John Slavicek claims to have created an "eye cure" that improves eyesight in three days, borrowing from ancient yogic eye exercises, visualizations from the Seth Material, and the Bates method. Although he has testimonials from his neighbor and others, several of his students indicate that he has greatly exaggerated their cases. Slavicek's self-published manual, Yoga for the Eyes, was rejected by an ophthalmologist who evaluated it, and evinced no interest from the World Health Organization and St. Erik's Eye Foundation in Sweden, as he had not conducted double-blind tests.
== Possible reasons for claimed improvements ==
Some eye conditions may naturally change for the better with age or in cycles (ophthalmologist Stewart Duke-Elder suggested that this happened with Aldous Huxley's keratitis). A cataract when first setting in sometimes results in much improved eyesight for a short time. One who has been practicing the Bates method will likely credit it for any improvement experienced regardless of the actual cause.
When corrective lenses are removed, vision can adapt to lessen the initial perceived blur, sometimes by more than two lines on an eye chart. This phenomenon is known as blur adaptation. Some studies have suggested that a learned ability to interpret blurred images may also account for perceived improvements in eyesight.
== General research ==
In 2004 the American Academy of Ophthalmology (AAO) published a review of various research regarding "visual training", which consisted of "eye exercises, muscle relaxation techniques, biofeedback, eye patches, or eye massages", "alone or in combinations". No evidence was found that such techniques could objectively benefit eyesight, though some studies noted changes, both positive and negative, in the visual acuity of nearsighted subjects as measured by a Snellen chart. In some cases noted improvements were maintained at subsequent follow-ups. However, these results were not seen as actual reversals of nearsightedness, and were attributed instead to factors such as "improvements in interpreting blurred images, changes in mood or motivation, creation of an artificial contact lens by tear film changes, or a pinhole effect from miosis of the pupil."
In 2005 the Ophthalmology Department of New Zealand's Christchurch Hospital published a review of forty-three studies regarding the use of eye exercises. They found that "As yet there is no clear scientific evidence published in the mainstream literature supporting the use of eye exercises" to improve visual acuity, and concluded that "their use therefore remains controversial."
== General criticisms ==
=== Dead-end ===
A frequent criticism of the Bates method is that it has remained relatively obscure, which is seen as proof that it is not truly effective. Writer Alan M. MacRobert concluded in a 1979 article that the "most telling argument against the Bates system" and other alternative therapies was that they "bore no fruit". In regards to the Bates method, he reasoned that "If palming, shifting, and swinging could really cure poor eyesight, glasses would be as obsolete by now as horse-drawn carriages."
Philosopher Frank J. Leavitt has argued that the method Bates described would be difficult to test scientifically due to his emphasis on relaxation and visualization. Leavitt asked, "How can we tell whether someone has relaxed or imagined something, or just thinks that he or she has imagined it?" Regarding the possibility of a placebo trial, Leavitt commented, "I cannot conceive of how we could put someone in a situation where he thinks he has imagined something while we know that he has not."
=== Corrective lenses and safety ===
Discarding one's corrective lenses, as Bates recommended, or wearing lenses weaker than one's prescribed correction, as some Bates method advocates suggest, poses a potential safety hazard in certain situations, especially when one is operating a motor vehicle. James Randi related that his father, shortly after discarding glasses for this reason, wrecked his car. Bates method teachers often caution that when driving, one should wear the correction legally required.
=== Avoidance of conventional treatment ===
A follower of the Bates method may neglect urgently needed medical treatment for a condition such as glaucoma, which can lead to blindness. Also, children with vision problems may require early attention by a professional in order to successfully prevent lazy eye. Such treatment may include exercises, but which are different from those associated with the Bates method, and parents who subscribe to Bates' ideas may delay seeking conventional care until it is too late. It may further be necessary for a child at risk of developing lazy eye to wear the proper correction.
== See also ==
List of topics characterized as pseudoscience
Iridology
Pinhole glasses
Tibetan eye chart
== References ==
== Further reading ==
Grosvenor, TP (2007). Nonsurgical Methods of Myopia Control or Reduction (5th ed.). Elsevier Health Sciences. p. 370. ISBN 978-0750675758. There has never been any clinical or scientific evidence that these procedures are of any help in controlling myopia. {{cite book}}: |work= ignored (help)
== External links ==
"The Unending Search for 'Normal' Vision". Life. 27 May 1957.
Orfield M.A. O.D., Antonia (1994). "Seeing Space: Undergoing Brain Re-Programming to Reduce Myopia" (PDF). Journal of Behavioral Optometry. 5 (5): 123–31.
"To See or Not to See–Natural Vision Correction". BBC. 27 September 2004.
Robertson, Kate (14 October 2007). "Seeing eye to eye". The Sydney Morning Herald. | Wikipedia/Bates_method |
In physics, theories of gravitation postulate mechanisms of interaction governing the movements of bodies with mass. There have been numerous theories of gravitation since ancient times. The first extant sources discussing such theories are found in ancient Greek philosophy. This work was furthered through the Middle Ages by Indian, Islamic, and European scientists, before gaining great strides during the Renaissance and Scientific Revolution—culminating in the formulation of Newton's law of gravity. This was superseded by Albert Einstein's theory of relativity in the early 20th century.
Greek philosopher Aristotle (fl. 4th century BC) found that objects immersed in a medium tend to fall at speeds proportional to their weight. Vitruvius (fl. 1st century BC) understood that objects fall based on their specific gravity. In the 6th century AD, Byzantine Alexandrian scholar John Philoponus modified the Aristotelian concept of gravity with the theory of impetus. In the 7th century, Indian astronomer Brahmagupta spoke of gravity as an attractive force. In the 14th century, European philosophers Jean Buridan and Albert of Saxony—who were influenced by Islamic scholars Ibn Sina and Abu'l-Barakat respectively—developed the theory of impetus and linked it to the acceleration and mass of objects. Albert also developed a law of proportion regarding the relationship between the speed of an object in free fall and the time elapsed.
Italians of the 16th century found that objects in free fall tend to accelerate equally. In 1632, Galileo Galilei put forth the basic principle of relativity. The existence of the gravitational constant was explored by various researchers from the mid-17th century, helping Isaac Newton formulate his law of universal gravitation. Newton's classical mechanics were superseded in the early 20th century, when Einstein developed the special and general theories of relativity. An elemental force carrier of gravity is hypothesized in quantum gravity approaches such as string theory, in a potentially unified theory of everything.
== Antiquity ==
=== Classical antiquity ===
==== Heraclitus, Anaxagoras, Empedocles and Leucippus ====
The pre-Socratic Greek philosopher Heraclitus (c. 535 – c. 475 BC) of the Ionian School used the word logos ('word') to describe a kind of law which keeps the cosmos in harmony, moving all objects, including the stars, winds, and waves. Anaxagoras (c. 500 – c. 428 BC), another Ionian philosopher, introduced the concept of nous ('cosmic mind') as an ordering force.
In the cosmogony of the Greek philosopher Empedocles (c. 494 – c. 434/443 BC), there were two opposing fundamental cosmic forces of "attraction" and "repulsion", which Empedocles personified as "Love" and "Strife" (Philotes and Neikos).
The ancient atomist Leucippus (5th century BC) proposed the cosmos was created when a large group of atoms came together and swirled as a vortex. The smaller atoms became the celestial bodies of the cosmos. The larger atoms in the center came together as a membrane from which the Earth was formed.
==== Aristotle ====
In the 4th century BC, Greek philosopher Aristotle taught that there is no effect or motion without a cause. The cause of the downward natural motion of heavy bodies, such as the classical elements of earth and water, was related to their nature (gravity), which caused them to move downward toward the center of the (geocentric) universe. For this reason Aristotle supported a spherical Earth, since "every portion of earth has weight until it reaches the centre, and the jostling of parts greater and smaller would bring about not a waved surface, but rather compression and convergence of part and part until the centre is reached". On the other hand, light bodies such as the element fire and air, were moved by their nature (levity) upward toward the celestial sphere of the Moon (see sublunary sphere). Astronomical objects near the fixed stars are composed of aether, whose natural motion is circular. Beyond them is the prime mover, the final cause of all motion in the cosmos. In his Physics, Aristotle correctly asserted that objects immersed in a medium tend to fall at speeds proportional to their weight and inversely proportional to the density of the medium.
==== Strato of Lampsacus, Epicurus and Aristarchus of Samos ====
Greek philosopher Strato of Lampsacus (c. 335 – c. 269 BC) rejected the Aristotelian belief of "natural places" in exchange for a mechanical view in which objects do not gain weight as they fall, instead arguing that the greater impact was due to an increase in speed.
Epicurus (c. 341 – 270 BC) viewed weight as an inherent property of atoms which influences their movement. These atoms move downward in constant free fall within an infinite vacuum without friction at equal speed, regardless of their mass. On the other hand, upward motion is due to atomic collisions. Epicureans deviated from older atomist theories like that of Democritus (c. 460 – c. 370 BC) by proposing the idea that atoms may randomly deviate from their expected course.
Greek astronomer Aristarchus of Samos (c. 310 – c. 230 BC) theorized Earth's rotation around its own axis, as well as Earth's orbit around the Sun in a heliocentric cosmology. Seleucus of Seleucia (c. 190 – c. 150 BC) supported his cosmology and also described gravitational effects of the Moon on the tidal range.
==== Archimedes ====
The 3rd-century BC Greek physicist Archimedes (c. 287 – c. 212 BC) discovered the centre of mass of a triangle. He also postulated that if the centres of gravity of two equal weights was not the same, it would be located in the middle of the line that joins them. In On Floating Bodies, Archimedes claimed that for any object submerged in a fluid there is an equivalent upward buoyant force to the weight of the fluid displaced by the object's volume. The fluids described by Archimedes are not self-gravitating, since he assumes that "any fluid at rest is the surface of a sphere whose centre is the same as that of the Earth".
==== Hipparchus of Nicaea, Lucretius and Vitruvius ====
Greek astronomer Hipparchus of Nicaea (c. 190 – c. 120 BC) also rejected Aristotelian physics and followed Strato in adopting some form of theory of impetus to explain motion. The poem De rerum natura by Lucretius (c. 99 – c. 55 BC) asserts that more massive bodies fall faster in a medium because the latter resists less, but in a vacuum fall with equal speed. Roman engineer and architect Vitruvius (c. 85 – c. 15 BC) contends in his De architectura that gravity is not dependent on a substance's weight but rather on its 'nature' (cf. specific gravity):
If the quicksilver is poured into a vessel, and a stone weighing one hundred pounds is laid upon it, the stone swims on the surface, and cannot depress the liquid, nor break through, nor separate it. If we remove the hundred pound weight, and put on a scruple of gold, it will not swim, but will sink to the bottom of its own accord. Hence, it is undeniable that the gravity of a substance depends not on the amount of its weight, but on its nature. (translated from the original Latin by W. Newton)
==== Plutarch, Pliny the Elder, and Claudius Ptolemy ====
Greek philosopher Plutarch (c. 46 – c. 120 AD) attested the existence of Roman astronomers who rejected Aristotelian physics, "even contemplating theories of inertia and universal gravitation", and suggested that gravitational attraction was not unique to the Earth. The gravitational effects of the Moon on the tides were noticed by Pliny the Elder (23–79 AD) in his Naturalis Historia and Claudius Ptolemy (c. 100 – c. 170 AD) in his Tetrabiblos.
=== Byzantine era ===
==== John Philoponus ====
In the 6th century AD, the Byzantine Alexandrian scholar John Philoponus proposed the theory of impetus, which modifies Aristotle's theory that "continuation of motion depends on continued action of a force" by incorporating a causative force which diminishes over time. In his commentary on Aristotle's Physics that "if one lets fall simultaneously from the same height two bodies differing greatly in weight, one will find that the ratio of the times of their motion does not correspond to the ratios of their weights, but the difference in time is a very small one".
== Indian subcontinent ==
=== Brahmagupta ===
Brahmagupta (c. 598 – c. 668 AD) was the first Indian scholar to describe gravity as an attractive force:
The earth on all its sides is the same; all people on the earth stand upright, and all heavy things fall down to the earth by a law of nature, for it is the nature of the earth to attract and to keep things, as it is the nature of water to flow ... If a thing wants to go deeper down than the earth, let it try. The earth is the only low thing, and seeds always return to it, in whatever direction you may throw them away, and never rise upwards from the earth.
=== Bhāskara II ===
Bhāskara II (c. 1114 – c. 1185), another Indian mathematician and astronomer, describes gravity as an inherent attractive property of Earth in the section "Golādhyāyah" ("On Spherics") of his treatise Siddhānta Shiromani:
The property of attraction is inherent in the Earth. By this property the Earth attracts any unsupported heavy thing towards it: The thing appears to be falling but it is in a state of being drawn to Earth. ... It is manifest from this that ... people situated at distances of a fourth part of the circumference [of earth] from us or in the opposite hemisphere, cannot by any means fall downwards [in space].
== Islamic world ==
=== Abu Ma'shar ===
Ancient Greeks like Posidonius had associated the tides in the sea with to be influenced by moonlight. Around 850, Abu Ma'shar al-Balkhi recorded the tides and the moon position and noticed high-tides when the Moon was below the horizon. Abu Ma'shar considered an alternative explanation where the Moon and the sea had to share some astrological virtue that attracted each other. This work was translated into Latin and became one of the two main theories for tides for European scholars.
=== Ibn Sina ===
In the 11th century, Persian polymath Ibn Sina (Avicenna) agreed with Philoponus' theory that "the moved object acquires an inclination from the mover" as an explanation for projectile motion. Ibn Sina then published his own theory of impetus in The Book of Healing (c. 1020). Unlike Philoponus, who believed that it was a temporary virtue that would decline even in a vacuum, Ibn Sina viewed it as a persistent, requiring external forces such as air resistance to dissipate it. Ibn Sina made distinction between force and inclination (mayl), and argued that an object gained inclination when the object is in opposition to its natural motion. He concluded that continuation of motion is attributed to the inclination that is transferred to the object, and that object will be in motion until the inclination is spent. The Iraqi polymath Ibn al-Haytham describes gravity as a force in which heavier body moves towards the centre of the earth. He also describes the force of gravity will only move towards the direction of the centre of the earth not in different directions.
=== Al-Biruni ===
Another 11th-century Persian polymath, Al-Biruni, proposed that heavenly bodies have mass, weight, and gravity, just like the Earth. He criticized both Aristotle and Ibn Sina for holding the view that only the Earth has these properties. The 12th-century scholar Al-Khazini suggested that the gravity an object contains varies depending on its distance from the centre of the universe (referring to the centre of the Earth). Al-Biruni and Al-Khazini studied the theory of the centre of gravity, and generalized and applied it to three-dimensional bodies. Fine experimental methods were also developed for determining the specific gravity or specific weight of objects, based the theory of balances and weighing.
=== Abu'l-Barakāt al-Baghdādī ===
In the 12th century, Ibn Malka al-Baghdadi adopted and modified Ibn Sina's theory on projectile motion. In his Kitab al-Mu'tabar, Abu'l-Barakat stated that the mover imparts a violent inclination (mayl qasri) on the moved and that this diminishes as the moving object distances itself from the mover. According to Shlomo Pines, al-Baghdādī's theory of motion was "the oldest negation of Aristotle's fundamental dynamic law [namely, that a constant force produces a uniform motion], [and is thus an] anticipation in a vague fashion of the fundamental law of classical mechanics [namely, that a force applied continuously produces acceleration]."
== European Renaissance ==
=== 14th century ===
==== Jean Buridan, the Oxford Calculators, Albert of Saxony ====
In the 14th century, both the French philosopher Jean Buridan and the Oxford Calculators (the Merton School) of the Merton College of Oxford rejected the Aristotelian concept of gravity. They attributed the motion of objects to an impetus (akin to momentum), which varies according to velocity and mass; Buridan was influenced in this by Ibn Sina's Book of Healing. Buridan and the philosopher Albert of Saxony (c. 1320 – c. 1390) adopted Abu'l-Barakat's theory that the acceleration of a falling body is a result of its increasing impetus. Influenced by Buridan, Albert developed a law of proportion regarding the relationship between the speed of an object in free fall and the time elapsed. He also theorized that mountains and valleys are caused by erosion—displacing the Earth's centre of gravity.
==== Uniform and difform motion ====
The roots of Domingo de Soto's expression uniform difform motion [uniformly accelerated motion] lies in the Oxford Calculators terms "uniform" and "difform" motion: "uniform motion" was used differently then than it would be by later writers, and might have referred both to constant speed and to motion in which all parts of a body are moving at equal speed. The Calculators did not illustrate the different types of motion with real-world examples. John of Holland at the University of Prague, illustrated uniform motion with what would later be called uniform velocity, but also with a falling stone (all parts moving at the same speed), and with a sphere in uniform rotation. He did, however, make distinctions between different kinds of "uniform" motion. Difform motion was exemplified by walking at increasing speed.
==== Mean speed theorem ====
Also in the 14th century, the Merton School developed the mean speed theorem; a uniformly accelerated body starting from rest travels the same distance as a body with uniform speed whose speed is half the final velocity of the accelerated body. The mean speed theorem was proved by Nicole Oresme (c. 1323 – 1382) and would be influential in later gravitational equations. Written as a modern equation:
s
=
1
2
v
f
t
{\displaystyle \ s={\frac {1}{2}}v_{f}t}
However, since small time intervals could not be measured, the relationship between time and distance was not so evident as the equation suggests. More generally; equations, which were not widely used until after Galileo's time, imply a clarity that was not there.
=== 15th–17th centuries ===
==== Leonardo da Vinci ====
Leonardo da Vinci (1452–1519) made drawings recording the acceleration of falling objects. He wrote that the "mother and origin of gravity" is energy. He describes two pairs of physical powers which stem from a metaphysical origin and have an effect on everything: abundance of force and motion, and gravity and resistance. He associates gravity with the 'cold' classical elements, water and earth, and calls its energy infinite. In Codex Arundel, Leonardo recorded that if a water-pouring vase moves transversally (sideways), simulating the trajectory of a vertically falling object, it produces a right triangle with equal leg length, composed of falling material that forms the hypotenuse and the vase trajectory forming one of the legs. On the hypotenuse, Leonardo noted the equivalence of the two orthogonal motions, one effected by gravity and the other proposed by the experimenter.
==== Nicolaus Copernicus, Petrus Apianus ====
By 1514, Nicolaus Copernicus had written an outline of his heliocentric model, in which he stated that Earth's centre is the centre of both its rotation and the orbit of the Moon. In 1533, German humanist Petrus Apianus described the exertion of gravity:
Since it is apparent that in the descent [along the arc] there is more impediment acquired, it is clear that gravity is diminished on this account. But because this comes about by reason of the position of heavy bodies, let it be called a positional gravity [i.e. gravitas secundum situm]
==== Francesco Beato and Luca Ghini ====
By 1544, according to Benedetto Varchi, the experiments of at least two Italians, Francesco Beato, a Dominican philosopher at Pisa, and Luca Ghini, a physician and botanist from Bologna, had dispelled the Aristotelian claim that objects fall at speeds proportional to their weight.
==== Domingo de Soto ====
In 1551, Domingo de Soto theorized that objects in free fall accelerate uniformly in his book Physicorum Aristotelis quaestiones. This idea was subsequently explored in more detail by Galileo Galilei, who derived his kinematics from the 14th-century Merton College and Jean Buridan, and possibly De Soto as well.
==== Simon Stevin ====
In 1585, Flemish polymath Simon Stevin performed a demonstration for Jan Cornets de Groot, a local politician in the Dutch city of Delft. Stevin dropped two lead balls from the Nieuwe Kerk in that city. From the sound of the impacts, Stevin deduced that the balls had fallen at the same speed. The result was published in 1586.
Let us take (as ... Jan Cornets de Groot ... and I have done) two balls of lead, the one ten times larger and heavier than the other, and drop them together from a height of 30 feet on to a board or something on which they give a perceptible sound. Then it will be found that the lighter will not be ten times longer on its way than the heavier, but that they fall together on to the board so simultaneously that their two sounds seem to be one and the same. ... Therefore Aristotle ... is wrong.
==== Galileo Galilei ====
Galileo successfully applied mathematics to the acceleration of falling objects, correctly hypothesizing in a 1604 letter to Paolo Sarpi that the distance of a falling object is proportional to the square of the time elapsed.
I have arrived at a proposition, ... namely, that spaces traversed in natural motion are in the squared proportion of the times.
Written with modern symbols: s ∝ t2
The result was published in Two New Sciences in 1638. In the same book, Galileo suggested that the slight variance of speed of falling objects of different mass was due to air resistance, and that objects would fall completely uniformly in a vacuum. The relation of the distance of objects in free fall to the square of the time taken was confirmed by Italian Jesuits Grimaldi and Riccioli between 1640 and 1650. They also made a calculation of the gravity of Earth by recording the oscillations of a pendulum.
==== Johannes Kepler ====
In his Astronomia nova (1609), Johannes Kepler proposed an attractive force of limited radius between any "kindred" bodies:
Gravity is a mutual corporeal disposition among kindred bodies to unite or join together; thus the earth attracts a stone much more than the stone seeks the earth. (The magnetic faculty is another example of this sort).... If two stones were set near one another in some place in the world outside the sphere of influence of a third kindred body, these stones, like two magnetic bodies, would come together in an intermediate place, each approaching the other by a space proportional to the bulk [moles] of the other....
Kepler claimed that if the Earth and Moon were not held apart by some force they would come together. He recognized that mechanical forces cause action, resulting in a more modern view of planetary motion, in his view a celestial machine. On the other hand Kepler viewed the force of the Sun on the planets as magnetic and acting tangential to their orbits and he assumed with Aristotle that inertia meant objects tend to come to rest.: 846
==== Giovanni Borelli ====
In 1666, Giovanni Alfonso Borelli avoided the key problems that limited Kepler. By Borelli's time the concept of inertia had its modern meaning as the tendency of objects to remain in uniform motion and he viewed the Sun as just another heavenly body. Borelli developed the idea of mechanical equilibrium, a balance between inertia and gravity. Newton cited Borelli's influence on his theory.: 848
==== Evangelista Torricelli ====
A disciple of Galileo, Evangelista Torricelli reiterated Aristotle's model involving a gravitational centre, adding his view that a system can only be in equilibrium when the common centre itself is unable to fall.
== European Enlightenment ==
The relation of the distance of objects in free fall to the square of the time taken was confirmed by Francesco Maria Grimaldi and Giovanni Battista Riccioli between 1640 and 1650. They also made a calculation of the gravity of Earth constant by recording the oscillations of a pendulum.
=== Mechanical explanations ===
In 1644, René Descartes proposed that no empty space can exist and that a continuum of matter causes every motion to be curvilinear. Thus, centrifugal force thrusts relatively light matter away from the central vortices of celestial bodies, lowering density locally and thereby creating centripetal pressure. Using aspects of this theory, between 1669 and 1690, Christiaan Huygens designed a mathematical vortex model. In one of his proofs, he shows that the distance elapsed by an object dropped from a spinning wheel will increase proportionally to the square of the wheel's rotation time. In 1671, Robert Hooke speculated that gravitation is the result of bodies emitting waves in the aether. Nicolas Fatio de Duillier (1690) and Georges-Louis Le Sage (1748) proposed a corpuscular model using some sort of screening or shadowing mechanism. In 1784, Le Sage posited that gravity could be a result of the collision of atoms, and in the early 19th century, he expanded Daniel Bernoulli's theory of corpuscular pressure to the universe as a whole. A similar model was later created by Hendrik Lorentz (1853–1928), who used electromagnetic radiation instead of corpuscles.
English mathematician Isaac Newton used Descartes' argument that curvilinear motion constrains inertia, and in 1675, argued that aether streams attract all bodies to one another. Newton (1717) and Leonhard Euler (1760) proposed a model in which the aether loses density near mass, leading to a net force acting on bodies. Further mechanical explanations of gravitation (including Le Sage's theory) were created between 1650 and 1900 to explain Newton's theory, but mechanistic models eventually fell out of favor because most of them lead to an unacceptable amount of drag (air resistance), which was not observed. Others violate the energy conservation law and are incompatible with modern thermodynamics.
=== 'Weight' before Newton ===
Before Newton, 'weight' had the double meaning 'amount' and 'heaviness'.What we now know as mass was until the time of Newton called "weight." ... A goldsmith believed that an ounce of gold was a quantity of gold. ... But the ancients believed that a beam balance also measured "heaviness" which they recognized through their muscular senses. ... Mass and its associated downward force were believed to be the same thing.
Kepler formed a [distinct] concept of mass ("amount of matter" (copia materiae), but called it "weight" as did everyone at that time.
=== Mass as distinct from weight ===
In 1686, Newton gave the concept of mass its name. In the first paragraph of Principia, Newton defined quantity of matter as "density and bulk conjunctly", and mass as quantity of matter.The quantity of matter is the measure of the same, arising from its density and bulk conjunctly. ... It is this quantity that I mean hereafter everywhere under the name of body or mass. And the same is known by the weight of each body; for it is proportional to the weight.
=== Newton's law of universal gravitation ===
In 1679, Robert Hooke wrote to Isaac Newton of his hypothesis concerning orbital motion, which partly depends on an inverse-square force. In 1684, both Hooke and Newton told Edmond Halley that they had proven the inverse-square law of planetary motion, in January and August, respectively. While Hooke refused to produce his proofs, Newton was prompted to compose De motu corporum in gyrum ('On the motion of bodies in an orbit'), in which he mathematically derives Kepler's laws of planetary motion. In 1687, with Halley's support (and to Hooke's dismay), Newton published Philosophiæ Naturalis Principia Mathematica (Mathematical Principles of Natural Philosophy), which hypothesizes the inverse-square law of universal gravitation. In his own words:I deduced that the forces which keep the planets in their orbs must be reciprocally as the squares of their distances from the centres about which they revolve; and thereby compared the force requisite to keep the moon in her orb with the force of gravity at the surface of the earth; and found them to answer pretty nearly.
Newton's original formula was:
F
o
r
c
e
o
f
g
r
a
v
i
t
y
∝
m
a
s
s
o
f
o
b
j
e
c
t
1
×
m
a
s
s
o
f
o
b
j
e
c
t
2
d
i
s
t
a
n
c
e
f
r
o
m
c
e
n
t
e
r
s
2
{\displaystyle {\rm {Force\,of\,gravity}}\propto {\frac {\rm {mass\,of\,object\,1\,\times \,mass\,of\,object\,2}}{\rm {distance\,from\,centers^{2}}}}}
where the symbol
∝
{\displaystyle \propto }
means "is proportional to". To make this into an equal-sided formula or equation, there needed to be a multiplying factor or constant that would give the correct force of gravity no matter the value of the masses or distance between them – the gravitational constant. Newton would need an accurate measure of this constant to prove his inverse-square law. Reasonably accurate measurements were not available in until the Cavendish experiment by Henry Cavendish in 1797.
In Newton's theory (rewritten using more modern mathematics) the density of mass
ρ
{\displaystyle \rho \,}
generates a scalar field, the gravitational potential
φ
{\displaystyle \varphi \,}
in joules per kilogram, by
∂
2
φ
∂
x
j
∂
x
j
=
4
π
G
ρ
.
{\displaystyle {\partial ^{2}\varphi \over \partial x^{j}\,\partial x^{j}}=4\pi G\rho \,.}
Using the Nabla operator
∇
{\displaystyle \nabla }
for the gradient and divergence (partial derivatives), this can be conveniently written as:
∇
2
φ
=
4
π
G
ρ
.
{\displaystyle \nabla ^{2}\varphi =4\pi G\rho \,.}
This scalar field governs the motion of a free-falling particle by:
d
2
x
j
d
t
2
=
−
∂
φ
∂
x
j
.
{\displaystyle {d^{2}x^{j} \over dt^{2}}=-{\partial \varphi \over \partial x^{j}\,}.}
At distance r from an isolated mass M, the scalar field is
φ
=
−
G
M
r
.
{\displaystyle \varphi =-{\frac {GM}{r}}\,.}
The Principia sold out quickly, inspiring Newton to publish a second edition in 1713.
However the theory of gravity itself was not accepted quickly.
The theory of gravity faced two barriers. First scientists like Gottfried Wilhelm Leibniz complained that it relied on action at a distance, that the mechanism of gravity was "invisible, intangible, and not mechanical".: 339 : 144 The French philosopher Voltaire countered these concerns, ultimately writing his own book to explain aspects of it to French readers in 1738, which helped to popularize Newton's theory.
Second, detailed comparisons with astronomical data were not initially favorable. Among the most conspicuous issue was the so-called great inequality of Jupiter and Saturn. Comparisons of ancient astronomical observations to those of the early 1700s implied that the orbit of Saturn was increasing in diameter while that of Jupiter was decreasing. Ultimately this meant Saturn would exit the Solar System and Jupiter would collide with other planets or the Sun. The problem was tackled first by Leonhard Euler in 1748, then Joseph-Louis Lagrange in 1763, by Pierre-Simon Laplace in 1773. Each effort improved the mathematical treatment until the issue was resolved by Laplace in 1784 approximately 100 years after Newton's first publication on gravity. Laplace showed that the changes were periodic but with immensely long periods beyond any existing measurements.: 144
Successes such the solution to the great inequality of Jupiter and Saturn mystery accumulated. In 1755, Prussian philosopher Immanuel Kant published a cosmological manuscript based on Newtonian principles, in which he develops an early version of the nebular hypothesis. Edmond Halley proposed that similar looking objects appearing every 76 years was in fact a single comet. The appearance of the comet in 1759, now named after him, within a month of predictions based on Newton's gravity greatly improved scientific opinion of the theory. Newton's theory enjoyed its greatest success when it was used to predict the existence of Neptune based on motions of Uranus that could not be accounted by the actions of the other planets. Calculations by John Couch Adams and Urbain Le Verrier both predicted the general position of the planet. In 1846, Le Verrier sent his position to Johann Gottfried Galle, asking him to verify it. The same night, Galle spotted Neptune near the position Le Verrier had predicted.
Not every comparison was successful. By the end of the 19th century, Le Verrier showed that the orbit of Mercury could not be accounted for entirely under Newtonian gravity, and all searches for another perturbing body (such as a planet orbiting the Sun even closer than Mercury) were fruitless. Even so, Newton's theory is thought to be exceptionally accurate in the limit of weak gravitational fields and low speeds.
At the end of the 19th century, many tried to combine Newton's force law with the established laws of electrodynamics (like those of Wilhelm Eduard Weber, Carl Friedrich Gauss, and Bernhard Riemann) to explain the anomalous perihelion precession of Mercury. In 1890, Maurice Lévy succeeded in doing so by combining the laws of Weber and Riemann, whereby the speed of gravity is equal to the speed of light. In another attempt, Paul Gerber (1898) succeeded in deriving the correct formula for the perihelion shift (which was identical to the formula later used by Albert Einstein). These hypotheses were rejected because of the outdated laws they were based on, being superseded by those of James Clerk Maxwell.
== Modern era ==
In 1900, Hendrik Lorentz tried to explain gravity on the basis of his ether theory and Maxwell's equations. He assumed, like Ottaviano Fabrizio Mossotti and Johann Karl Friedrich Zöllner, that the attraction of opposite charged particles is stronger than the repulsion of equal charged particles. The resulting net force is exactly what is known as universal gravitation, in which the speed of gravity is that of light. Lorentz calculated that the value for the perihelion advance of Mercury was much too low.
In the late 19th century, Lord Kelvin pondered the possibility of a theory of everything. He proposed that every body pulsates, which might be an explanation of gravitation and electric charges. His ideas were largely mechanistic and required the existence of the aether, which the Michelson–Morley experiment failed to detect in 1887. This, combined with Mach's principle, led to gravitational models which feature action at a distance.
Albert Einstein developed his revolutionary theory of relativity in papers published in 1905 and 1915; these account for the perihelion precession of Mercury. In 1914, Gunnar Nordström attempted to unify gravity and electromagnetism in his theory of five-dimensional gravitation. General relativity was proven in 1919, when Arthur Eddington observed gravitational lensing around a solar eclipse, matching Einstein's equations. This resulted in Einstein's theory superseding Newtonian physics. Thereafter, German mathematician Theodor Kaluza promoted the idea of general relativity with a fifth dimension, which in 1921 Swedish physicist Oskar Klein gave a physical interpretation of in a prototypical string theory, a possible model of quantum gravity and potential theory of everything.
Einstein's field equations include a cosmological constant to account for the alleged staticity of the universe. However, Edwin Hubble observed in 1929 that the universe appears to be expanding. By the 1930s, Paul Dirac developed the hypothesis that gravitation should slowly and steadily decrease over the course of the history of the universe. Alan Guth and Alexei Starobinsky proposed in 1980 that cosmic inflation in the very early universe could have been driven by a negative pressure field, a concept later coined 'dark energy'—found in 2013 to have composed around 68.3% of the early universe.
In 1922, Jacobus Kapteyn proposed the existence of dark matter, an unseen force that moves stars in galaxies at higher velocities than gravity alone accounts for. It was found in 2013 to have comprised 26.8% of the early universe. Along with dark energy, dark matter is an outlier in Einstein's relativity, and an explanation for its apparent effects is a requirement for a successful theory of everything.
In 1957, Hermann Bondi proposed that negative gravitational mass (combined with negative inertial mass) would comply with the strong equivalence principle of general relativity and Newton's laws of motion. Bondi's proof yielded singularity-free solutions for the relativity equations.
Early theories of gravity attempted to explain planetary orbits (Newton) and more complicated orbits (e.g. Lagrange). Then came unsuccessful attempts to combine gravity and either wave or corpuscular theories of gravity. The whole landscape of physics was changed with the discovery of Lorentz transformations, and this led to attempts to reconcile it with gravity. At the same time, experimental physicists started testing the foundations of gravity and relativity—Lorentz invariance, the gravitational deflection of light, the Eötvös experiment. These considerations led to and past the development of general relativity.
=== Einstein (1905–1912) ===
In 1905, Albert Einstein published a series of papers in which he established the special theory of relativity and the fact that mass and energy are equivalent. In 1907, in what he described as "the happiest thought of my life", Einstein realized that someone who is in free fall experiences no gravitational field. In other words, gravitation is exactly equivalent to acceleration.
Einstein's two-part publication in 1912 (and before in 1908) is really only important for historical reasons. By then he knew of the gravitational redshift and the deflection of light. He had realized that Lorentz transformations are not generally applicable, but retained them. The theory states that the speed of light is constant in free space but varies in the presence of matter. The theory was only expected to hold when the source of the gravitational field is stationary. It includes the principle of least action:
δ
∫
d
τ
=
0
{\displaystyle \delta \int d\tau =0\,}
d
τ
2
=
−
η
μ
ν
d
x
μ
d
x
ν
{\displaystyle {d\tau }^{2}=-\eta _{\mu \nu }\,dx^{\mu }\,dx^{\nu }\,}
where
η
μ
ν
{\displaystyle \eta _{\mu \nu }\,}
is the Minkowski metric, and there is a summation from 1 to 4 over indices
μ
{\displaystyle \mu \,}
and
ν
{\displaystyle \nu \,}
.
Einstein and Grossmann includes Riemannian geometry and tensor calculus.
δ
∫
d
τ
=
0
{\displaystyle \delta \int d\tau =0\,}
d
τ
2
=
−
g
μ
ν
d
x
μ
d
x
ν
{\displaystyle {d\tau }^{2}=-g_{\mu \nu }\,dx^{\mu }\,dx^{\nu }\,}
The equations of electrodynamics exactly match those of general relativity. The equation
T
μ
ν
=
ρ
d
x
μ
d
τ
d
x
ν
d
τ
{\displaystyle T^{\mu \nu }=\rho {dx^{\mu } \over d\tau }{dx^{\nu } \over d\tau }\,}
is not in general relativity. It expresses the stress–energy tensor as a function of the matter density.
=== Lorentz-invariant models (1905–1910) ===
Based on the principle of relativity, Henri Poincaré (1905, 1906), Hermann Minkowski (1908), and Arnold Sommerfeld (1910) tried to modify Newton's theory and to establish a Lorentz invariant gravitational law, in which the speed of gravity is that of light. As in Lorentz's model, the value for the perihelion advance of Mercury was much too low.
=== Abraham (1912) ===
Meanwhile, Max Abraham developed an alternative model of gravity in which the speed of light depends on the gravitational field strength and so is variable almost everywhere. Abraham's 1914 review of gravitation models is said to be excellent, but his own model was poor.
=== Nordström (1912) ===
The first approach of Nordström (1912) was to retain the Minkowski metric and a constant value of
c
{\displaystyle c\,}
but to let mass depend on the gravitational field strength
φ
{\displaystyle \varphi \,}
. Allowing this field strength to satisfy
◻
φ
=
ρ
{\displaystyle \Box \varphi =\rho \,}
where
ρ
{\displaystyle \rho \,}
is rest mass energy and
◻
{\displaystyle \Box \,}
is the d'Alembertian,
m
=
m
0
exp
(
φ
c
2
)
{\displaystyle m=m_{0}\exp \left({\frac {\varphi }{c^{2}}}\right)\,}
where
m
0
{\displaystyle m_{0}}
is the mass when gravitational potential vanishes and,
−
∂
φ
∂
x
μ
=
u
˙
μ
+
u
μ
c
2
φ
˙
{\displaystyle -{\partial \varphi \over \partial x^{\mu }}={\dot {u}}_{\mu }+{u_{\mu } \over c^{2}{\dot {\varphi }}}\,}
where
u
{\displaystyle u\,}
is the four-velocity and the dot is a differential with respect to time.
The second approach of Nordström (1913) is remembered as the first logically consistent relativistic field theory of gravitation ever formulated. (notation from Pais not Nordström):
δ
∫
ψ
d
τ
=
0
{\displaystyle \delta \int \psi \,d\tau =0\,}
d
τ
2
=
−
η
μ
ν
d
x
μ
d
x
ν
{\displaystyle {d\tau }^{2}=-\eta _{\mu \nu }\,dx^{\mu }\,dx^{\nu }\,}
where
ψ
{\displaystyle \psi \,}
is a scalar field,
−
∂
T
μ
ν
∂
x
ν
=
T
1
ψ
∂
ψ
∂
x
μ
{\displaystyle -{\partial T^{\mu \nu } \over \partial x^{\nu }}=T{1 \over \psi }{\partial \psi \over \partial x_{\mu }}\,}
This theory is Lorentz invariant, satisfies the conservation laws, correctly reduces to the Newtonian limit and satisfies the weak equivalence principle.
=== Einstein and Fokker (1914) ===
This theory is Einstein's first treatment of gravitation in which general covariance is strictly obeyed. Writing:
δ
∫
d
s
=
0
{\displaystyle \delta \int ds=0\,}
d
s
2
=
g
μ
ν
d
x
μ
d
x
ν
{\displaystyle {ds}^{2}=g_{\mu \nu }\,dx^{\mu }\,dx^{\nu }\,}
g
μ
ν
=
ψ
2
η
μ
ν
{\displaystyle g_{\mu \nu }=\psi ^{2}\eta _{\mu \nu }\,}
they relate Einstein–Grossmann to Nordström. They also state:
T
∝
R
.
{\displaystyle T\,\propto \,R\,.}
That is, the trace of the stress energy tensor is proportional to the curvature of space.
Between 1911 and 1915, Einstein developed the idea that gravitation is equivalent to acceleration, initially stated as the equivalence principle, into his general theory of relativity, which fuses the three dimensions of space and the one dimension of time into the four-dimensional fabric of spacetime. However, it does not unify gravity with quanta—individual particles of energy, which Einstein himself had postulated the existence of in 1905.
=== General relativity ===
In general relativity, the effects of gravitation are ascribed to spacetime curvature instead of to a force. The starting point for general relativity is the equivalence principle, which equates free fall with inertial motion. The issue that this creates is that free-falling objects can accelerate with respect to each other. To deal with this difficulty, Einstein proposed that spacetime is curved by matter, and that free-falling objects are moving along locally straight paths in curved spacetime. More specifically, Einstein and David Hilbert discovered the field equations of general relativity, which relate the presence of matter and the curvature of spacetime. These field equations are a set of 10 simultaneous, non-linear, differential equations. The solutions of the field equations are the components of the metric tensor of spacetime, which describes its geometry. The geodesic paths of spacetime are calculated from the metric tensor.
Notable solutions of the Einstein field equations include:
The Schwarzschild solution, which describes spacetime surrounding a spherically symmetrical non-rotating uncharged massive object. For objects with radii smaller than the Schwarzschild radius, this solution generates a black hole with a central singularity.
The Reissner–Nordström solution, in which the central object has an electrical charge. For charges with a geometrized length less than the geometrized length of the mass of the object, this solution produces black holes with an event horizon surrounding a Cauchy horizon.
The Kerr solution for rotating massive objects. This solution also produces black holes with multiple horizons.
The cosmological Robertson–Walker solution (from 1922 and 1924), which predicts the expansion of the universe.
General relativity has enjoyed much success because its predictions (not called for by older theories of gravity) have been regularly confirmed. For example:
General relativity accounts for the anomalous perihelion precession of Mercury.
Gravitational lensing was first confirmed in 1919, and has more recently been strongly confirmed through the use of a quasar which passes behind the Sun as seen from the Earth.
The expansion of the universe (predicted by the Robertson–Walker metric) was confirmed by Edwin Hubble in 1929.
The prediction that time runs slower at lower potentials has been confirmed by the Pound–Rebka experiment, the Hafele–Keating experiment, and the GPS.
The time delay of light passing close to a massive object was first identified by Irwin Shapiro in 1964 in interplanetary spacecraft signals.
Gravitational radiation has been indirectly confirmed through studies of binary pulsars such as PSR 1913+16.
In 2015, the LIGO experiments directly detected gravitational radiation from two colliding black holes, making this the first direct observation of both gravitational waves and black holes.
It is believed that neutron star mergers (since detected in 2017) and black hole formation may also create detectable amounts of gravitational radiation.
=== Quantum gravity ===
Several decades after the discovery of general relativity, it was realized that it cannot be the complete theory of gravity because it is incompatible with quantum mechanics. Later it was understood that it is possible to describe gravity in the framework of quantum field theory like the other fundamental forces. In this framework, the attractive force of gravity arises due to exchange of virtual gravitons, in the same way as the electromagnetic force arises from exchange of virtual photons. This reproduces general relativity in the classical limit, but only at the linearized level and postulating that the conditions for the applicability of Ehrenfest theorem holds, which is not always the case. Moreover, this approach fails at short distances of the order of the Planck length.
== See also ==
Anti-gravity
History of physics
== Notes ==
== References ==
=== Citations ===
=== Sources ===
Gillispie, Charles Coulston (1960). The Edge of Objectivity: An Essay in the History of Scientific Ideas. Princeton University Press. ISBN 0-691-02350-6. {{cite book}}: ISBN / Date incompatibility (help)
Wallace, W. A. (2004a). "The enigma of Domingo de Soto: Uniformiter difformis and falling bodies in late medieval physics". In Wallace, W. A. (ed.). Domingo de Soto and the early Galileo: Essays on intellectual history. Routledge. (Reprinted from "The enigma of Domingo de Soto: Uniformiter difformis and falling bodies in late medieval physics". (1968). Isis, 59(4), 384–401).
Wallace, W. A. (2004b). "Domingo de Soto and the Iberian roots of Galileo's science". In Wallace, W. A. (ed.). Domingo de Soto and the early Galileo: Essays on intellectual history. Routledge. (Reprinted from White, K. (Ed.). (1997). Hispanic philosophy in the age of discovery. Studies in Philosophy and the History of Philosophy 29. Catholic University of America Press). | Wikipedia/Gravitational_theory |
Synergetic theory, also known as "synergy" and referred to by some as a pseudoscientific theory, was developed by René-Louis Vallée and first disseminated in 1971 with the publication of his book L'énergie électromagnétique matérielle et gravitationally (Material and Gravitational Electromagnetic Energy).
The magazine Science et Vie published several articles on the subject, and in 1975, it reported on an experiment that allegedly generated more energy than was input into the system. This sparked a long-standing controversy over the discovery of "free energy." The following year, La Recherche examined Vallée's book and, under his guidance, commissioned physicists to conduct a rigorous test to verify or refute the initial claims. The results were negative: no excess energy was observed.
A critical examination of the theory in question reveals a multitude of inconsistencies. It becomes evident that the author's work is based on his personal beliefs, formulating a set of disconnected equations. Vallée opposed modern physics, viewing the theoretical advancements of the 20th century as overly intricate and incompatible with reality.
Vallée was affiliated with the Alexandre Dufour Physics Circle and supported by free-energy enthusiasts until the early 2000s, which enabled him to achieve a certain degree of media presence before synergetics faded from public discourse.
== History ==
René-Louis Vallée (1926–2007), a 1951 graduate of Supélec, was employed by Alsthom from 1953 to 1958 and subsequently by the French Atomic Energy Commission (CEA) until 1976. Between 1970 and 1974, he authored several books about his professional expertise.
Vallée, a student of Louis de Broglie during his studies, developed a lifelong interest in physics and an alternative theory aimed at unifying the four fundamental forces. This culminated in the publication of his book, L'énergie électromagnétique matérielle et gravitationnelle, in 1971.
As a member of the Alexandre Dufour Physics Circle, Vallée promoted his book and theory during a 1972 lecture. The main objective of the circle was to challenge the tenets of modern physics. Despite presenting his critiques of physics objectively in his written works, Vallée expressed clear anti-relativist sentiments in his speeches, rejecting what he described as a "blind worship of revealed relativity."
In the context of the initial oil crisis, Vallée advanced his theory as a radical departure from conventional wisdom, asserting that global capitalism had hastily embraced relativity with the fervor of a religious doctrine. He leveled accusations against several physicists, characterizing their views as those of members of a "discreet philosophical-scientific sect." In a letter to La Recherche, he referred to Richard Feynman as a "man in black."
Following his dismissal from the CEA in 1976, Vallée engaged in a public debate with Industry Minister André Giraud on the radio program Le téléphone sonne in 1979. He challenged the prevailing preference for nuclear power, advocating instead for his concept of "free energy."
In February 1974, Science et Vie commenced coverage of synergistic theory, subsequently revisiting the topic in January 1975. During this latter period, Vallée employed his theory to elucidate the failure of nuclear fusion experiments in tokamaks, asserting that conventional scientific paradigms lacked rational explanations.
In 1976, forming a support committee for Vallée resulted in the establishment of the SEPED (Society for the Study and Promotion of Diffuse Energy), which was operational between 1976 and 1984.
In the context of the 1978 French nuclear debate, anti-nuclear activist René Barjavel expressed support for Vallée's Lettre ouverte aux vivants et à ceux qui veulent le rester (An open letter to the living and those who wish to remain living), citing the latter's theory as a disruption to the habits of thought and work that had been based on relativity for approximately half a century. Barjavel further noted that Einstein and his contemporaries had asserted that space vehicles could never exceed the speed of light, a claim that he regarded as untenable.
Vallée expressed dismay at the apparent lack of interest in synergistic, suggesting that there were conspiracies at play, involving official science, global capitalism, and even the World Zionist Organization, which were preventing scientific progress. In a letter to Prime Minister Jacques Chirac dated May 21, 1986, he reiterated these accusations.
Vallée was unable to disseminate his theory through conventional channels; therefore, he turned to the Internet as a means of sharing his ideas.
By the year 2000, he had become a member of the New York Academy of Sciences and had written the preface for a scientific document in which he discussed his theory, which was subsequently renamed GUST (Grand Unified Synergetic Theory).
While Vallée's work receded from public consciousness, the concept of free energy endured. In 2003, the Swiss-based GIFNET (Global Institute for New Energy Technologies) was established, with its French director Jean-Luc Naudin espousing the tenets of the synergistic theory. The institute has since ceased to maintain an online presence.
== Definitions ==
In 1973, Vallée submitted the terms "synergy" and "synergetic theory" to the French Academy's Committee for Technical Terms. In his 1971 book, he introduced the concept of "synergetic potential", which he defined as follows:
V
=
c
2
{\displaystyle V=c^{2}}
: The square of the propagation speed of electromagnetic waves in a vacuum filled with matter.
Science et Vie widely adopted the terms " synergistic" and "synergetic theory", which described the "synergetic generator" or "battery" as a device purportedly capable of harnessing the diffuse energy present in the universe.
Vallée discussed the potential for harnessing "diffuse electromagnetic energy that traverses the immensity of the Universe", which could be realized with a more profound comprehension of the characteristics of matter, particularly within "diffuse energetic environments."
This central notion of synergetic theory inspired the designation of the SEPED (Society for the Study and Promotion of Diffuse Energy), which was operational for less than a decade.
== Synergy ==
René-Louis Vallée offered a critique of the complexity of special relativity but drew extensively upon its conceptual framework. He put forth a concept of "synergy", or total energy, which he expressed through the formula S=mc2. This formula is identical to Albert Einstein's, but it incorporates not only the system's energy but also the diffuse energy of the medium surrounding it. However, his other theoretical propositions diverged from the prevailing consensus. For Vallée, space was Euclidean, time was universal, and the speed of light was not constant. He also proposed that gravitation is a force of electromagnetic origin, which contrasts with Einstein's advancements in the field, which deepened understanding but lacked definitive explanations.
=== Laws ===
Synergetics puts forth two hypotheses regarding the conversion between energy and matter. The first is the "law of materialization", which posits that energy can be transformed into matter. The second is the "upper limit value of the electric field", which suggests that matter can be transformed into energy when a field reaches a value of 39 × 1015 V/m. These laws are, in fact, hypotheses. Vallée characterizes the law of materialization as "a fundamental law of nature that was missing from the known laws of physics."
He claimed to have discovered an "inexhaustible source of cosmic energy" available everywhere, asserting that matter is a localized form of this diffuse energy, explained through his upper limit field hypothesis.
=== Diffuse energy ===
Vallée put forth the theory that the universe is permeated by a vast, hitherto undiscovered form of "diffuse energy", which can account for all observable physical phenomena. According to this hypothesis, elementary particles represent distinct manifestations of this energy.
In Chapter 9 of his book, Vallée posited that "gravitation and cosmic radiation have a common origin in diffuse electromagnetic energy." He put forth the hypothesis that the speed of light is variable and dependent on the diffuse medium through which it propagates, deriving a formula for the "energy equivalence of gravitational fields:"
δ
W
δ
t
=
ρ
0
−
1
8
π
k
(
γ
)
2
{\displaystyle {\frac {\delta W}{\delta t}}=\rho _{0}-{\frac {1}{8\pi {k}}}(\gamma )^{2}}
A simple calculation shows that a cubic metre of empty space on the Earth's surface contains 57,000 Megajoules less energy than a cubic metre of interstellar space.
This formula is, apart from one factor, the same as that for gravitational potential energy. The added constant,
ρ
0
{\displaystyle \rho _{0}}
, is the energy density of the matter-free diffuse medium, but the theory doesn't know how to calculate it, and Vallée merely gives orders of magnitude.
=== Experiments ===
In 1975, Belgian scientist Eric d'Hoker conducted the inaugural experiment based on synergetic theory in Mortsel. The results indicated that the generated energy was four times the input. The experiment entailed charging a capacitor with a battery and then discharging the current through a graphite rod. Vallée ascribed the surplus energy to a reaction in which a carbon-12 atom transformed a radioactive boron-12 atom, which subsequently reverted to carbon via beta decay, thereby releasing additional energy.
A second experiment was conducted on January 23, 1976, at the Physics Faculty of Paris 7, by Francis Kovacs, to validate the aforementioned findings. The experiment was designed to confirm the energy surplus and convert it into usable electric current, using parameters provided by Vallée. A capacitor was used to discharge a current through a glass tube filled with powdered graphite, surrounded by a coil that recovered a secondary current, which was then visualized on an oscilloscope. Tests were conducted in three configurations: no magnetic field, a field aligned with the electric current, and a field opposed to it. In all cases, the results matched the predictions made by the Lenz-Faraday law, showing no "synergetic" effects.
== Criticism ==
Vallée posited that synergetic theory could be used to harness limitless energy from any point in space using a simple, inexpensive device. In November 1975, Science et Vie published an article endorsing Vallée's theory based on a single experiment and critiqued the lack of interest from physicists.
In the wake of the 1976 verification, which yielded negative results, Michel de Pracontal drew parallels between synergetics and a contemporary iteration of perpetual motion, noting that both promised the generation of free energy from seemingly unlimited sources.
The individual who conducted the counter-experiment, Jean-Marc Lévy-Leblond, was highly critical of Vallée, who postulated a conspiracy against his theory. Lévy-Leblond argued that the principles of synergetics were not susceptible to refutation, as they were not formalized and predictive, and therefore not scientific. He described Vallée's theoretical framework as incomprehensible, likening it to the peculiar calligraphy of Saul Steinberg, composed of recognizable symbols but lacking an intelligible whole.
Vallée's apparent objective was to develop a comprehensive theoretical framework, which he referred to as a "theory of everything." He sought to portray synergetics as a "quantum and gravitational energy theory" that would restore objectivity to science by making it "accessible to the general public."
Nevertheless, this assertion of accessibility proved to be illusory upon examination of the text in question. Furthermore, Vallée himself never subjected his theories to empirical testing, thereby rendering them inherently unverifiable.
== Legacy ==
Synergetic theory, which was promoted by free-energy advocates from the 1970s to the early 2000s, enjoyed a brief period of popularity between its coverage in Science et Vie and its definitive refutation in La Recherche. It has since become an example of "alter-science", according to Alexandre Moatti, and a scientific imposture, per Michel de Pracontal.
Moatti drew a parallel between Vallée and Maurice Allais, who developed an interest in physics at a relatively advanced age and published his inaugural theory on the subject at the age of 86. Allais is renowned for challenging the prevailing theories of Newton and Einstein. He shares similarities with Vallée in this regard. Nevertheless, the term "synergetics" is more frequently linked with Nikola Tesla and his notion of free energy. In the early 20th century, renowned engineer Nikola Tesla sought to transmit electricity wirelessly and harness cosmic radiation energy. Despite the discovery of X-rays in 1895, Tesla rejected the concept of energy contained within matter. In 1931, he claimed to have constructed a "cosmic energy receiver" and used it to power a vehicle. Like Vallée, Tesla rejected overly theoretical science, dismissed the theory of relativity as false, and announced a "unified theory of gravitation" that explained this force simply and denied Einstein's concept of curved space.
== René-Louis Vallée bibliography ==
Reference Work
Vallée, René-Louis (1971). L'énergie électromagnétique matérielle et gravitationnelle : Hypothèse d'existence des milieux énergétiques et d'une valeur limite supérieure du champ électrique [Material and gravitational electromagnetic energy: Hypothesis of the existence of energetic media and an upper limit value for the electric field] (in French). Paris: Masson et Cie.
Presentations and writings
Vallée, René-Louis (2005). "Les bases de la mécanique synergétique" [The basics of synergetic mechanics]. webalors.org (in French). Archived from the original (PDF) on November 22, 2024. Retrieved February 6, 2018.
Vallée, René-Louis. "Étude du mouvement des particules chargées en milieu diélectrique non homogène »" [Study of the motion of charged particles in inhomogeneous dielectric media]. webalors.org (in French). Archived from the original on November 22, 2024. Retrieved February 6, 2018.
Vallée, René-Louis. Notes sur la nature diélectrique des champs de gravitation [Notes on the dielectric nature of gravitational fields] (in French).
Vallée, René-Louis. La Synergie des noyaux et la radioactivité [Nucleus synergy and radioactivity] (in French).
Vallée, René-Louis. La théorie synergétique : Exposé d'ensemble fait par René-Louis Vallée à la mutualité le 4 février 1976 [Synergetic theory: Comprehensive presentation by René-Louis Vallée at the Mutualité on February 4, 1976] (in French).
Vallée, René-Louis. "La théorie synergétique modèle cosmologique" [Synergetic theory cosmological model]. webalors.org (in French). Archived from the original (PDF) on November 22, 2024. Retrieved February 6, 2018.
Vallée, René-Louis. "Le vide producteur d'énergie - Captation de l'énergie diffuse de l'espace" [The energy-producing vacuum - Capturing the diffuse energy of space]. jlnlabs.online.fr (in French). Archived from the original on July 21, 2024. Retrieved February 6, 2018.
Vallée, René-Louis. "PROTELF - (PROTon-ELectron-Fusion)". jlnlabs.online.fr (in French). Archived from the original on March 25, 2023. Retrieved February 6, 2018.
== Notes ==
== References ==
== Bibliography ==
Lévy-Leblond, Jean-Marc (1976). "La « théorie synergétique » de monsieur Vallée" [Mr. Vallée's “Synergetic Theory"]. La Recherche (in French). 7 (69): 661–662.
Lisan, Benjamin (1978). "La Théorie Synergétique, une étude critique". Archived from the original on May 1, 2016.
Moatti, Alexandre (2013). Alterscience : Postures, dogmes, idéologies [Alterscience: Postures, dogmas, ideologies]. Sciences (in French). Paris: Odile Jacob. pp. 85–97. ISBN 978-2-7381-2887-4.
de Pracontal, Michel (2005). L'imposture scientifique en dix leçons [The scientific imposture in ten lessons]. Points - Sciences (in French) (3rd ed.). Seuil. pp. 92–94. ISBN 978-2-02-063944-6.
de La Taille, Renaud (1975). "Qui osera réfuter la synergétique ? : Alors que le premier générateur synergétique vient de fonctionner, la science officielle continue à ignorer les travaux du Pr. Vallée. Ceci est d'autant plus grave que les travaux mènent à l'indépendance énergétique. Aussi demandons-nous aux chercheurs de se prononcer sans équivoque sur la valeur de la théorie synergétique" [Who will dare to refute Synergetics? While the first Synergetic generator has just been put into operation, official science continues to ignore Prof. Vallée's work. This is all the more serious as the work is leading to energy independence. We therefore ask researchers to state unequivocally their position on the value of synergy theory] (PDF). Science & Vie (in French) (698). Archived from the original (PDF) on July 13, 2024.
de La Taille, Renaud (1976). "Un jeune français construit une pile inépuisable" [A young Frenchman builds an inexhaustible battery]. Science & Vie (in French) (700).
Articles from the circle of friends of Vallée or SEPED
Friang, Claude Y. (1979). "Énergie : Einstein, Maxwell et la synergétique" [Energy: Einstein, Maxwell and Synergetics]. Impact science et société (in French). 29 (4). UNESCO: 415–417. Archived from the original on December 2, 2022. Retrieved February 6, 2018. | Wikipedia/Synergetic_theory |
The Strauss–Howe generational theory, devised by William Strauss and Neil Howe, is a psychohistorical theory which describes a theorized recurring generation cycle in American and Western history.
According to the theory, historical events are associated with recurring generational personas (archetypes). Each generational persona unleashes a new era (called a turning) lasting around 21 years, in which a new social, political, and economic climate (mood) exists. They are part of a larger cyclical "saeculum" (a long human life, which usually spans around 85 years, although some saecula have lasted longer). The theory states that a crisis recurs in American history after every saeculum, which is followed by a recovery (high). During this recovery, institutions and communitarian values are strong. Ultimately, succeeding generational archetypes attack and weaken institutions in the name of autonomy and individualism, which eventually creates a tumultuous political environment that ripens conditions for another crisis.
Academic response to the theory has been mixed, with some applauding Strauss and Howe for their "bold and imaginative thesis", while others have criticized the theory as being overly deterministic, unfalsifiable, and unsupported by rigorous evidence. The theory has been influential in the fields of generational studies, marketing, and business management literature. However, the theory has also been described by some historians and journalists as pseudoscientific, "kooky", and "an elaborate historical horoscope that will never withstand scholarly scrutiny". Academic criticism has focused on the lack of rigorous empirical evidence for their claims, as well as the authors' view that generational groupings are more powerful than other social groupings, such as economic class, race, sex, religion, and political parties. However, Strauss and Howe later suggested that there are no exact generational boundaries – the speed of their development cannot be predicted. The authors also compared the cycles with the seasons, which may come sooner or later.
== History ==
William Strauss and Neil Howe's partnership began in the late 1980s when they began writing their first book Generations, which discusses the history of the United States as a succession of generational biographies. Each had written on generational topics previously. The authors' interest in generations as a broader topic emerged after they met in Washington, D.C., and began discussing the connections between each of their previous works.
They attempted to find the reason why the Boomers and the G.I.s had developed such different ways of looking at the world, and what it was about these generations' experiences growing up that prompted their different outlooks. They also wanted to find patterns in previous generations, and their research discussed historical analogs to the current generations. They ultimately described a recurring pattern in the Anglo-American history of four generational types, each with a distinct collective persona, and a corresponding cycle of four different types of eras, each with a distinct "mood".
Strauss and Howe laid the groundwork for their theory in their book Generations: The History of America's Future, 1584 to 2069 (1991), which discusses the history of the United States as a series of generational biographies going back to 1584.
Strauss and Howe followed in 1993 with their second book 13th Gen: Abort, Retry, Ignore, Fail?, which was published while Gen Xers were teenagers and young adults. The book examines the generation born between 1961 and 1981, "Gen-Xers" (which they called "13ers", describing them as the thirteenth generation since the US became a nation). The book asserts that 13ers' location in history as under-protected children during the Consciousness Revolution explains their pragmatic attitude. They describe Gen Xers as growing up during a time when society was less focused on children and more focused on adults and their self-actualization.
Strauss and Howe's theory made various predictions regarding the Millennial generation, a group consisting of young children at the time. These predictions lacked significant historical data. In Generations (1991) and The Fourth Turning (1997), the two authors discussed the generation gap between Baby Boomers and their parents and predicted there would be no such gap between Millennials and their elders.
In 2000, they published Millennials Rising: The Next Great Generation. This work discussed the personality of the Millennial Generation, whose oldest members were described as the high school graduating class of the year 2000. In the 2000 book, Strauss and Howe asserted that Millennial teens and young adults were recasting the image of youth from "downbeat and alienated to upbeat and engaged", crediting increased parental attention and protection for these positive changes. They asserted that Millennials are held to higher standards than adults apply to themselves and that they are much less vulgar and violent than the teen culture older people produce for them. They described them as less sexually charged and as ushering in a new sexual modesty, with an increasing belief that sex should be saved for marriage and a return to conservative family values.
The authors predicted that over the following decade, Millennials would transform what it means to be young, and could emerge as the next "Great Generation". The work was described as an optimistic, feel-good book for the parents of the Millennial Generation, predominantly the Baby Boomers.
The theory was expanded in The Fourth Turning (1997), to focus on a fourfold cycle of generational types and recurring mood eras to describe the history of the United States, including the Thirteen Colonies and their British antecedents. However, the authors have also examined generational trends elsewhere in the world and described similar cycles in several developed countries.The terminology for generational archetypes were updated(e.g. "Civics" became "Heroes", which they applied to the Millennial Generation, "Adaptives" became "Artists"), and the terms "Turning" and "Saeculum" were introduced.
In the mid-1990s, Strauss and Howe began receiving inquiries about how their research could be applied to strategic problems in organizations. They started speaking frequently about their work at events and conferences.
In July 2023 Howe released a new book, titled The Fourth Turning Is Here.
Steve Bannon, former Chief Strategist and Senior Counselor to president Donald Trump during his first term, is a prominent proponent of the theory. As a documentary filmmaker, Bannon discussed the details of Strauss–Howe generational theory in Generation Zero. According to historian David Kaiser, who was consulted for the film, Generation Zero "focused on the key aspect of their theory, the idea that every 80 years of American history has been marked by a crisis, or 'fourth turning', that destroyed an old order and created a new one". Kaiser said Bannon is "very familiar with Strauss and Howe's theory of crisis, and has been thinking about how to use it to achieve particular goals for quite a while." A February 2017 article from Business Insider titled: "Steve Bannon's obsession with a dark theory of history should be worrisome", commented: "Bannon seems to be trying to bring about the 'Fourth Turning'."
== Defining a generation ==
Strauss and Howe describe the history of the U.S. as a succession of Anglo-American generational biographies from 1433 to the present, and theorized a recurring generational cycle in American history. The authors posit a pattern of four repeating phases, generational types, and a recurring cycle of spiritual awakenings and secular crises, from the founding colonials of America through the present day.
Strauss and Howe define a social generation as the aggregate of all people born over a span of roughly 21 years or about the length of one phase of life: childhood, young adulthood, midlife, and old age. Generations are identified (from the first birthyear to last) by looking for cohort groups of this length that share three criteria. First, members of a generation share what the authors call an age location in history: they encounter key historical events and social trends while occupying the same phase of life. In this view, members of a generation are shaped in lasting ways by the eras they encounter as children and young adults and they share certain common beliefs and behaviors. Aware of the experiences and traits that they share with their peers, members of a generation would also share a sense of common perceived membership in that generation.
They based their definition of a generation on the work of various writers and social thinkers, from ancient writers such as Polybius and Ibn Khaldun to modern social theorists such as José Ortega y Gasset, Karl Mannheim, John Stuart Mill, Émile Littré, Auguste Comte, and François Mentré.
=== Turnings ===
While writing Generations, Strauss and Howe described a theorized pattern in the historical generations they examined, which they say revolved around generational events which they call turnings. In Generations, and in greater detail in The Fourth Turning, they describe a four-stage cycle of social or mood eras which they call "turnings". The turnings include: "the high", "the awakening", "the unraveling", and "the crisis".
==== High ====
According to Strauss and Howe, the first turning is a high, which occurs after a crisis. During the high, institutions are strong and individualism is weak. Society is confident about where it wants to go collectively, though those outside the majoritarian center often feel stifled by conformity.
According to the authors, the most recent first turning in the US was the post–World War II American high, beginning in 1946 and ending with the assassination of John F. Kennedy on November 22, 1963.
==== Awakening ====
According to the theory, the second turning is an awakening. This is an era when institutions are attacked in the name of personal and spiritual autonomy. Just when society is reaching its high tide of public progress, people suddenly tire of social discipline and want to recapture a sense of "self-awareness", "spirituality" and "personal authenticity". Young activists look back at the previous High as an era of cultural and spiritual poverty.
Strauss and Howe say the U.S.'s most recent awakening was the "consciousness revolution", which spanned from the campus and inner-city revolts of the mid-1960s to the tax revolts of the early 1980s.
==== Unraveling ====
According to Strauss and Howe, the third turning is an unraveling. The mood of this era they say is in many ways the opposite of a high: Institutions are weak and distrusted, while individualism is strong and flourishing. The authors say highs come after crises when society wants to coalesce and build and avoid the death and destruction of the previous crisis. Unravelings come after awakenings when society wants to atomize and enjoy. They say the most recent unraveling in the US began in the 1980s and includes the long boom and the culture war.
==== Crisis ====
According to the authors, the fourth turning is a crisis. This is an era of destruction, often involving war or revolution, in which institutional life is destroyed and rebuilt in response to a perceived threat to the nation's survival. After the crisis, civic authority revives, cultural expression redirects toward community purpose, and people begin to locate themselves as members of a larger group.
The authors say the previous fourth turning in the US began with the Wall Street Crash of 1929 and climaxed with the end of World War II. The G.I. generation (which they call a hero archetype, born 1901 to 1924) came of age during this era. They say their confidence, optimism, and collective outlook epitomized the mood of that era. The authors assert the millennial generation (which they also describe as a hero archetype, born 1982 to 2005) shows many similar traits to those of the G.I. youth, which they describe as including rising civic engagement, improving behavior, and collective confidence.
=== Cycle ===
The authors describe each turning as lasting circa 21 years. Four turnings make up a full cycle of circa 85 years, which the authors term a saeculum, after the Latin word meaning both "a long human life" and "a natural century".
Generational change drives the cycle of turnings and determines its periodicity. As each generation ages into the next life phase (and a new social role) society's mood and behavior fundamentally change, giving rise to a new turning. Historical events shape generations in childhood and young adulthood; then, as parents and leaders in midlife and old age, generations in turn shape history.
Each of the four turnings has a distinct "mood" that recurs every saeculum. Strauss and Howe describe these turnings as the "seasons of history". At one extreme is the Awakening, which is analogous to summer, and at the other extreme is the Crisis, which is analogous to winter. The High and the Unraveling are similar to spring and autumn, respectively. Strauss and Howe have discussed 26 theorized turnings over 7 saecula in Anglo-American history, from the year 1433 through today.
The core of Strauss and Howe's ideas is a basic alternation between two different types of eras, Crises and Awakenings. Both of these are defining eras in which people observe that historic events are radically altering their social environment. Crises are periods marked by major secular upheaval, when society focuses on reorganizing the outer world of institutions and public behavior (they say the last American Crisis was the period spanning the Great Depression and World War II). Awakenings are periods marked by cultural or religious renewal when society focuses on changing the inner world of values and private behavior (the last American Awakening was the "Consciousness Revolution" of the 1960s and 1970s).
During Crises, an ethic of collectivism emerges. During Awakenings, an ethic of individualism emerges, and the institutional order is attacked by new social ideals and spiritual agendas. According to the authors, about every 85 years—the length of a long human life—a national Crisis occurs in American society. Roughly halfway to the next Crisis, a cultural Awakening occurs (historically, these have often been called Great Awakenings).
In describing this cycle of Crises and Awakenings, they draw from the work of other historians and social scientists who have also discussed long cycles in American and European history, which have grown to show a trend of economic downturns the more a society has industrialised. The cycle of Crises corresponds with long cycles of war identified by such scholars as Arnold J. Toynbee, Quincy Wright, and L. L. Ferrar Jr., and with geopolitical cycles identified by William R. Thompson and George Modelski. Strauss and Howe say their cycle of Awakenings corresponds with Anthony Wallace's work on revitalization movements; they also say recurring Crises and Awakenings correspond with two-stroke cycles in politics (Walter Dean Burnham, Arthur Schlesinger Sr. and Jr.), foreign affairs (Frank L. Klingberg), and the economy (Nikolai Kondratieff) as well as with long-term oscillations in crime and substance abuse.
=== Archetypes ===
The authors say two different types of eras and two formative age locations associated with them (childhood and young adulthood) produce four generational archetypes that repeat sequentially, in rhythm with the cycle of Crises and Awakenings. In Generations, they refer to these four archetypes as Idealist, Reactive, Civic, and Adaptive. In The Fourth Turning (1997) they change this terminology to Prophet, Nomad, Hero, and Artist. They say the generations in each archetype not only share a similar age-location in history, but they also share some basic attitudes towards family, risk, culture and values, and civic engagement. In essence, generations shaped by similar early-life experiences develop similar collective personas and follow similar life trajectories. To date, Strauss and Howe have described 25 generations in Anglo-American history, each with a corresponding archetype. The authors describe the archetypes as follows:
==== Prophet ====
Prophet (Idealist) generations enter childhood during a High, a time of rejuvenated community life and consensus around a new societal order. Examples: Transcendental Generation, Missionary Generation, Baby Boomers.
==== Nomad ====
Nomad (Reactive) generations enter childhood during an Awakening, a time of social ideals and spiritual agendas when young adults are passionately attacking the established institutional order. Examples: Gilded Generation, Lost Generation, Generation X.
==== Hero ====
Hero (Civic) generations enter childhood during an Unraveling, a time of individual pragmatism, self-reliance, and unrestrained. Examples: Republican Generation, G.I. Generation, Millennials.
==== Artist ====
Artist (Adaptive) generations enter childhood during a Crisis, a time when public consensus, aggressive institutions, and an ethic of personal sacrifice were favored. Examples: Progressive Generation, Silent Generation, Homeland Generation.
=== Summary ===
An average modern life is around 85 years and consists of four periods of ~21 years
Childhood → Young adult → Midlife → Elderhood
A generation is an aggregate of people born every ~21 years
Baby Boomers → Gen X → Millennials → Homelanders
Each generation experiences "four turnings" every ~85 years
High → Awakening → Unraveling → Crisis
A generation is considered "dominant" or "recessive" according to the turning experienced as young adults. But as a youth generation comes of age and defines its collective persona an opposing generational archetype is in its midlife peak of power.
Dominant: independent behavior + attitudes in defining an era
Recessive: dependent role in defining an era
Dominant generations
Prophet (idealist): Awakening as young adults. Awakening, defined: Institutions are attacked in the name of personal and spiritual autonomy
Hero (civic): Crisis as young adults. Crisis, defined: Institutional life is destroyed and rebuilt in response to a perceived threat to the nation's survival
Recessive generations
Nomad (reactive): Unraveling as young adults. Unraveling, defined: Institutions are weak and distrusted, individualism is strong and flourishing
Artist (adaptive): High [when they become] young adults. High, defined: Institutions are strong and individualism is weak
== Generations ==
=== Late Medieval Saeculum ===
==== Arthurian Generation ====
The arthurian generation was born between 1433 and 1460 and is of the hero archetype. Members of the generation grew up during England's retreat from the Hundred Years' War in France, during an era of rising civil unrest.
==== Humanist Generation ====
The humanist generation was born between 1461 and 1482 and is of the artist/adaptive archetype.
This generation grew up at the height of the Middle Ages, just prior to the Reformation and Renaissance. The educated middle classes are influenced by Renaissance Humanist teaching and presented with a clear career path through the church or State bureaucracy. Humanist influences took hold across Europe, and in many ways prepared the intellectual landscape for the coming reformation. Their youth coincided with the development of the European Printing press allowing greater dissemination of knowledge.
According to Strauss and Howe, became Greek language tutors, international scholars, poets, prelates, and literate merchants and yeomen. They described their education produced by the humanist generation as being focused on the qualitative and the subjective, rather than the quantitative and the objective.
Some of the notable people who influenced this generation include Thomas More, Erasmus, Thomas Linacre, John Colet, Cardinal Wolsey, Michelangelo, Copernicus, Francisco Pizarro and Cesare Borgia. King Edward V was also born into this generation, but as he died at only 15 years old, it is difficult to properly place him in this archetype. However, according to the historian Dominic Mancini Edward was very fascinated with science and philosophy, and was very well learned beyond his years.
=== Reformation Saeculum ===
==== Reformation Generation ====
The reformation generation was born between 1483 and 1511 and is of the prophet archetype. This generation rebelled as youths, prompting the first colleges in the 1520s.
==== Reprisal Generation ====
The reprisal generation was born between 1512 and 1540 and is of the nomad/reactive archetype. They grew up during the wars of the Spanish Armada and saw the expansion of British territories and colonization in the New World overseas.
==== Elizabethan Generation ====
The Elizabethan generation was born between 1541 and 1565 and is of the hero archetype. They benefited as children from growth in academies. They grew up during the Anglo-Spanish War (1585–1604). They regulated commerce, explored overseas empires, built English country houses, pursued science, and wrote poetry that celebrated an orderly universe.
==== Parliamentary Generation ====
The parliamentary generation was born between 1566 and 1587 and is of the artist archetype. Their grew up during an era of foreign threats and war. They built credentials in law, scholarship, religion, and arts and crafts guilds.
=== New World Saeculum ===
==== Puritan Generation ====
The puritan generation was born between 1588 and 1617 and is of the prophet archetype. Members of the generation were led through the Wars of the Three Kingdoms (1639–1651) by King Charles I and others led a large migration to the Americas. The generation was very religious.
==== Cavalier Generation ====
The cavalier generation was born from 1618 to 1647 and was of the nomad archetype. Members of this generation grew up in an era of religious upheaval and family collapse. Their generation was notoriously violent and uneducated, causing men to take great risks, and resulting in many young deaths.
Their generation acted in many ways in reaction against the harsh piety and frugality of the puritans, with a more laissez-faire social attitude. This was the time of Merry Old England and the zeitgeist of this generation was possibly best displayed by king Charles II.
==== Glorious Generation ====
The glorious generation was born from 1648 to 1673 and was of the hero archetype. They had a protected childhood with tax-supported schools and new laws discouraging the kidnapping of young people. After participating in the Indian Wars and the Glorious Revolution, they became involved in the electoral office at a young age. As young adults, they took pride in the growing political, commercial, and scientific achievements of England. They designed insurance, paper money, and public works.
==== Enlightenment Generation ====
The enlightenment generation' was born between 1674 and 1700 and was of the artist archetype. They grew up as protected children when families were close, youth risk discouraged, and good educations and well-connected marriages highly prized. As adults, they provided America's first large cadre of credentialed professionals, political managers, and plantation administrators. Examples in Europe include George Frederic Handel, Antonio Vivaldi, Domenico Scarlatti, and Johann Sebastian Bach.
=== Revolutionary Saeculum ===
==== Awakening Generation ====
The awakening generation was born between 1701 and 1723 and was of the prophet archetype. They were the first colonial generation to consist mostly of the offspring of native-born parents. As adults, they attacked their elders' moral complacency. Benjamin Franklin was born in this generation.
==== Liberty Generation ====
Strauss and Howe define the liberty generation (nomad archetype) as those born between 1724 and 1741. The first two U.S. Presidents, George Washington and John Adams, were born during this period. Also born in this era were 35 out of the 56 signatories of the United States Declaration of Independence.
==== Republican Generation ====
The republican generation (hero archetype) was born between 1742 and 1766. This generation is known for participating in several global revolutionary movements during the Age of Revolution. This generation witnessed political turmoil in response to the widespread expansion of European imperialism and the vast social inequalities exacerbated by ruthless competition between rival empires in Europe, the Americas and Asia.
They came of age during a time when the viability of mercantilism and imperialism was being questioned both in Europe and the Americas. Relying on Enlightenment philosophy, they unleashed violent episodes of revolution, vilified Monarchy, and promoted Republicanism. In colonial America, they participated in the American Revolutionary War, secured America's independence from British rule, and established the American government.
Many founding fathers and leading figures in the early years of the independent United States belong to this generation, including U.S. presidents Thomas Jefferson, James Madison, and James Monroe, as well as the leading figures of the French Revolution such as Maximilien Robespierre, Georges Danton, and Camille Desmoulins.
==== Compromise Generation ====
The compromise generation was born between 1767 and 1791 and was of the artist archetype. They "rocked in the cradle of the Revolution" as they watched brave adults struggle and triumph. Notable persons affiliated with this generation include Andrew Jackson, Napoleon Bonaparte and Simón Bolívar.
=== Civil War Saeculum ===
==== Transcendental Generation ====
The transcendental generation was born between 1792 and 1821 and was of the prophet archetype. They started the Second Great Awakening across the United States.
==== Gilded Generation ====
Strauss and Howe define the gilded generation (nomad archetype) as those born from 1822 to 1842. They came of age during rising national tempers, torrential immigration, rampant commercialism and consumerism, declining college enrollment, and economic disputes. This led to a distrust of zealotry and institutional involvement, shifting focus to a life of materialism.. Most of the American Civil War soldiers were born during this period (the average age was 26).
==== Progressive Generation ====
The progressive generation (hero and artist archetypes) was born from 1843 to 1859 and grew up during or fought in the American Civil War.
=== Great Power Saeculum ===
==== Missionary Generation ====
The missionary generation was born from 1860 to 1882 and is of the prophet/idealist archetype. Members of the missionary generation have been described as the "home-and-hearth children of the post-Civil War era". They were an idealist generation and as young adults; their leaders were famous preachers. Some were graduates of newly formed black and women's colleges. Their defining characteristics were missionary and social crusades: "muckraker" journalism, prohibitionism, workers' rights, trade unionism and women's suffrage. In midlife, they developed prohibition in the United States, immigration control, and organized vice squads.
Because the lost generation were severely impacted by World War I, the leadership of the missionary generation lasted longer than previous generations and in the 1930s and 1940s, their elite became the "wise old men" who enacted a "New Deal" and Social Security, led the World War II, and reaffirmed America's highest ideals during this period. This generation is fully ancestral, with the last known member of the missionary generation, the American Sarah Knauss, having died on December 30, 1999, at 119 years of age.
==== Lost Generation ====
The lost generation (nomad archetype) is the generation that came of age during World War I. "Lost" in this context also means "disoriented, wandering, directionless"—a recognition that there was great confusion and aimlessness among the war's survivors in the early post-war years. Strauss and Howe define the cohort as individuals born between 1883 and 1900. Like the previous generation the Lost Generation is fully ancestral, with the last known member of the lost generation, the Japanese Nabi Tajima, having died on April 21, 2018, at 117 years of age.
==== G.I. Generation ====
The greatest generation (hero archetype), also known as the G.I. generation and the World War II generation, is the demographic cohort following the lost generation and preceding the silent generation. Strauss and Howe define the cohort as individuals born between 1901 and 1924. They were shaped by the Great Depression and were the primary participants in World War II.
==== Silent Generation ====
The silent generation (artist archetype) is the demographic cohort following the greatest generation and preceding the baby boomers. Strauss and Howe define the cohort as individuals born between 1925 and 1942.
=== Millennial Saeculum ===
==== Baby Boom Generation ====
Strauss and Howe define the baby boom generation (prophet archetype) as those born from 1943 to 1960.
==== 13th Generation/Generation X ====
Strauss and Howe define the 13th generation (nomad archetype) as those born from 1961 to 1981.
==== Millennial Generation ====
(As of 2023): Neil Howe defines the millennial generation (hero archetype) as those born from 1982 to 2005.
==== Homeland Generation ====
(As of 2023): Neil Howe defines the homeland generation (artist archetype) as those born from 2006 to 2029.
== Timing of generations and turnings ==
Strauss and Howe argue that the basic length of both generations and turnings—approximately 21 years—derives from longstanding socially and biologically determined phases of life. This is the reason it has remained relatively constant over centuries. Some have argued that rapid increases in technology in recent decades are shortening the length of a generation. According to Strauss and Howe, this is not the case. As long as the transition to adulthood occurs around age 21, the transition to midlife around age 43, and the transition to old age around age 65, they say the basic length of both generations and turnings will remain the same.
In their book, The Fourth Turning, however, Strauss and Howe say that the precise boundaries of generations and turnings are erratic. Strauss and Howe compare the saecular rhythm to the four seasons, which they say similarly occur in the same order, but with slightly varying timing, they claimed that the same is true for a Fourth Turning in any given saeculum.
== Critical reception ==
The Strauss and Howe interpretation of history through a generational lens has received mixed reviews and described as a form of pseudoscience. Some reviewers have praised the authors for their ambition, erudition, and accessibility. For example, former U.S. Vice President Al Gore called Generations: The History of America's Future, 1584 to 2069 the most stimulating book on American history he'd ever read, and sent a copy to each member of Congress. The theory has been influential in the fields of generational studies, marketing, and business management literature. However, it has also been criticized by historians, political scientists, and journalists, as being overly deterministic, non-falsifiable, and unsupported by rigorous evidence.
=== Generations: The History of America's Future, 1584 to 2069 ===
After the publication of their first book Generations, Morton Keller, a professor of history at Brandeis University, said that the authors "had done their homework". He said that their theory could be seen as pop sociology and that it would "come in for a lot more criticism as history. But it's almost always true that the broader you cast your net, the more holes it's going to have. And I admire [the authors'] boldness." Sociologist David Riesman and political scientist Richard Neustadt offered strong, if qualified, praise. Riesman found in the work an "impressive grasp of a great many theoretical and historical bits and pieces" and Neustadt said Strauss and Howe "are asking damned important questions, and I honor them." The Times Literary Supplement called it "fascinating", but also "about as vague and plausible as astrological predictions". Publishers Weekly called it "as woolly as a newspaper horoscope".
In 1991, Jonathan Alter wrote in Newsweek that Generations was a "provocative, erudite and engaging analysis of the rhythms of American life". However, he believed it was also "an elaborate historical horoscope that will never withstand scholarly scrutiny." He continued, "these sequential 'peer personalities' are often silly, but the book provides reams of fresh evidence that American history is indeed cyclical, as Arthur Schlesinger Jr. and others have long argued." But he complained, "The generational boundaries are plainly arbitrary. The authors lump together everyone born from 1943 through the end of 1960 (Baby Boomers), a group whose two extremes have little in common. And the predictions are facile and reckless." He concluded: "However fun and informative, the truth about generational generalizations is that they're generally unsatisfactory." Arthur E. Levine, a former president of the Teachers College of Columbia University said "Generational images are stereotypes. There are some differences that stand out, but there are more similarities between students of the past and the present. But if you wrote a book saying that, how interesting would it be?"
In response to criticism that they stereotype or generalize all members of a generation, the authors have said, "We've never tried to say that any individual generation is going to be monochromatic. It'll obviously include all kinds of people. But as you look at generations as social units, we consider it to be at least as powerful and, in our view, far more powerful than other social groupings such as economic class, race, sex, religion, and political parties."
Gerald Pershall wrote in 1991: "Generations is guaranteed to attract pop history and pop social science buffs. Among professional historians, it faces a tougher sell. Period specialists will resist the idea that their period is akin to several others. Sweeping theories of history are long out of fashion in the halls of ivy, and the authors' lack of academic standing won't help their cause. Their generational quartet is "just too wooden" and "too neat," says one Yale historian. "Prediction is for prophets," scoffed William McLoughlin (a former history professor at Brown), who said it is wrong to think that "if you put enough data together and have enough charts and graphs, you've made history into a science." He also said the book might get a friendlier reception in the sociology and political science departments than in the science department.
In 1991, professor and New York Times writer Jay Dolan critiqued Generations for not talking more about class, race, and sex, to which Neil Howe replied that they "are probably generalizations not even as effective as a generation to say something about how people think and behave. One of the things to understand is that most historians never look at history in terms of generations. They prefer to tell history as a seamless row of 55-year-old leaders who always tend to think and behave the same way -- but they don't and they never have. If you look at the way America's 55-year-old leaders were acting in the 1960s -- you know, the ebullience and confidence of the JFKs and LBJs and Hubert Humphreys -- and compare them with today's leaders in Congress -- the indecision, the lack of sure-footedness -- I think you would have to agree that 55-year-olds do not always act the same way and you're dealing with powerful generational forces at work that explain why one generation of war veterans, war heroes, and another generation which came of age in very different circumstances tend to have very different instincts about acting in the world."
Responding to criticisms in 1991, William Strauss accepted that some historians might not like their theory, responding with:
"People are looking for a new way to connect themselves to the larger story of America. That is the problem. We've felt adrift over the past 10 years, and we think that the way history has been presented over the past couple of decades has been more in terms of the little pieces and people are not as interested in the little pieces now. They're looking for a unifying vision. We haven't had unifying visions of the story of America for decades now, and we're trying to provide it in this book.
The kinds of historians who are drawn to our book -- and I'm sure it will be very controversial among academics because we are presenting something that is so new -- but the kinds who are drawn to it are the ones who themselves have focused on the human life cycle rather than just the sequential series of events. Some good examples of that are Morton Keller up at Brandeis and David Hackett Fischer. These are people who have noticed the power in not just generations, but the shifts that have happened over time in the way Americans have treated children and older people and have tried to link that to the broader currents of history."
=== The Fourth Turning ===
In his review for the Boston Globe, historian David Kaiser called The Fourth Turning "a provocative and immensely entertaining outline of American history, Strauss and Howe have taken a gamble". "If the United States calmly makes it to 2015, their work will end up in the ashcan of history, but if they are right, they will take their place among the great American prophets." Kaiser has since argued that Strauss and Howe's predictions of coming crisis seems to have occurred, citing events such as 9/11, the 2008 financial crisis, and the recent political gridlock.
Kaiser has incorporated Strauss and Howe's theory in two historical works of his own, American Tragedy: Kennedy, Johnson, and the Origins of the Vietnam War (2000), and No End Save Victory: How FDR Led the Nation into War (2014).
Michael Lind, a historian and co-founder of the New America Foundation, wrote that The Fourth Turning (1997) was vague and verged into the realm of "pseudoscience"; "most of the authors' predictions about the American future turn out to be as vague as those of fortune cookies". Lind said that the theory is essential "non-falsifiable" and "mystifying."
For The New York Times in 2017, Pulitzer-winning journalist Jeremy Peters wrote that "many academic historians dismiss the book as about as scientific as astrology or a Nostradamus text."
=== 13th Gen ===
In 1993, Andrew Leonard reviewed the book 13th Gen: Abort, Retry, Ignore, Fail?. He wrote "as the authors (Strauss and Howe) relentlessly attack the iniquitous 'child-abusive culture' of the 1960s and '70s and exult in heaping insult after insult on their own generation -- they caricature Baby Boomers as countercultural, long-haired, sex-obsessed hedonists -- their real agenda begins to surface. That agenda becomes clear in part of their wish list for how the 13th generation may influence the future: "13ers will reverse the frenzied and centrifugal cultural directions of their younger years. They will clean up entertainment, de-diversify the culture, reinvent core symbols of national unity, reaffirm rituals of family and neighborhood bonding, and re-erect barriers to cushion communities from unwanted upheaval."
Again in 1993, writing for The Globe and Mail, Jim Cormier reviewed the same book: "self-described boomers Howe and Strauss add no profound layer of analysis to previous pop press observations. But in cobbling together a more extensive overview of the problems and concerns of the group they call the 13ers, they've created a valuable primer for other fogeys who are feeling seriously out of touch." Cormier wrote that the authors "raised as many new questions as answers about the generation that doesn't want to be a generation. But at least they've made an honest, empathetic, and good-humoured effort to bridge the bitter gap between the twentysomethings and fortysomethings."
In 1993, Charles Laurence at the London Daily Telegraph wrote that, in 13th Gen, Strauss and Howe offered this youth generation "a relatively neutral definition as the 13th American generation from the Founding Fathers,". According to Alexander Ferron's review in Eye Magazine, "13th Gen is best read as the work of two top-level historians. While its agenda is the 13th generation, it can also be seen as an incredibly well-written and exhaustive history of America from 1960 to 1981--examining the era through everything except the traditional historical subjects (war, politics, famine, etc)."
In 2011, Jon D. Miller, at the Longitudinal Study of American Youth, funded by the National Science Foundation, wrote that the birth year definition (1961 to 1981) of "Generation X" ("13th Gen") has been widely used in popular and academic literature.
=== Millennials Rising ===
David Brooks reviewed the follow-up book about the next generation titled Millennials Rising (2000). "Millennials" is a term coined by Strauss and Howe. Brooks wrote: "This is not a good book, if by good you mean the kind of book in which the authors have rigorously sifted the evidence and carefully supported their assertions with data. But it is a very good bad book. It's stuffed with interesting nuggets. It's brightly written. And if you get away from the generational mumbo jumbo, it illuminates changes that really do seem to be taking place." Further, Brooks wrote that the generations aren't treated equally: "Basically, it sounds as if America has two greatest generations at either end of the age scale and two crummiest in the middle".
A 2000 New York Times book review for this book titled: What's the Matter With Kids Today? Not a Thing, described the message of Millennials Rising as "we boomers are raising a cohort of kids who are smarter, more industrious and better behaved than any generation before", saying the book complimented the Baby Boomer cohort by way of their parenting skills.
In 2001, reviewer Dina Gomez wrote in NEA Today that they make their case "convincingly," with "intriguing analysis of popular culture" but conceded that it "over-generalizes". Gomez argued that it is "hard to resist its hopeful vision for our children and future."
Millennials Rising ascribes seven "core traits" to Millennials: special, sheltered, confident, team-oriented, conventional, pressured, and achieving. A 2009, Chronicle of Higher Education report commented Howe and Strauss based these core traits on a "hodgepodge of anecdotes, statistics, and pop-culture references" and on surveys of approximately 600 high-school seniors from Fairfax County, Virginia, an affluent county with median household income approximately twice the national average. The report described Millennials Rising as a "good-news revolution" making "sweeping predictions" and describing Millennials as "rule followers who were engaged, optimistic, and downright pleasant", commenting the "book gave educators and tens of millions of parents, a warm feeling, saying who wouldn't want to hear that their kids are special?"
=== General ===
In 2006, Frank Giancola wrote an article in Human Resource Planning that stated "the emphasis on generational differences is not generally borne out by empirical research, despite its popularity".
In 2016 an article was published that explains the differences in generations, observed with the employer's position, through the development of working conditions, initiated by the employer. This development is due to the competition of firms on the job market for receiving more highly skilled workers. New working conditions as a product on the market have a classic product life-cycle and when they become widespread standard expectations of employees change accordingly.
One criticism of Strauss and Howe's theory and generational studies is that conclusions are overly broad and do not reflect the reality of every person in each generation regardless of their race, color, national origin, religion, sex, age, disability, or genetic information. For example, Hoover cited the case of Millennials, noted that in 2009 commentators have tended to label white, affluent teenagers who accomplish great things as they grow up in the suburbs, who confront anxiety when applying to super-selective colleges, and who multitask with ease as their helicopter parents hover reassuringly above them as Millennials. The label tends not to appear in renderings of teenagers who happen to be minorities, poor, or who have never won a spelling bee. Nor does the term often refer to students from big cities and small towns that are nothing like Fairfax County, Virginia, or who lack technological know-how. Or who struggle to complete high school. Or who never even consider college. Or who commit crimes. Or who suffer from too little parental support. Or who drop out of college. Aren't they Millennials too?" In their 2000 book Millennials Rising they brought attention to the Millennial children of immigrants in the United States, "who face daunting challenges." They wrote "one-third have no health insurance, live below the poverty line and live in overcrowded housing".
In a February 2017 article from Quartz two journalists commented on the theory saying: "it is too vague to be proven wrong, and has not been taken seriously by most professional historians. But it is superficially compelling, and plots out to some degree how America's history has unfolded since its founding". A May 2017 article from Quartz described the Strauss–Howe generational theory as "pseudoscience".
In an April 2017 article from Politico, David Greenberg, a professor of history and media studies at Rutgers University, described Strauss–Howe generational theory as "crackpot theories".
Peter Turchin, a scientist and specialist in the fields of cultural evolution, cliodynamics and structural-demographic theory, has criticized the theory, stating that it is not a scientific theory and that it is more akin to a prophecy since it "forces the historical record to fit a postulated cycle by stretching in some places and cutting off a bit here and there in others".
== In popular culture ==
American electronic musician Oneohtrix Point Never was inspired by The Fourth Turning for the concept of his 2018 album Age Of and its accompanying performance installation MYRIAD.
Will Arbery's play Heroes of the Fourth Turning, first produced at New York's Playwrights Horizons in 2019, is inspired by the theories of Strauss and Howe, and the character Teresa is a vocal proponent of them.
The 2022 Netflix series The Watcher features a scene citing postulations from The Fourth Turning.
== See also ==
== Notes ==
== References ==
== Bibliography ==
Strauss, William; Howe, Neil (1991). Generations: The History of America's Future, 1584 to 2069 (1 ed.). New York. ISBN 978-0-688-08133-1. OCLC 22306142.{{cite book}}: CS1 maint: location missing publisher (link)
Howe, Neil; Strauss, William (1993). 13th Gen: Abort, Retry, Ignore, Fail? (1 ed.). New York: Vintage Books. ISBN 978-0-679-74365-1. OCLC 26632626.
Strauss, William; Howe, Neil (1997). The Fourth Turning: An American Prophecy (1 ed.). New York. ISBN 978-0-553-06682-1. OCLC 35008291.{{cite book}}: CS1 maint: location missing publisher (link)
Howe, Neil; Strauss, William (2000). Millennials Rising: The Next Great Generation. William Strauss. New York: Vintage Books. ISBN 978-0-375-70719-3. OCLC 44118080.
Howe, Neil; Strauss, William (2007). Millennials Go to College: Strategies for a New Generation on Campus: Recruiting and Admissions, Campus Life, and the Classroom (2 ed.). Great Falls, Va.: LifeCourse Associates. ISBN 978-0-9712606-1-0. OCLC 123907203.
Howe, Neil; Strauss, William; Nadler, Reena (2008). Millennials & K-12 Schools: Educational Strategies for a New Generation. Great Falls, Va.: LifeCourse Associates. ISBN 978-0-9712606-5-8. OCLC 311800406.
== External links ==
Discussion forum of the Strauss and Howe generation theory | Wikipedia/Strauss–Howe_generational_theory |
Melanin theory is a set of pseudoscientific claims made by some proponents of Afrocentrism, which holds that black people, including ancient Egyptians, have superior mental, physical, and paranormal powers because they have higher levels of melanin, the primary skin pigment in humans.
== Claims ==
Melanin theory posits that individuals' responses to social stimuli are determined by the prevalence of the skin pigment melanin. Historian Stephen Ferguson describes melanin theory as a component of "strong" Afrocentrism, which assigns biological causes to social phenomena such as white supremacy.: 66 Proponents of melanin theory ("melanists") argue that insecurity among European males leads to efforts to socially dominate and emasculate African males, taking the form of unemployment, incarceration, and political and social marginalization.
Some black supremacists, including professor of black studies Leonard Jeffries: 56 and psychologist Frances Cress Welsing, argue without evidence that higher levels of melanin give black people inherently superior qualities to white people, including supernatural abilities such as extrasensory perception.: 67 According to Bernard Ortiz de Montellano, "the alleged properties of melanin, mostly unsupported, irrelevant, or distortions of the scientific literature, are [...] used to justify Afrocentric assertions. One of the most common is that humans evolved as blacks in Africa, and that whites are mutants (albinos, or melanin recessives)". Ortiz de Montellano wrote in 1993 that melanin theory as an ideological movement would increase scientific illiteracy and would contribute to "widening the gap between the races".
Welsing states that Africans possess dominant genes in comparison to the recessive genes of Europeans, which, she posits, leads to a struggle by Europeans to maintain their genetic distinctness. Welsing derived her hypothesis partly through a neo-Freudian analysis of cultural symbols rather than scientific evidence, arguing that the motivation for white supremacy is an unconscious response to white genetic and sexual inferiority. Ferguson equates this argument with "white male penis envy" toward black men.: 67–68
== In popular culture ==
In 2006, the views of adherents and critics of melanin theory were dramatized in Cassandra Medley's play Relativity.
== See also ==
The Bell Curve
Race and intelligence
Scientific racism
Skin colour § Genetics
== References == | Wikipedia/Melanin_theory |
Data sharing is the practice of making data used for scholarly research available to other investigators. Many funding agencies, institutions, and publication venues have policies regarding data sharing because transparency and openness are considered by many to be part of the scientific method.
A number of funding agencies and science journals require authors of peer-reviewed papers to share any supplemental information (raw data, statistical methods or source code) necessary to understand, develop or reproduce published research. A great deal of scientific research is not subject to data sharing requirements, and many of these policies have liberal exceptions. In the absence of any binding requirement, data sharing is at the discretion of the scientists themselves. In addition, in certain situations governments and institutions prohibit or severely limit data sharing to protect proprietary interests, national security, and subject/patient/victim confidentiality. Data sharing may also be restricted to protect institutions and scientists from use of data for political purposes.
Data and methods may be requested from an author years after publication. In order to encourage data sharing and prevent the loss or corruption of data, a number of funding agencies and journals established policies on data archiving. Access to publicly archived data is a recent development in the history of science made possible by technological advances in communications and information technology. To take full advantage of modern rapid communication may require consensual agreement on the criteria underlying mutual recognition of respective contributions. Models recognized for improving the timely sharing of data for more effective response to emergent infectious disease threats include the data sharing mechanism introduced by the GISAID Initiative.
Despite policies on data sharing and archiving, data withholding still happens. Authors may fail to archive data or they only archive a portion of the data. Failure to archive data alone is not data withholding. When a researcher requests additional information, an author sometimes refuses to provide it. When authors withhold data like this, they run the risk of losing the trust of the science community. A 2022 study identified about 3500 research papers which contained statements that the data was available, but upon request and further seeking the data, found that it was unavailable for 94% of papers.
Data sharing may also indicate the sharing of personal information on a social media platform.
== U.S. government policies ==
=== Federal law ===
On August 9, 2007, President Bush signed the America COMPETES Act (or the "America Creating Opportunities to Meaningfully Promote Excellence in Technology, Education, and Science Act") requiring civilian federal agencies to provide guidelines, policies and procedures, to facilitate and optimize the open exchange of data and research between agencies, the public and policymakers. See Section 1009.
=== NIH data sharing policy ===
‘The National Institutes of Health (NIH) Grants Policy Statement defines "data" as "recorded information, regardless of the form or medium on which it may be recorded, and includes writings, films, sound recordings, pictorial reproductions, drawings, designs, or other graphic representations, procedural manuals, forms, diagrams, work flow charts, equipment descriptions, data files, data processing or computer programs (software), statistical records, and other research data."’
The NIH Final Statement of Sharing of Research Data says:
‘NIH reaffirms its support for the concept of data sharing. We believe that data sharing is essential for expedited translation of research results into knowledge, products, and procedures to improve human health. The NIH endorses the sharing of final research data to serve these and other important scientific goals. The NIH expects and supports the timely release and sharing of final research data from NIH-supported studies for use by other researchers.
‘NIH recognizes that the investigators who collect the data have a legitimate interest in benefiting from their investment of time and effort. We have therefore revised our definition of "the timely release and sharing" to be no later than the acceptance for publication of the main findings from the final data set. NIH continues to expect that the initial investigators may benefit from first and continuing use but not from prolonged exclusive use.’
=== NSF Policy from Grant General Conditions ===
36. Sharing of Findings, Data, and Other Research Products
a. NSF …expects investigators to share with other researchers, at no more than incremental cost and within a reasonable time, the data, samples, physical collections and other supporting materials created or gathered in the course of the work. It also encourages awardees to share software and inventions or otherwise act to make the innovations they embody widely useful and usable.
b. Adjustments and, where essential, exceptions may be allowed to safeguard the rights of individuals and subjects, the validity of results, or the integrity of collections or to accommodate legitimate interests of investigators.
== Office of Research Integrity ==
Allegations of misconduct in medical research carry severe consequences. The United States Department of Health and Human Services established an office to oversee investigations of allegations of misconduct, including data withholding. The website defines the mission:
"The Office of Research Integrity (ORI) promotes integrity in biomedical and behavioral research supported by the U.S. Public Health Service (PHS) at about 4,000 institutions worldwide. ORI monitors institutional investigations of research misconduct and facilitates the responsible conduct of research (RCR) through educational, preventive, and regulatory activities."
== Ideals in data sharing ==
Some research organizations feel particularly strongly about data sharing. Stanford University's WaveLab has a philosophy about reproducible research and disclosing all algorithms and source code necessary to reproduce the research. In a paper titled "WaveLab and Reproducible Research," the authors describe some of the problems they encountered in trying to reproduce their own research after a period of time. In many cases, it was so difficult they gave up the effort. These experiences are what convinced them of the importance of disclosing source code. The philosophy is described:
The idea is: An article about computational science in a scientific publication is not the scholarship itself, it is merely advertising of the scholarship. The actual scholarship is the complete software development environment and the complete set of instructions which generated the figures.
The Data Observation Network for Earth (DataONE) and Data Conservancy are projects supported by the National Science Foundation to encourage and facilitate data sharing among research scientists and better support meta-analysis. In environmental sciences, the research community is recognizing that major scientific advances involving integration of knowledge in and across fields will require that researchers overcome not only the technological barriers to data sharing but also the historically entrenched institutional and sociological barriers. Dr. Richard J. Hodes, director of the National Institute on Aging has stated, "the old model in which researchers jealously guarded their data is no longer applicable".
The Alliance for Taxpayer Access is a group of organizations that support open access to government sponsored research. The group has expressed a "Statement of Principles" explaining why they believe open access is important. They also list a number of international public access policies. This is no more so than in timely communication of essential information to effectively respond to health emergencies. While public domain archives have been embraced for depositing data, mainly post formal publication, they have failed to encourage rapid data sharing during health emergencies, among them the Ebola and Zika, outbreaks. More clearly defined principles are required to recognize the interests of those generating the data while permitting free, unencumbered access to and use of the data (pre-publication) for research and practical application, such as those adopted by the GISAID Initiative to counter emergent threats from influenza.
== International policies ==
Australia
Austria
Europe — Commission of European Communities
Germany
United Kingdom
'Omic Data Sharing — a list of policies of major science funders FAIRsharing.org Catalogue of Data Policies
India -National Data Sharing and Accessibility Policy – Government of India
== Data sharing problems in academia ==
=== Genetics ===
Withholding of data has become so commonplace in genetics that researchers at Massachusetts General Hospital published a journal article on the subject. The study found that "Because they were denied access to data, 28% of geneticists reported that they had been unable to confirm published research."
=== Psychology ===
In a 2006 study, it was observed that, of 141 authors of a publication from the American Psychological Association (APA) empirical articles, 103 (73%) did not respond with their data over a 6-month period. In a follow-up study published in 2015, it was found that 246 out of 394 contacted authors of papers in APA journals did not share their data upon request (62%).
=== Archaeology ===
A 2018 study reported on study of a random sample of 48 articles published during February–May 2017 in the Journal of Archaeological Science which found openly available raw data for 18 papers (53%), with compositional and dating data being the most frequently shared types. The same study also emailed authors of articles on experiments with stone artifacts that were published during 2009 and 2015 to request data relating to the publications. They contacted the authors of 23 articles and received 15 replies, resulting in a 70% response rate. They received five responses that included data files, giving an overall sharing rate of 20%.
=== Scientists in training ===
A study of scientists in training indicated many had already experienced data withholding. This study has given rise to the fear the future generation of scientists will not abide by the established practices.
== Differing approaches in different fields ==
Requirements for data sharing are more commonly imposed by institutions, funding agencies, and publication venues in the medical and biological sciences than in the physical sciences. Requirements vary widely regarding whether data must be shared at all, with whom the data must be shared, and who must bear the expense of data sharing.
Funding agencies such as the NIH and NSF tend to require greater sharing of data, but even these requirements tend to acknowledge the concerns of patient confidentiality, costs incurred in sharing data, and the legitimacy of the request. Private interests and public agencies with national security interests (defense and law enforcement) often discourage sharing of data and methods through non-disclosure agreements.
Data sharing poses specific challenges in participatory monitoring initiatives, for example where forest communities collect data on local social and environmental conditions. In this case, a rights-based approach to the development of data-sharing protocols can be based on principles of free, prior and informed consent, and prioritise the protection of the rights of those who generated the data, and/or those potentially affected by data-sharing.
== See also ==
Data archive
Data dissemination
Data privacy
Data publishing
Data citation
FAIR data
File sharing
Information sharing
Knowledge sharing
Open data
Registry of Research Data Repositories
== References ==
== Literature ==
Committee on Issues in the Transborder Flow of Scientific Data, National Research Council (1997). Bits of Power: Issues in Global Access to Scientific Data. Washington, D.C.: National Academy Press. doi:10.17226/5504. ISBN 978-0-309-05635-9. — discusses the international exchange of data in the natural sciences.
== External links ==
"The Selfish Gene Archived 2008-08-05 at the Wayback Machine: Data Sharing and Withholding in Academic Genetics" by Eric Campbell and David Blumenthal published May 31, 2002.
Data sharing and data archiving ― American Psychological Association
The Public Domain of Digital Research Data
WaveLab and Reproducible Research by Jonathan B. Buckheit and David L. Donoho of Stanford University
The Role of Data and Program Code Archives in the Future of Economic Research published by The Federal Reserve Bank of St. Louis
Ecological Society of America data sharing and archiving initiative Archived 2008-03-10 at the Wayback Machine
FAIRsharing.org A website on data sharing and data policies in biology
UK Data Archive: Manage and Share data
Data Management Plan Resources and Examples - Inter-university Consortium for Political and Social Research.
DataONE
Nature Scientific Data: open-access, online-only publication for descriptions of scientifically valuable datasets. | Wikipedia/Data_sharing_(Science) |
A randomized controlled trial (or randomized control trial; RCT) is a form of scientific experiment used to control factors not under direct experimental control. Examples of RCTs are clinical trials that compare the effects of drugs, surgical techniques, medical devices, diagnostic procedures, diets or other medical treatments.
Participants who enroll in RCTs differ from one another in known and unknown ways that can influence study outcomes, and yet cannot be directly controlled. By randomly allocating participants among compared treatments, an RCT enables statistical control over these influences. Provided it is designed well, conducted properly, and enrolls enough participants, an RCT may achieve sufficient control over these confounding factors to deliver a useful comparison of the treatments studied.
== Definition and examples ==
An RCT in clinical research typically compares a proposed new treatment against an existing standard of care; these are then termed the 'experimental' and 'control' treatments, respectively. When no such generally accepted treatment is available, a placebo may be used in the control group so that participants are blinded, or not given information, about their treatment allocations. This blinding principle is ideally also extended as much as possible to other parties including researchers, technicians, data analysts, and evaluators. Effective blinding experimentally isolates the physiological effects of treatments from various psychological sources of bias.
The randomness in the assignment of participants to treatments reduces selection bias and allocation bias, balancing both known and unknown prognostic factors, in the assignment of treatments. Blinding reduces other forms of experimenter and subject biases.
A well-blinded RCT is considered the gold standard for clinical trials. Blinded RCTs are commonly used to test the efficacy of medical interventions and may additionally provide information about adverse effects, such as drug reactions. A randomized controlled trial can provide compelling evidence that the study treatment causes an effect on human health.
The terms "RCT" and "randomized trial" are sometimes used synonymously, but the latter term omits mention of controls and can therefore describe studies that compare multiple treatment groups with each other in the absence of a control group. Similarly, the initialism is sometimes expanded as "randomized clinical trial" or "randomized comparative trial", leading to ambiguity in the scientific literature. Not all RCTs are randomized controlled trials (and some of them could never be, as in cases where controls would be impractical or unethical to use). The term randomized controlled clinical trial is an alternative term used in clinical research; however, RCTs are also employed in other research areas, including many of the social sciences.
== History ==
The first reported clinical trial was conducted by James Lind in 1747 to identify a treatment for scurvy. The first blind experiment was conducted by the French Royal Commission on Animal Magnetism in 1784 to investigate the claims of mesmerism. An early essay advocating the blinding of researchers came from Claude Bernard in the latter half of the 19th century. Bernard recommended that the observer of an experiment should not have knowledge of the hypothesis being tested. This suggestion contrasted starkly with the prevalent Enlightenment-era attitude that scientific observation can only be objectively valid when undertaken by a well-educated, informed scientist. The first study recorded to have a blinded researcher was published in 1907 by W. H. R. Rivers and H. N. Webber to investigate the effects of caffeine.
Randomized experiments first appeared in psychology, where they were introduced by Charles Sanders Peirce and Joseph Jastrow in the 1880s, and in education. The earliest experiments comparing treatment and control groups were published by Robert Woodworth and Edward Thorndike in 1901, and by John E. Coover and Frank Angell in 1907.
In the early 20th century, randomized experiments appeared in agriculture, due to Jerzy Neyman and Ronald A. Fisher. Fisher's experimental research and his writings popularized randomized experiments.
The first published Randomized Controlled Trial in medicine appeared in the 1948 paper entitled "Streptomycin treatment of pulmonary tuberculosis", which described a Medical Research Council investigation. One of the authors of that paper was Austin Bradford Hill, who is credited as having conceived the modern RCT.
Trial design was further influenced by the large-scale ISIS trials on heart attack treatments that were conducted in the 1980s.
By the late 20th century, RCTs were recognized as the standard method for "rational therapeutics" in medicine. As of 2004, more than 150,000 RCTs were in the Cochrane Library. To improve the reporting of RCTs in the medical literature, an international group of scientists and editors published Consolidated Standards of Reporting Trials (CONSORT) Statements in 1996, 2001 and 2010, and these have become widely accepted. Randomization is the process of assigning trial subjects to treatment or control groups using an element of chance to determine the assignments in order to reduce the bias.
== Ethics ==
Although the principle of clinical equipoise ("genuine uncertainty within the expert medical community... about the preferred treatment") common to clinical trials has been applied to RCTs, the ethics of RCTs have special considerations. For one, it has been argued that equipoise itself is insufficient to justify RCTs. For another, "collective equipoise" can conflict with a lack of personal equipoise (e.g., a personal belief that an intervention is effective). Finally, Zelen's design, which has been used for some RCTs, randomizes subjects before they provide informed consent, which may be ethical for RCTs of screening and selected therapies, but is likely unethical "for most therapeutic trials."
Although subjects almost always provide informed consent for their participation in an RCT, studies since 1982 have documented that RCT subjects may believe that they are certain to receive treatment that is best for them personally; that is, they do not understand the difference between research and treatment. Further research is necessary to determine the prevalence of and ways to address this "therapeutic misconception".
The RCT method variations may also create cultural effects that have not been well understood. For example, patients with terminal illness may join trials in the hope of being cured, even when treatments are unlikely to be successful.
=== Trial registration ===
In 2004, the International Committee of Medical Journal Editors (ICMJE) announced that all trials starting enrolment after July 1, 2005, must be registered prior to consideration for publication in one of the 12 member journals of the committee. However, trial registration may still occur late or not at all.
Medical journals have been slow in adapting policies requiring mandatory clinical trial registration as a prerequisite for publication.
== Classifications ==
=== By study design ===
One way to classify RCTs is by study design. From most to least common in the healthcare literature, the major categories of RCT study designs are:
Parallel-group – each participant is randomly assigned to a group, and all the participants in the group receive (or do not receive) an intervention.
Crossover – over time, each participant receives (or does not receive) an intervention in a random sequence.
Cluster – pre-existing groups of participants (e.g., villages, schools) are randomly selected to receive (or not receive) an intervention.
Factorial – each participant is randomly assigned to a group that receives a particular combination of interventions or non-interventions (e.g., group 1 receives vitamin X and vitamin Y, group 2 receives vitamin X and placebo Y, group 3 receives placebo X and vitamin Y, and group 4 receives placebo X and placebo Y).
An analysis of the 616 RCTs indexed in PubMed during December 2006 found that 78% were parallel-group trials, 16% were crossover, 2% were split-body, 2% were cluster, and 2% were factorial.
=== By outcome of interest (efficacy vs. effectiveness) ===
RCTs can be classified as "explanatory" or "pragmatic." Explanatory RCTs test efficacy in a research setting with highly selected participants and under highly controlled conditions. In contrast, pragmatic RCTs (pRCTs) test effectiveness in everyday practice with relatively unselected participants and under flexible conditions; in this way, pragmatic RCTs can "inform decisions about practice."
=== By hypothesis (superiority vs. noninferiority vs. equivalence) ===
Another classification of RCTs categorizes them as "superiority trials", "noninferiority trials", and "equivalence trials", which differ in methodology and reporting. Most RCTs are superiority trials, in which one intervention is hypothesized to be superior to another in a statistically significant way. Some RCTs are noninferiority trials "to determine whether a new treatment is no worse than a reference treatment." Other RCTs are equivalence trials in which the hypothesis is that two interventions are indistinguishable from each other.
== Randomization ==
The advantages of proper randomization in RCTs include:
"It eliminates bias in treatment assignment," specifically selection bias and confounding.
"It facilitates blinding (masking) of the identity of treatments from investigators, participants, and assessors."
"It permits the use of probability theory to express the likelihood that any difference in outcome between treatment groups merely indicates chance."
There are two processes involved in randomizing patients to different interventions. First is choosing a randomization procedure to generate an unpredictable sequence of allocations; this may be a simple random assignment of patients to any of the groups at equal probabilities, may be "restricted", or may be "adaptive." A second and more practical issue is allocation concealment, which refers to the stringent precautions taken to ensure that the group assignment of patients are not revealed prior to definitively allocating them to their respective groups. Non-random "systematic" methods of group assignment, such as alternating subjects between one group and the other, can cause "limitless contamination possibilities" and can cause a breach of allocation concealment.
However empirical evidence that adequate randomization changes outcomes relative to inadequate randomization has been difficult to detect.
=== Procedures ===
The treatment allocation is the desired proportion of patients in each treatment arm.
An ideal randomization procedure would achieve the following goals:
Maximize statistical power, especially in subgroup analyses. Generally, equal group sizes maximize statistical power, however, unequal groups sizes may be more powerful for some analyses (e.g., multiple comparisons of placebo versus several doses using Dunnett's procedure ), and are sometimes desired for non-analytic reasons (e.g., patients may be more motivated to enroll if there is a higher chance of getting the test treatment, or regulatory agencies may require a minimum number of patients exposed to treatment).
Minimize selection bias. This may occur if investigators can consciously or unconsciously preferentially enroll patients between treatment arms. A good randomization procedure will be unpredictable so that investigators cannot guess the next subject's group assignment based on prior treatment assignments. The risk of selection bias is highest when previous treatment assignments are known (as in unblinded studies) or can be guessed (perhaps if a drug has distinctive side effects).
Minimize allocation bias (or confounding). This may occur when covariates that affect the outcome are not equally distributed between treatment groups, and the treatment effect is confounded with the effect of the covariates (i.e., an "accidental bias"). If the randomization procedure causes an imbalance in covariates related to the outcome across groups, estimates of effect may be biased if not adjusted for the covariates (which may be unmeasured and therefore impossible to adjust for).
However, no single randomization procedure meets those goals in every circumstance, so researchers must select a procedure for a given study based on its advantages and disadvantages.
==== Simple ====
This is a commonly used and intuitive procedure, similar to "repeated fair coin-tossing." Also known as "complete" or "unrestricted" randomization, it is robust against both selection and accidental biases. However, its main drawback is the possibility of imbalanced group sizes in small RCTs. It is therefore recommended only for RCTs with over 200 subjects.
==== Restricted ====
To balance group sizes in smaller RCTs, some form of "restricted" randomization is recommended. The major types of restricted randomization used in RCTs are:
Permuted-block randomization or blocked randomization: a "block size" and "allocation ratio" (number of subjects in one group versus the other group) are specified, and subjects are allocated randomly within each block. For example, a block size of 6 and an allocation ratio of 2:1 would lead to random assignment of 4 subjects to one group and 2 to the other. This type of randomization can be combined with "stratified randomization", for example by center in a multicenter trial, to "ensure good balance of participant characteristics in each group." A special case of permuted-block randomization is random allocation, in which the entire sample is treated as one block. The major disadvantage of permuted-block randomization is that even if the block sizes are large and randomly varied, the procedure can lead to selection bias. Another disadvantage is that "proper" analysis of data from permuted-block-randomized RCTs requires stratification by blocks.
Adaptive biased-coin randomization methods (of which urn randomization is the most widely known type): In these relatively uncommon methods, the probability of being assigned to a group decreases if the group is overrepresented and increases if the group is underrepresented. The methods are thought to be less affected by selection bias than permuted-block randomization.
==== Adaptive ====
At least two types of "adaptive" randomization procedures have been used in RCTs, but much less frequently than simple or restricted randomization:
Covariate-adaptive randomization, of which one type is minimization: The probability of being assigned to a group varies in order to minimize "covariate imbalance." Minimization is reported to have "supporters and detractors" because only the first subject's group assignment is truly chosen at random, the method does not necessarily eliminate bias on unknown factors.
Response-adaptive randomization, also known as outcome-adaptive randomization: The probability of being assigned to a group increases if the responses of the prior patients in the group were favorable. Although arguments have been made that this approach is more ethical than other types of randomization when the probability that a treatment is effective or ineffective increases during the course of an RCT, ethicists have not yet studied the approach in detail.
=== Allocation concealment ===
"Allocation concealment" (defined as "the procedure for protecting the randomization process so that the treatment to be allocated is not known before the patient is entered into the study") is important in RCTs. In practice, clinical investigators in RCTs often find it difficult to maintain impartiality. Stories abound of investigators holding up sealed envelopes to lights or ransacking offices to determine group assignments in order to dictate the assignment of their next patient. Such practices introduce selection bias and confounders (both of which should be minimized by randomization), possibly distorting the results of the study. Adequate allocation concealment should defeat patients and investigators from discovering treatment allocation once a study is underway and after the study has concluded. Treatment related side-effects or adverse events may be specific enough to reveal allocation to investigators or patients thereby introducing bias or influencing any subjective parameters collected by investigators or requested from subjects.
Some standard methods of ensuring allocation concealment include sequentially numbered, opaque, sealed envelopes (SNOSE); sequentially numbered containers; pharmacy controlled randomization; and central randomization. It is recommended that allocation concealment methods be included in an RCT's protocol, and that the allocation concealment methods should be reported in detail in a publication of an RCT's results; however, a 2005 study determined that most RCTs have unclear allocation concealment in their protocols, in their publications, or both. On the other hand, a 2008 study of 146 meta-analyses concluded that the results of RCTs with inadequate or unclear allocation concealment tended to be biased toward beneficial effects only if the RCTs' outcomes were subjective as opposed to objective.
=== Sample size ===
The number of treatment units (subjects or groups of subjects) assigned to control and treatment groups, affects an RCT's reliability. If the effect of the treatment is small, the number of treatment units in either group may be insufficient for rejecting the null hypothesis in the respective statistical test. The failure to reject the null hypothesis would imply that the treatment shows no statistically significant effect on the treated in a given test. But as the sample size increases, the same RCT may be able to demonstrate a significant effect of the treatment, even if this effect is small.
== Blinding ==
An RCT may be blinded, (also called "masked") by "procedures that prevent study participants, caregivers, or outcome assessors from knowing which intervention was received." Unlike allocation concealment, blinding is sometimes inappropriate or impossible to perform in an RCT; for example, if an RCT involves a treatment in which active participation of the patient is necessary (e.g., physical therapy), participants cannot be blinded to the intervention.
Traditionally, blinded RCTs have been classified as "single-blind", "double-blind", or "triple-blind"; however, in 2001 and 2006 two studies showed that these terms have different meanings for different people. The 2010 CONSORT Statement specifies that authors and editors should not use the terms "single-blind", "double-blind", and "triple-blind"; instead, reports of blinded RCT should discuss "If done, who was blinded after assignment to interventions (for example, participants, care providers, those assessing outcomes) and how."
RCTs without blinding are referred to as "unblinded", "open", or (if the intervention is a medication) "open-label". In 2008 a study concluded that the results of unblinded RCTs tended to be biased toward beneficial effects only if the RCTs' outcomes were subjective as opposed to objective; for example, in an RCT of treatments for multiple sclerosis, unblinded neurologists (but not the blinded neurologists) felt that the treatments were beneficial. In pragmatic RCTs, although the participants and providers are often unblinded, it is "still desirable and often possible to blind the assessor or obtain an objective source of data for evaluation of outcomes."
== Analysis of data ==
The types of statistical methods used in RCTs depend on the characteristics of the data and include:
For dichotomous (binary) outcome data, logistic regression (e.g., to predict sustained virological response after receipt of peginterferon alfa-2a for hepatitis C) and other methods can be used.
For continuous outcome data, analysis of covariance (e.g., for changes in blood lipid levels after receipt of atorvastatin after acute coronary syndrome) tests the effects of predictor variables.
For time-to-event outcome data that may be censored, survival analysis (e.g., Kaplan–Meier estimators and Cox proportional hazards models for time to coronary heart disease after receipt of hormone replacement therapy in menopause) is appropriate.
Regardless of the statistical methods used, important considerations in the analysis of RCT data include:
Whether an RCT should be stopped early due to interim results. For example, RCTs may be stopped early if an intervention produces "larger than expected benefit or harm", or if "investigators find evidence of no important difference between experimental and control interventions."
The extent to which the groups can be analyzed exactly as they existed upon randomization (i.e., whether a so-called "intention-to-treat analysis" is used). A "pure" intention-to-treat analysis is "possible only when complete outcome data are available" for all randomized subjects; when some outcome data are missing, options include analyzing only cases with known outcomes and using imputed data. Nevertheless, the more that analyses can include all participants in the groups to which they were randomized, the less bias that an RCT will be subject to.
Whether subgroup analysis should be performed. These are "often discouraged" because multiple comparisons may produce false positive findings that cannot be confirmed by other studies.
== Reporting of results ==
The CONSORT 2010 Statement is "an evidence-based, minimum set of recommendations for reporting RCTs." The CONSORT 2010 checklist contains 25 items (many with sub-items) focusing on "individually randomised, two group, parallel trials" which are the most common type of RCT.
For other RCT study designs, "CONSORT extensions" have been published, some examples are:
Consort 2010 Statement: Extension to Cluster Randomised Trials
Consort 2010 Statement: Non-Pharmacologic Treatment Interventions
"Reporting of surrogate endpoints in randomised controlled trial reports (CONSORT-Surrogate): extension checklist with explanation and elaboration"
=== Relative importance and observational studies ===
Two studies published in The New England Journal of Medicine in 2000 found that observational studies and RCTs overall produced similar results. The authors of the 2000 findings questioned the belief that "observational studies should not be used for defining evidence-based medical care" and that RCTs' results are "evidence of the highest grade." However, a 2001 study published in Journal of the American Medical Association concluded that "discrepancies beyond chance do occur and differences in estimated magnitude of treatment effect are very common" between observational studies and RCTs. According to a 2014 (updated in 2024) Cochrane review, there is little evidence for significant effect differences between observational studies and randomized controlled trials. To evaluate differences it is necessary to consider things other than design, such as heterogeneity, population, intervention or comparator.
Two other lines of reasoning question RCTs' contribution to scientific knowledge beyond other types of studies:
If study designs are ranked by their potential for new discoveries, then anecdotal evidence would be at the top of the list, followed by observational studies, followed by RCTs.
RCTs may be unnecessary for treatments that have dramatic and rapid effects relative to the expected stable or progressively worse natural course of the condition treated. One example is combination chemotherapy including cisplatin for metastatic testicular cancer, which increased the cure rate from 5% to 60% in a 1977 non-randomized study.
=== Interpretation of statistical results ===
Like all statistical methods, RCTs are subject to both type I ("false positive") and type II ("false negative") statistical errors. Regarding Type I errors, a typical RCT will use 0.05 (i.e., 1 in 20) as the probability that the RCT will falsely find two equally effective treatments significantly different. Regarding Type II errors, despite the publication of a 1978 paper noting that the sample sizes of many "negative" RCTs were too small to make definitive conclusions about the negative results, by 2005-2006 a sizeable proportion of RCTs still had inaccurate or incompletely reported sample size calculations.
=== Peer review ===
Peer review of results is an important part of the scientific method. Reviewers examine the study results for potential problems with design that could lead to unreliable results (for example by creating a systematic bias), evaluate the study in the context of related studies and other evidence, and evaluate whether the study can be reasonably considered to have proven its conclusions. To underscore the need for peer review and the danger of overgeneralizing conclusions, two Boston-area medical researchers performed a randomized controlled trial in which they randomly assigned either a parachute or an empty backpack to 23 volunteers who jumped from either a biplane or a helicopter. The study was able to accurately report that parachutes fail to reduce injury compared to empty backpacks. The key context that limited the general applicability of this conclusion was that the aircraft were parked on the ground, and participants had only jumped about two feet.
== Advantages ==
RCTs are considered to be the most reliable form of scientific evidence in the hierarchy of evidence that influences healthcare policy and practice because RCTs reduce spurious causality and bias. Results of RCTs may be combined in systematic reviews which are increasingly being used in the conduct of evidence-based practice. Some examples of scientific organizations' considering RCTs or systematic reviews of RCTs to be the highest-quality evidence available are:
As of 1998, the National Health and Medical Research Council of Australia designated "Level I" evidence as that "obtained from a systematic review of all relevant randomised controlled trials" and "Level II" evidence as that "obtained from at least one properly designed randomised controlled trial."
Since at least 2001, in making clinical practice guideline recommendations the United States Preventive Services Task Force has considered both a study's design and its internal validity as indicators of its quality. It has recognized "evidence obtained from at least one properly randomized controlled trial" with good internal validity (i.e., a rating of "I-good") as the highest quality evidence available to it.
The GRADE Working Group concluded in 2008 that "randomised trials without important limitations constitute high quality evidence."
For issues involving "Therapy/Prevention, Aetiology/Harm", the Oxford Centre for Evidence-based Medicine as of 2011 defined "Level 1a" evidence as a systematic review of RCTs that are consistent with each other, and "Level 1b" evidence as an "individual RCT (with narrow Confidence Interval)."
Notable RCTs with unexpected results that contributed to changes in clinical practice include:
After Food and Drug Administration approval, the antiarrhythmic agents flecainide and encainide came to market in 1986 and 1987 respectively. The non-randomized studies concerning the drugs were characterized as "glowing", and their sales increased to a combined total of approximately 165,000 prescriptions per month in early 1989. In that year, however, a preliminary report of an RCT concluded that the two drugs increased mortality. Sales of the drugs then decreased.
Prior to 2002, based on observational studies, it was routine for physicians to prescribe hormone replacement therapy for post-menopausal women to prevent myocardial infarction. In 2002 and 2004, however, published RCTs from the Women's Health Initiative claimed that women taking hormone replacement therapy with estrogen plus progestin had a higher rate of myocardial infarctions than women on a placebo, and that estrogen-only hormone replacement therapy caused no reduction in the incidence of coronary heart disease. Possible explanations for the discrepancy between the observational studies and the RCTs involved differences in methodology, in the hormone regimens used, and in the populations studied. The use of hormone replacement therapy decreased after publication of the RCTs.
== Disadvantages ==
Many papers discuss the disadvantages of RCTs. Among the most frequently cited drawbacks are:
=== Time and costs ===
RCTs can be expensive; one study found 28 Phase III RCTs funded by the National Institute of Neurological Disorders and Stroke prior to 2000 with a total cost of US$335 million, for a mean cost of US$12 million per RCT. Nevertheless, the return on investment of RCTs may be high, in that the same study projected that the 28 RCTs produced a "net benefit to society at 10-years" of 46 times the cost of the trials program, based on evaluating a quality-adjusted life year as equal to the prevailing mean per capita gross domestic product.
The conduct of an RCT takes several years until being published; thus, data is restricted from the medical community for long years and may be of less relevance at time of publication.
It is costly to maintain RCTs for the years or decades that would be ideal for evaluating some interventions.
Interventions to prevent events that occur only infrequently (e.g., sudden infant death syndrome) and uncommon adverse outcomes (e.g., a rare side effect of a drug) would require RCTs with extremely large sample sizes and may, therefore, best be assessed by observational studies.
Due to the costs of running RCTs, these usually only inspect one variable or very few variables, rarely reflecting the full picture of a complicated medical situation; whereas the case report, for example, can detail many aspects of the patient's medical situation (e.g. patient history, physical examination, diagnosis, psychosocial aspects, follow up).
=== Conflict of interest dangers ===
A 2011 study done to disclose possible conflicts of interests in underlying research studies used for medical meta-analyses reviewed 29 meta-analyses and found that conflicts of interests in the studies underlying the meta-analyses were rarely disclosed. The 29 meta-analyses included 11 from general medicine journals; 15 from specialty medicine journals, and 3 from the Cochrane Database of Systematic Reviews. The 29 meta-analyses reviewed an aggregate of 509 randomized controlled trials (RCTs). Of these, 318 RCTs reported funding sources with 219 (69%) industry funded. 132 of the 509 RCTs reported author conflict of interest disclosures, with 91 studies (69%) disclosing industry financial ties with one or more authors. The information was, however, seldom reflected in the meta-analyses. Only two (7%) reported RCT funding sources and none reported RCT author-industry ties. The authors concluded "without acknowledgment of COI due to industry funding or author industry financial ties from RCTs included in meta-analyses, readers' understanding and appraisal of the evidence from the meta-analysis may be compromised."
Some RCTs are fully or partly funded by the health care industry (e.g., the pharmaceutical industry) as opposed to government, nonprofit, or other sources. A systematic review published in 2003 found four 1986–2002 articles comparing industry-sponsored and nonindustry-sponsored RCTs, and in all the articles there was a correlation of industry sponsorship and positive study outcome. A 2004 study of 1999–2001 RCTs published in leading medical and surgical journals determined that industry-funded RCTs "are more likely to be associated with statistically significant pro-industry findings." These results have been mirrored in trials in surgery, where although industry funding did not affect the rate of trial discontinuation it was however associated with a lower odds of publication for completed trials. One possible reason for the pro-industry results in industry-funded published RCTs is publication bias. Other authors have cited the differing goals of academic and industry sponsored research as contributing to the difference. Commercial sponsors may be more focused on performing trials of drugs that have already shown promise in early stage trials, and on replicating previous positive results to fulfill regulatory requirements for drug approval.
=== Ethics ===
If a disruptive innovation in medical technology is developed, it may be difficult to test this ethically in an RCT if it becomes "obvious" that the control subjects have poorer outcomes—either due to other foregoing testing, or within the initial phase of the RCT itself. Ethically it may be necessary to abort the RCT prematurely, and getting ethics approval (and patient agreement) to withhold the innovation from the control group in future RCTs may not be feasible.
Historical control trials (HCT) exploit the data of previous RCTs to reduce the sample size; however, these approaches are controversial in the scientific community and must be handled with care.
== In social science ==
Due to the recent emergence of RCTs in social science, the use of RCTs in social sciences is a contested issue. Some writers from a medical or health background have argued that existing research in a range of social science disciplines lacks rigour, and should be improved by greater use of randomized control trials.
=== Transport science ===
Researchers in transport science argue that public spending on programmes such as school travel plans could not be justified unless their efficacy is demonstrated by randomized controlled trials. Graham-Rowe and colleagues reviewed 77 evaluations of transport interventions found in the literature, categorising them into 5 "quality levels". They concluded that most of the studies were of low quality and advocated the use of randomized controlled trials wherever possible in future transport research.
Dr. Steve Melia took issue with these conclusions, arguing that claims about the advantages of RCTs, in establishing causality and avoiding bias, have been exaggerated. He proposed the following eight criteria for the use of RCTs in contexts where interventions must change human behaviour to be effective:
The intervention:
Has not been applied to all members of a unique group of people (e.g. the population of a whole country, all employees of a unique organisation etc.)
Is applied in a context or setting similar to that which applies to the control group
Can be isolated from other activities—and the purpose of the study is to assess this isolated effect
Has a short timescale between its implementation and maturity of its effects
And the causal mechanisms:
Are either known to the researchers, or else all possible alternatives can be tested
Do not involve significant feedback mechanisms between the intervention group and external environments
Have a stable and predictable relationship to exogenous factors
Would act in the same way if the control group and intervention group were reversed
=== Criminology ===
A 2005 review found 83 randomized experiments in criminology published in 1982–2004, compared with only 35 published in 1957–1981. The authors classified the studies they found into five categories: "policing", "prevention", "corrections", "court", and "community". Focusing only on offending behavior programs, Hollin (2008) argued that RCTs may be difficult to implement (e.g., if an RCT required "passing sentences that would randomly assign offenders to programmes") and therefore that experiments with quasi-experimental design are still necessary.
=== Education ===
RCTs have been used in evaluating a number of educational interventions. Between 1980 and 2016, over 1,000 reports of RCTs have been published. For example, a 2009 study randomized 260 elementary school teachers' classrooms to receive or not receive a program of behavioral screening, classroom intervention, and parent training, and then measured the behavioral and academic performance of their students. Another 2009 study randomized classrooms for 678 first-grade children to receive a classroom-centered intervention, a parent-centered intervention, or no intervention, and then followed their academic outcomes through age 19.
== Criticism ==
A 2018 review of the 10 most cited randomised controlled trials noted poor distribution of background traits, difficulties with blinding, and discussed other assumptions and biases inherent in randomised controlled trials. These include the "unique time period assessment bias", the "background traits remain constant assumption", the "average treatment effects limitation", the "simple treatment at the individual level limitation", the "all preconditions are fully met assumption", the "quantitative variable limitation" and the "placebo only or conventional treatment only limitation".
== See also ==
Drug development
Hypothesis testing
Impact evaluation
Jadad scale
Pipeline planning
Patient and public involvement
Observational study
Blinded experiment
Statistical inference
Royal Commission on Animal Magnetism – 1784 French scientific bodies' investigations involving systematic controlled trials
== References ==
== Further reading == | Wikipedia/Randomized_controlled_trials |
The DPT vaccine or DTP vaccine is a class of combination vaccines to protect
against three infectious diseases in humans: diphtheria, pertussis (whooping cough), and tetanus (lockjaw). The vaccine components include diphtheria and tetanus toxoids, and either killed whole cells of the bacterium that causes pertussis or pertussis antigens. The term toxoid refers to vaccines which use an inactivated toxin produced by the pathogen which they are targeted against to generate an immune response. In this way, the toxoid vaccine generates an immune response which is targeted against the toxin which is produced by the pathogen and causes disease, rather than a vaccine which is targeted against the pathogen itself. The whole cells or antigens will be depicted as either "DTwP" or "DTaP", where the lower-case "w" indicates whole-cell inactivated pertussis and the lower-case "a" stands for "acellular". In comparison to alternative vaccine types, such as live attenuated vaccines, the DTP vaccine does not contain any live pathogen, but rather uses inactivated toxoid (and for pertussis, either a dead pathogen or pure antigens) to generate an immune response; therefore, there is not a risk of use in populations that are immune compromised since there is not any known risk of causing the disease itself. As a result, the DTP vaccine is considered a safe vaccine to use in anyone and it generates a much more targeted immune response specific for the pathogen of interest.
In the United States, the DPT (whole-cell) vaccine was administered as part of the childhood vaccines recommended by the Centers for Disease Control and Prevention (CDC) until 1996, when the acellular DTaP vaccine was licensed for use.
== History ==
Diphtheria and tetanus toxoids and whole-cell pertussis (DTP; now also "DTwP" to differentiate from the broader class of triple-combination vaccines) vaccination was licensed in 1949. Since the introduction of the combination vaccine, there has been an extensive decline in the incidence of pertussis, or whooping cough, the disease which the vaccine protects against. Additionally, the rates of disease have continued to decline as more extensive immunization strategies have been implemented, including booster doses and increased emphasis on increasing health literacy.
In the 20th century, the advancements in vaccinations helped to reduce the incidence of childhood pertussis and had a dramatically positive effect on the health of populations in the United States. However, in the early 21st century, reported instances of the disease increased 20-fold due to a downturn in the number of immunizations received and resulted in numerous fatalities. During the 21st century, many parents declined to vaccinate their children against pertussis for fear of perceived side effects, despite scientific evidence showing vaccines to be highly effective and safe. In 2009, the journal Pediatrics concluded the largest risk among unvaccinated children was not the contraction of side effects, but rather the disease that the vaccination aims to protect against.
DTP vaccines with acellular pertussis (DTaP; see below) were introduced in the 1990s. The reduced range of antigens causes fewer side effects, but results in a more expensive, shorter-lasting, and possibly less protective vaccine compared to DTwP. High-income countries have mostly switched to DTaP. As of 2023, global production of aP remains limited.
=== Vaccination rates ===
In 2016, the CDC reported that 80.4% of children in the US had received four or more DTaP vaccinations by 2 years of life. Vaccination rates for children aged 13–17 with one or more TDaP shots was 90.2% in 2019. Only 43.6% of adults (older than 18) have received a TDaP shot in the last 10 years. The CDC aimed to increase vaccination rate among 2-year-olds from 80.4% to 90.0%
The World Health Organization (WHO) estimated that 89% of people globally had received at least one dose of DTP vaccine and 84% had received three doses of the vaccine, completing the WHO-recommended primary series (DTP3). The WHO also tracks the DTP3 completion rate among one-year-olds on a yearly basis. Yearly DTP3 completion rate is considered a good proxy for the completeness of childhood vaccination in general.
== Combination vaccines with acellular pertussis ==
DTaP and Tdap are both combination vaccines against diphtheria, tetanus, and pertussis. The "a" indicates that the pertussis toxoids are acellular, while the lower-case "d" and "p" in "Tdap" indicate smaller concentrations of diphtheria toxoids and pertussis antigens.
=== DTaP ===
DTaP (also DTP and TDaP) is a combination vaccine against diphtheria, tetanus, and pertussis, in which the pertussis component is acellular. This is in contrast to whole-cell, inactivated DTP (or DTwP). The acellular vaccine uses selected antigens of the pertussis pathogen to induce immunity. Because it uses fewer antigens than the whole-cell vaccines, it is considered to cause fewer side effects, but it is also more expensive. Research suggests that the DTwP vaccine is more effective than DTaP in conferring immunity, because DTaP's narrower antigen base is less effective against current pathogen strains.
=== Tdap ===
Tdap (also TDP) is a tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine. It was licensed in the United States for use in adults and adolescents on 10 June 2005. Two Tdap vaccines are available in the US. In January 2011, the US Centers for Disease Control and Prevention (CDC) Advisory Committee on Immunization Practices (ACIP) recommended the use of Tdap in adults of all ages, including those age 65 and above. In October 2011, in an effort to reduce the burden of pertussis in infants, the ACIP recommended that unvaccinated pregnant women receive a dose of Tdap. On 24 October 2012, the ACIP voted to recommend the use of Tdap during every pregnancy.
The ACIP and Canada's National Advisory Committee on Immunization (NACI) recommended that both adolescents and adults receive Tdap in place of their next Td booster (recommended to be given every ten years). Tdap and Td can be used as prophylaxis for tetanus in wound management. People who will be in contact with young infants are encouraged to get Tdap even if it has been less than five years since Td or TT to reduce the risk of infants being exposed to pertussis. NACI suggests intervals shorter than five years can be used for catch-up programs and other instances where programmatic concerns make five-year intervals difficult.
The WHO recommends a pentavalent vaccine, combining the DTP vaccine with vaccines against Haemophilus influenzae type B and hepatitis B. Evidence on how effective this pentavalent vaccine is compared to the individual vaccines has not yet been determined.
A 2019 study found that state requirements mandating the use of the Tdap vaccine "increased Tdap vaccine take-up and reduced pertussis (whooping cough) incidence by about 32%."
== Related combination vaccines ==
=== Excluding pertussis ===
DT and Td vaccines lack the pertussis component. The Td vaccine is administered to children over the age of seven as well as to adults. It is most commonly administered as a booster shot every 10 years. The Td booster shot may also be administered as protection from a severe burn or dirty wound. The DT vaccine is given to children under the age of seven who are unable to receive the pertussis antigen in the DTaP vaccine due to a contraindication.
=== Additional targets ===
In the United States, a combined inactivated polio (IPV), DTaP, and hepatitis B DTaP-IPV-HepB vaccine is available for children. In the UK, all babies born on or after 1 August 2017 are offered a hexavalent vaccine: DTaP, IPV, Haemophilus influenzae, and hepatitis B (DTaP-Hib-HepB-IPV in short).
As of 2023, most of the DTP vaccine procured by UNICEF is of the DTwP-HepB-Hib (pentavalent whole-cell) type. The UNICEF plans to procure the DTwP-HepB-Hib-IPV (hexavalent whole-cell) vaccine starting in 2024.
== Contraindications ==
The DPT vaccine should be avoided in persons who experienced a severe allergic reaction, such as anaphylaxis, to a past vaccine containing tetanus, diphtheria, or pertussis. It should also be avoided in persons with a known severe allergy to an ingredient in the vaccine. If the reaction was caused by tetanus toxoids, the CDC recommends considering a passive immunization with tetanus immune globulin (TIG) if a person has a large or unclean wound. The DPT vaccine should also be avoided if a person developed encephalopathy (seizures, coma, declined consciousness) within seven days of receiving any pertussis-containing vaccine and the encephalopathy cannot be traced to another cause. A DT vaccine is available for children under the ages of seven who have contraindications or precautions to pertussis-containing vaccines.
== Side effects ==
=== DTaP ===
Common side effects include soreness where the shot was given, fever, irritability, tenderness, loss of appetite, and vomiting. Most side effects are mild to moderate and may last from one to three days. More serious but rare reactions after a DTaP vaccination may include seizures, lowered consciousness, or a high fever over 105 °F (41 °C). Allergic reactions are uncommon, but are medical emergencies. Signs of an allergic reaction include hives, dyspnea, wheezing, swelling of face and throat, syncope, and tachycardia and the child should be rushed to the nearest hospital.
=== Tdap ===
Common side effects include pain or swelling where the shot was given, mild fever, headache, tiredness, nausea, vomiting, diarrhea, and stomach ache. Allergic reactions are possible and have the same presentation and indications as described above for allergic reactions in DTaP. Any individual who has experienced a life-threatening allergic reaction after receiving a previous dose of diphtheria, tetanus, or pertussis containing vaccine should not receive the Tdap vaccination.
In pregnant women, research suggests that Tdap administration may be associated with an increased risk of chorioamnionitis, a placental infection. Increased incidence of fever is also noted in pregnant women. Despite the observed increase in incidence of chorioamnionitis in pregnant women following Tdap administration, there has been no observed increase in the incidence of preterm birth, for which chorioamnionitis is a risk factor. Research has not discerned an association between Tdap administration during pregnancy and other serious pregnancy complications such as neonatal death and stillbirth. An association between Tdap administration during pregnancy and pregnancy-related hypertensive disorders (such as pre-eclampsia) has not been identified.
== Immunization schedules and requirements ==
=== Australia ===
In Australia, the DTP vaccine is part of the National Immunisation Program (NIP). The vaccine is administered to infants in a series of doses: the first three doses are given at 2, 4, and 6 months of age, followed by a fourth dose at 18 months and a fifth dose at 4 years. Adolescents receive a single booster dose at 12-13 years.
Adults are recommended to receive a dTpa booster every 10 years, especially those in close contact with infants. Pregnant women are advised to receive a dTpa booster during each pregnancy, ideally between 20-32 weeks of gestation, to protect newborns from pertussis.
=== France ===
In France, children are given DTaP-Hib-HepB-IPV vaccines at 2 months (first dose) and 4 months (second dose) with a booster at 11 months of age. A tetravalent booster for diphtheria, pertussis, tetanus and poliomyelitis is given at 6 years, at 11–13 years, then at 25, 45, 65 years of age, then every 10 years.
=== Netherlands ===
In the Netherlands, pertussis is known as kinkhoest and DKTP refers to the DTaP-IPV combination vaccine against diphtheria, kinkhoest, tetanus, and polio. DTaP is given as part of the National Immunisation Programme.
=== United Kingdom ===
In the United Kingdom, Td/IPV is called the "3-in-1 teenage booster" and protects against tetanus, diphtheria and polio. It is given by the NHS to all teenagers aged 14 (the hexavalent vaccine is given to infants and provides the first stage of protection against diphtheria, tetanus, and polio, as well as pertussis, Haemophilus influenzae type B and hepatitis B). Subsequent boosters are recommended for foreign travellers where more than 10 years has passed since their last booster. This is provided on the NHS free of charge due to the significant risk that an imported case of polio could pose to public health in Britain.
=== United States ===
The standard immunization regimen for children within the United States is five doses of DTaP between the ages of two months and fifteen years. To be considered fully vaccinated, the Centers for Disease Control and Prevention (CDC) typically requires five doses of Tdap. The CDC recommends that children receive their first dose at two months, the second dose at four months, the third dose at six months, the fourth dose between 15 and 18 months, and the fifth dose between 4–6 years. If the fourth dose of the DTaP immunization regimen falls on or subsequent to the recipient's fourth birthday, the CDC states that only four doses are required to be fully vaccinated. In the instance that an individual under 18 has not received the DTaP vaccine, individuals should be vaccinated on the schedule in accordance with the vaccination "catch up schedule" provided by the CDC.
Infants younger than twelve months of age, specifically less than three months of age, are at highest risk of acquiring pertussis. In U.S., there is no current tetanus-diphtheria-pertussis vaccination (whooping cough) recommended or licensed for new born infants. As a result, in their first few months of life, unprotected infants are at highest risk of life-threatening complications and infections from pertussis. Infants should not receive pertussis vaccination younger than six weeks of age. Ideally, Infants should receive DTaP (name of whooping cough vaccine for children from age 2 months through 6 years) at 2, 4, 6 months of age and they are not protected until the full series is completed. To protect infants younger than twelve months of age not vaccinated with Tdap against pertussis, ACIP also recommends adults (e.g., parents, siblings, grandparents, childcare providers, and healthcare personnel) and children to receive Tdap at least two weeks before being in contact with the infant.
The CDC recommends that adults who have received their childhood DTP series receive a Td or Tdap booster every ten years. For adults that have not received the DTP series, the CDC recommends a three-part vaccine series followed by a Td or Tdap booster every ten years.
==== In pregnancy ====
According to the CDC's Advisory Committee on Immunization Practices (ACIP) guidelines, one dose of Tdap is recommended during each pregnancy to ensure protection against pertussis in newborn infants. Optimal timing to administer a dose of Tdap during each pregnancy is between 27 through 36 weeks gestation. If Tdap is administered early in pregnancy, it is not recommended to administer again during the 27 through 36 weeks gestation period as only one dose is recommended during pregnancy. In October 2022, Boostrix (Tetanus Toxoid, Reduced Diphtheria Toxoid and Acellular Pertussis Vaccine, Adsorbed [Tdap]) was approved for immunization during the third trimester of pregnancy to prevent pertussis, commonly known as whooping cough, in infants younger than two months of age.
Pregnant women who have not previously vaccinated with Tdap (i.e., have never received DTP, DTaP, or DT as child or Td or TT as an adult) are recommended to receive a series of three Td vaccinations starting during pregnancy to ensure protection against maternal and neonatal tetanus. In such cases, administration of Tdap is recommended after 20 weeks' gestation, and in earlier pregnancy a single dose of Tdap can be substituted for one dose of Td, and then the series completed with Td. For pregnant women not previously vaccinated with Tdap, if Tdap is not administered during pregnancy, it should be administered immediately postpartum. Postpartum administration of TDaP is not equivalent to administration of the vaccination during pregnancy. Because the vaccine is administered postpartum, the mother is unable to develop antibodies that can be transferred to the infant in utero, consequently, leaving the infant vulnerable to the diseases preventable by the Tdap Vaccine. Postpartum administration of the TdaP vaccine to the mother seeks to reduce the likelihood that the mother will contract disease that can be subsequently passed on the infant, albeit there will still be a two-week period prior to the protective effects of the vaccine setting in. Postpartum administration is an extension of the concept of "cocooning", a term that refers to the full vaccination of all individuals that may come into direct contact with the infant. Cocooning, like postpartum Tdap administration, is not recommended by the CDC. Cocooning depends on ensuring full vaccination of all individuals that the infant may come into contact with, and there may be financial, administrative or personal barriers that preclude full and timely vaccination of all individuals within the "cocoon".
== Brand names ==
=== Australia ===
=== United Kingdom ===
Brand names in the United Kingdom include Revaxis (Sanofi Pasteur).
=== United States ===
As of January 2020, there are six DTaP vaccines and two Tdap vaccines licensed and available for use in the United States. All of them are indicated as childhood vaccinations with the schedules as follows:
== References ==
== Further reading ==
=== Diphtheria ===
World Health Organization (2009). The immunological basis for immunization : module 2: diphtheria — update 2009. World Health Organization (WHO). hdl:10665/44094. ISBN 9789241597869.
Ramsay M, ed. (2013). "Chapter 15: Diphtheria". Immunisation against infectious disease. Public Health England.
Roush SW, Baldy LM, Hall MA, eds. (March 2019). Manual for the surveillance of vaccine-preventable diseases. Atlanta GA: U.S. Centers for Disease Control and Prevention (CDC).
=== Pertussis ===
World Health Organization (2017). The immunological basis for immunization series: module 4: pertussis, update 2017. World Health Organization (WHO). hdl:10665/259388. ISBN 9789241513173.
Ramsay M, ed. (2013). "Chapter 24: Pertussis". Immunisation against infectious disease. Public Health England.
Hamborsky J, Kroger A, Wolfe S, eds. (2015). "Chapter 16: Pertussis". Epidemiology and Prevention of Vaccine-Preventable Diseases (13th ed.). Washington D.C.: U.S. Centers for Disease Control and Prevention (CDC). ISBN 978-0990449119.
Roush SW, Baldy LM, Hall MA, eds. (March 2019). "Chapter 10: Pertussis". Manual for the surveillance of vaccine-preventable diseases. Atlanta GA: U.S. Centers for Disease Control and Prevention (CDC).
=== Tetanus ===
World Health Organization (2018). The immunological basis for immunization series: module 3: tetanus: update 2018. World Health Organization (WHO). hdl:10665/275340. ISBN 9789241513616.
Ramsay M, ed. (2013). "Chapter 30: Tetanus". Immunisation against infectious disease. Public Health England.
Hamborsky J, Kroger A, Wolfe S, eds. (2015). "Chapter 21: Tetanus". Epidemiology and Prevention of Vaccine-Preventable Diseases (13th ed.). Washington D.C.: U.S. Centers for Disease Control and Prevention (CDC). ISBN 978-0990449119.
Roush SW, Baldy LM, Hall MA, eds. (March 2019). "Chapter 16: Tetanus". Manual for the surveillance of vaccine-preventable diseases. Atlanta GA: U.S. Centers for Disease Control and Prevention (CDC).
== External links ==
"Tdap (Tetanus, Diphtheria, Pertussis) Vaccine Information Statement". U.S. Centers for Disease Control and Prevention (CDC). 19 May 2023.
"DTaP (Diphtheria, Tetanus, Pertussis) Vaccine Information Statement". U.S. Centers for Disease Control and Prevention (CDC). 21 July 2023.
"DTaP/Tdap/Td ACIP Vaccine Recommendations". U.S. Centers for Disease Control and Prevention (CDC). 24 September 2024.
Tetanus Toxoid at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
Diphtheria-Tetanus Vaccine at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
Diphtheria-Tetanus-Pertussis Vaccine at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
Diphtheria-Tetanus-acellular Pertussis Vaccines at the U.S. National Library of Medicine Medical Subject Headings (MeSH) | Wikipedia/DTP_vaccine |
An attenuated vaccine (or a live attenuated vaccine, LAV) is a vaccine created by reducing the virulence of a pathogen, but still keeping it viable (or "live"). Attenuation takes an infectious agent and alters it so that it becomes harmless or less virulent. These vaccines contrast to those produced by "killing" the pathogen (inactivated vaccine).
Attenuated vaccines stimulate a strong and effective immune response that is long-lasting. In comparison to inactivated vaccines, attenuated vaccines produce a stronger and more durable immune response with a quick immunity onset. They are generally avoided in pregnancy and in patients with severe immunodeficiencies. Attenuated vaccines function by encouraging the body to create antibodies and memory immune cells in response to the specific pathogen which the vaccine protects against. Common examples of live attenuated vaccines are measles, mumps, rubella, yellow fever, varicella, and some influenza vaccines.
== Development ==
=== Attenuated viruses ===
Viruses may be attenuated using the principles of evolution with serial passage of the virus through a foreign host species, such as:
Tissue culture
Embryonated eggs (often chicken)
Live animals
The initial virus population is applied to a foreign host. Through natural genetic variability or induced mutation, a small percentage of the viral particles should have the capacity to infect the new host. These strains will continue to evolve within the new host and the virus will gradually lose its efficacy in the original host, due to lack of selection pressure. This process is known as "passage" in which the virus becomes so well adapted to the foreign host that it is no longer harmful to the subject that is to receive the vaccine. This makes it easier for the host immune system to eliminate the agent and create the immunological memory cells which will likely protect the patient if they are infected with a similar version of the virus in "the wild".
Viruses may also be attenuated via reverse genetics. Attenuation by genetics is also used in the production of oncolytic viruses.
=== Attenuated bacteria ===
Bacteria is typically attenuated by passage, similar to the method used in viruses. Gene knockout guided by reverse genetics is also used.
== Administration ==
Attenuated vaccines can be administered in a variety of ways:
Injections:
Subcutaneous (e.g. measles, mumps and rubella vaccine, varicella vaccine, yellow fever vaccine)
Intradermal (e.g. tuberculosis vaccine, smallpox vaccine)
Mucosal:
Nasal (e.g. live attenuated influenza vaccine)
Oral (e.g. oral polio vaccine, recombinant live attenuated cholera vaccine, oral typhoid vaccine, oral rotavirus vaccine)
Oral vaccines or subcutaneous/intramuscular injection are for individuals older than 12 months. Live attenuated vaccines, with the exception of the rotavirus vaccine given at 6 weeks, is not indicated for infants younger than 9 months.
== Mechanism ==
Vaccines function by encouraging the creation of immune cells, such as CD8+ and CD4+ T lymphocytes, or molecules, such as antibodies, that are specific to the pathogen. The cells and molecules can either prevent or reduce infection by killing infected cells or by producing interleukins. The specific effectors evoked can be different based on the vaccine. Live attenuated vaccines tend to help with the production of CD8+ cytotoxic T lymphocytes and T-dependent antibody responses. A vaccine is only effective for as long as the body maintains a population of these cells.
Attenuated vaccines are “weakened” versions of pathogens (virus or bacteria). They are modified so that it cannot cause harm or disease in the body but are still able to activate the immune system. This type of vaccine works by activating both the cellular and humoral immune responses of the adaptive immune system. When a person receives an oral or injection of the vaccine, B cells, which help make antibodies, are activated in two ways: T cell-dependent and T-cell independent activation.
In T-cell dependent activation of B cells, B cells first recognize and present the antigen on MHCII receptors. T-cells can then recognize this presentation and bind to the B cell, resulting in clonal proliferation. This also helps IgM and plasma cells production as well as immunoglobulin switching. On the other hand, T-cell independent activation of B cells is due to non-protein antigens. This can lead to production of IgM antibodies. Being able to produce a B-cell response as well as memory killer T cells is a key feature of attenuated virus vaccines that help induce a potent immunity.
== Safety ==
Live-attenuated vaccines are safe and stimulate a strong and effective immune response that is long-lasting. Given that pathogens are attenuated, it is extremely rare for pathogens to revert to their pathogenic form and subsequently cause disease. Additionally, amongst the five WHO-recommended live attenuated vaccines (tuberculosis, oral polio, measles, rotavirus, and yellow fever), severe adverse reactions are extremely rare.
Individuals with severely compromised immune systems (e.g., HIV-infection, chemotherapy, immunosuppressive therapy, lymphoma, leukemia, combined immunodeficiencies) typically should not receive live-attenuated vaccines as they may not be able to produce an adequate and safe immune response. Household contacts of immunodeficient individuals are still able to receive most attenuated vaccines since there is no increased risk of infection transmission, with the exception being the oral polio vaccine.
As a precaution, live-attenuated vaccines are not typically administered during pregnancy. This is due to the risk of transmission of virus between mother and fetus. In particular, the varicella and yellow fever vaccines have been shown to have adverse effects on fetuses and nursing babies.
Some live attenuated vaccines have additional common, mild adverse effects due to their administration route. For example, the live attenuated influenza vaccine is given nasally and is associated with nasal congestion.
Compared to inactivated vaccines, live-attenuated vaccines are more prone to immunization errors as they must be kept under strict conditions during the cold chain and carefully prepared (e.g., during reconstitution).
== History ==
The history of vaccine development started with the creation of the smallpox vaccine by Edward Jenner in the late 18th century. Jenner discovered that inoculating a human with an animal pox virus would grant immunity against smallpox, a disease considered to be one of the most devastating in human history. Although the original smallpox vaccine is sometimes considered to be an attenuated vaccine due to its live nature, it was not strictly-speaking attenuated since it was not derived directly from smallpox. Instead, it was based on the related and milder cowpox disease. The discovery that diseases could be artificially attenuated came in the late 19th century when Louis Pasteur was able to derive an attenuated strain of chicken cholera. Pasteur applied this knowledge to develop an attenuated anthrax vaccine and demonstrating its effectiveness in a public experiment. The first rabies vaccine was subsequently produced by Pasteur and Emile Roux by growing the virus in rabbits and drying the affected nervous tissue.
The technique of cultivating a virus repeatedly in artificial media and isolating less virulent strains was pioneered in the early 20th century by Albert Calmette and Camille Guérin who developed an attenuated tuberculosis vaccine called the BCG vaccine. This technique was later used by several teams when developing the vaccine for yellow fever, first by Sellards and Laigret, and then by Theiler and Smith. The vaccine developed by Theiler and Smith proved to be hugely successful and helped establish recommended practices and regulations for many other vaccines. These include the growth of viruses in primary tissue culture (e.g., chick embryos), as opposed to animals, and the use of the seed stock system which uses the original attenuated viruses as opposed to derived viruses (done to reduce variance in vaccine development and decrease the chance of adverse effects). The middle of the 20th century saw the work of many prominent virologists including Sabin, Hilleman, and Enders, and the introduction of several successful attenuated vaccines, such as those against polio, measles, mumps, and rubella.
== Advantages and disadvantages ==
=== Advantages ===
Accurately imitate natural infections.
Are effective at evoking both strong antibody and cell-mediated immune reactions.
Can elicit long-lasting or life-long immunity.
Often only one or two doses are required.
Quick immunity onset.
Cost-effective (compared to some other health interventions).
Can have strong beneficial non-specific effects.
=== Disadvantages ===
In rare cases, particularly when there is inadequate vaccination of the population, natural mutations during viral replication, or interference by related viruses, can cause an attenuated virus to revert to its wild-type form or mutate to a new strain, potentially resulting in the new virus being infectious or pathogenic.
Often not recommended in pregnancy or for severely immunocompromised patients due to the risk of potential complications.
Live strains typically require advanced maintenance, such as refrigeration and fresh media, making transport to remote areas difficult and costly.
== List of attenuated vaccines ==
=== Currently in-use ===
For many of the pathogens listed below there are many vaccines, the list below simply indicates that there are one (or more) attenuated vaccines for that particular pathogen, not that all vaccines for that pathogen are attenuated.
==== Bacterial vaccines ====
Anthrax vaccine
Cholera vaccine
Plague vaccine
Salmonella vaccine
Tuberculosis vaccine
Typhoid vaccine
==== Viral vaccines ====
Live attenuated influenza vaccine (LAIV)
Japanese encephalitis vaccine
Measles vaccine
Mumps vaccine
Measles and rubella (MR) vaccine
Measles, mumps, and rubella (MMR) vaccine
Measles, mumps, rubella and varicella (MMRV) vaccine
Polio vaccine
Rotavirus vaccine
Rubella vaccine
Smallpox vaccine
Varicella vaccine
Yellow fever vaccine
Zoster/shingles vaccine
=== In development ===
==== Bacterial vaccines ====
Enterotoxigenic Escherichia coli vaccine
==== Viral vaccines ====
Tick-borne encephalitis vaccine
COVID-19
== References ==
== External links ==
Global Polio Eradication Initiative: Advantages and Disadvantages of Vaccine Types
CDC H1N1 Flu / 2009 H1N1 Nasal Spray Vaccine Q&A at the website of the US Centers for Disease Control and Prevention | Wikipedia/Live_attenuated_vaccines |
Environmental Science & Technology is a biweekly peer-reviewed scientific journal published since 1967 by the American Chemical Society. It covers research in environmental science and environmental technology, including environmental policy. Environmental Science & Technology has a sister journal, Environmental Science & Technology Letters, which publishes short communications.
The editor-in-chief of Environmental Science & Technology is Prof. Julie Zimmerman (Yale University). Previous editors have been: David Sedlak (University of California, Berkeley, 2014 - 2020), James J. Morgan (California Institute of Technology; founding editor, 1967–1975), Russell F. Christman (University of North Carolina, 1975–1987), William H. Glaze (University of North Carolina, 1987–2003) and Jerald L. Schnoor (University of Iowa, 2002–2014).
== Abstracting and indexing ==
According to the Journal Citation Reports, the journal has a 2022 impact factor of 11.4. The journal is abstracted and indexed in:
Chemical Abstracts Service
Current Contents/Physical, Chemical & Earth Sciences
Ei Compendex
Science Citation Index Expanded
Scopus
== See also ==
Environmental Science & Technology Letters
== References ==
== External links ==
Official website | Wikipedia/Environmental_Science_&_Technology |
The classic Monod–Wyman–Changeux model (MWC) for cooperativity is generally published in an irreversible form. That is, there are no product terms in the rate equation which can be problematic for those wishing to build metabolic models since there are no product inhibition terms. However, a series of publications by Popova and Sel'kov derived the MWC rate equation for the reversible, multi-substrate, multi-product reaction.
The same problem applies to the classic Hill equation which is almost always shown in an irreversible form. Hofmeyr and Cornish-Bowden first published the reversible form of the Hill equation. The equation has since been discussed elsewhere and the model has also been used in a number of kinetic models such as a model of Phosphofructokinase and Glycolytic Oscillations in the Pancreatic β-cells or a model of a glucose-xylose co-utilizing S. cerevisiae strain. The model has also been discussed in modern enzyme kinetics textbooks.
== Derivation ==
Consider the simpler case where there are two binding sites. See the scheme shown below. Each site is assumed to bind either molecule of substrate S or product P. The catalytic reaction is shown by the two reactions at the base of the scheme triangle, that is S to P and P to S. The model assumes the binding steps are always at equilibrium. The reaction rate is given by:
v
=
k
1
(
E
S
+
2
E
S
2
+
E
S
P
)
−
k
2
(
E
P
+
2
E
P
2
+
E
S
P
)
{\displaystyle v=k_{1}\left(ES+2ES_{2}+ESP\right)-k_{2}\left(EP+2EP_{2}+ESP\right)}
Invoking the rapid-equilibrium assumption we can write the various complexes in terms of equilibrium constants to give:
v
=
V
f
σ
(
1
−
ρ
)
(
σ
+
π
)
1
+
(
σ
+
π
)
2
{\displaystyle v={\frac {V_{f}\sigma (1-\rho )(\sigma +\pi )}{1+(\sigma +\pi )^{2}}}}
where
ρ
=
Γ
/
K
e
q
{\displaystyle \rho =\Gamma /K_{eq}}
. The
σ
{\displaystyle \sigma }
and
π
{\displaystyle \pi }
terms are the ratio of substrate and product to their respective half-saturation constants, namely
σ
=
S
/
S
0.5
{\displaystyle \sigma =S/S_{0.5}}
and
π
=
P
/
P
0.5
{\displaystyle \pi =P/P_{0.5}}
and
Using the author's own notation, if an enzyme has
h
{\displaystyle h}
sites that can bind ligand, the form, in the general case, can be shown to be:
v
=
V
f
σ
(
1
−
ρ
)
(
σ
+
π
)
h
−
1
1
+
(
σ
+
π
)
h
{\displaystyle v={\frac {V_{f}\sigma (1-\rho )(\sigma +\pi )^{h-1}}{1+(\sigma +\pi )^{h}}}}
The non-cooperative reversible Michaelis-Menten equation can be seen to emerge when we set the Hill coefficient to one.
If the enzyme is irreversible the equation turns into the simple Michaelis-Menten equation that is irreversible. When setting the equilibrium constant to infinity, the equation can be seen to revert to the simpler case where the product inhibits the reverse step.
A comparison has been made between the MWC and reversible Hill equation.
A modification of the reversible Hill equation was published by Westermark et al where modifiers affected the catalytic properties instead. This variant was shown to provide a much better fit for describing the kinetics of muscle phosphofructokinase.
== References == | Wikipedia/Reversible_Hill_Equation |
In statistics, a logistic model (or logit model) is a statistical model that models the log-odds of an event as a linear combination of one or more independent variables. In regression analysis, logistic regression (or logit regression) estimates the parameters of a logistic model (the coefficients in the linear or non linear combinations). In binary logistic regression there is a single binary dependent variable, coded by an indicator variable, where the two values are labeled "0" and "1", while the independent variables can each be a binary variable (two classes, coded by an indicator variable) or a continuous variable (any real value). The corresponding probability of the value labeled "1" can vary between 0 (certainly the value "0") and 1 (certainly the value "1"), hence the labeling; the function that converts log-odds to probability is the logistic function, hence the name. The unit of measurement for the log-odds scale is called a logit, from logistic unit, hence the alternative names. See § Background and § Definition for formal mathematics, and § Example for a worked example.
Binary variables are widely used in statistics to model the probability of a certain class or event taking place, such as the probability of a team winning, of a patient being healthy, etc. (see § Applications), and the logistic model has been the most commonly used model for binary regression since about 1970. Binary variables can be generalized to categorical variables when there are more than two possible values (e.g. whether an image is of a cat, dog, lion, etc.), and the binary logistic regression generalized to multinomial logistic regression. If the multiple categories are ordered, one can use the ordinal logistic regression (for example the proportional odds ordinal logistic model). See § Extensions for further extensions. The logistic regression model itself simply models probability of output in terms of input and does not perform statistical classification (it is not a classifier), though it can be used to make a classifier, for instance by choosing a cutoff value and classifying inputs with probability greater than the cutoff as one class, below the cutoff as the other; this is a common way to make a binary classifier.
Analogous linear models for binary variables with a different sigmoid function instead of the logistic function (to convert the linear combination to a probability) can also be used, most notably the probit model; see § Alternatives. The defining characteristic of the logistic model is that increasing one of the independent variables multiplicatively scales the odds of the given outcome at a constant rate, with each independent variable having its own parameter; for a binary dependent variable this generalizes the odds ratio. More abstractly, the logistic function is the natural parameter for the Bernoulli distribution, and in this sense is the "simplest" way to convert a real number to a probability. In particular, it maximizes entropy (minimizes added information), and in this sense makes the fewest assumptions of the data being modeled; see § Maximum entropy.
The parameters of a logistic regression are most commonly estimated by maximum-likelihood estimation (MLE). This does not have a closed-form expression, unlike linear least squares; see § Model fitting. Logistic regression by MLE plays a similarly basic role for binary or categorical responses as linear regression by ordinary least squares (OLS) plays for scalar responses: it is a simple, well-analyzed baseline model; see § Comparison with linear regression for discussion. The logistic regression as a general statistical model was originally developed and popularized primarily by Joseph Berkson, beginning in Berkson (1944), where he coined "logit"; see § History.
== Applications ==
=== General ===
Logistic regression is used in various fields, including machine learning, most medical fields, and social sciences. For example, the Trauma and Injury Severity Score (TRISS), which is widely used to predict mortality in injured patients, was originally developed by Boyd et al. using logistic regression. Many other medical scales used to assess severity of a patient have been developed using logistic regression. Logistic regression may be used to predict the risk of developing a given disease (e.g. diabetes; coronary heart disease), based on observed characteristics of the patient (age, sex, body mass index, results of various blood tests, etc.). Another example might be to predict whether a Nepalese voter will vote Nepali Congress or Communist Party of Nepal or Any Other Party, based on age, income, sex, race, state of residence, votes in previous elections, etc. The technique can also be used in engineering, especially for predicting the probability of failure of a given process, system or product. It is also used in marketing applications such as prediction of a customer's propensity to purchase a product or halt a subscription, etc. In economics, it can be used to predict the likelihood of a person ending up in the labor force, and a business application would be to predict the likelihood of a homeowner defaulting on a mortgage. Conditional random fields, an extension of logistic regression to sequential data, are used in natural language processing. Disaster planners and engineers rely on these models to predict decisions taken by householders or building occupants in small-scale and large-scales evacuations, such as building fires, wildfires, hurricanes among others. These models help in the development of reliable disaster managing plans and safer design for the built environment.
=== Supervised machine learning ===
Logistic regression is a supervised machine learning algorithm widely used for binary classification tasks, such as identifying whether an email is spam or not and diagnosing diseases by assessing the presence or absence of specific conditions based on patient test results. This approach utilizes the logistic (or sigmoid) function to transform a linear combination of input features into a probability value ranging between 0 and 1. This probability indicates the likelihood that a given input corresponds to one of two predefined categories. The essential mechanism of logistic regression is grounded in the logistic function's ability to model the probability of binary outcomes accurately. With its distinctive S-shaped curve, the logistic function effectively maps any real-valued number to a value within the 0 to 1 interval. This feature renders it particularly suitable for binary classification tasks, such as sorting emails into "spam" or "not spam". By calculating the probability that the dependent variable will be categorized into a specific group, logistic regression provides a probabilistic framework that supports informed decision-making.
== Example ==
=== Problem ===
As a simple example, we can use a logistic regression with one explanatory variable and two categories to answer the following question:
A group of 20 students spends between 0 and 6 hours studying for an exam. How does the number of hours spent studying affect the probability of the student passing the exam?
The reason for using logistic regression for this problem is that the values of the dependent variable, pass and fail, while represented by "1" and "0", are not cardinal numbers. If the problem was changed so that pass/fail was replaced with the grade 0–100 (cardinal numbers), then simple regression analysis could be used.
The table shows the number of hours each student spent studying, and whether they passed (1) or failed (0).
We wish to fit a logistic function to the data consisting of the hours studied (xk) and the outcome of the test (yk =1 for pass, 0 for fail). The data points are indexed by the subscript k which runs from
k
=
1
{\displaystyle k=1}
to
k
=
K
=
20
{\displaystyle k=K=20}
. The x variable is called the "explanatory variable", and the y variable is called the "categorical variable" consisting of two categories: "pass" or "fail" corresponding to the categorical values 1 and 0 respectively.
=== Model ===
The logistic function is of the form:
p
(
x
)
=
1
1
+
e
−
(
x
−
μ
)
/
s
{\displaystyle p(x)={\frac {1}{1+e^{-(x-\mu )/s}}}}
where μ is a location parameter (the midpoint of the curve, where
p
(
μ
)
=
1
/
2
{\displaystyle p(\mu )=1/2}
) and s is a scale parameter. This expression may be rewritten as:
p
(
x
)
=
1
1
+
e
−
(
β
0
+
β
1
x
)
{\displaystyle p(x)={\frac {1}{1+e^{-(\beta _{0}+\beta _{1}x)}}}}
where
β
0
=
−
μ
/
s
{\displaystyle \beta _{0}=-\mu /s}
and is known as the intercept (it is the vertical intercept or y-intercept of the line
y
=
β
0
+
β
1
x
{\displaystyle y=\beta _{0}+\beta _{1}x}
), and
β
1
=
1
/
s
{\displaystyle \beta _{1}=1/s}
(inverse scale parameter or rate parameter): these are the y-intercept and slope of the log-odds as a function of x. Conversely,
μ
=
−
β
0
/
β
1
{\displaystyle \mu =-\beta _{0}/\beta _{1}}
and
s
=
1
/
β
1
{\displaystyle s=1/\beta _{1}}
.
Note that this model is actually an oversimplification, since it assumes everybody will pass if they learn long enough (limit = 1).
=== Fit ===
The usual measure of goodness of fit for a logistic regression uses logistic loss (or log loss), the negative log-likelihood. For a given xk and yk, write
p
k
=
p
(
x
k
)
{\displaystyle p_{k}=p(x_{k})}
. The
p
k
{\displaystyle p_{k}}
are the probabilities that the corresponding
y
k
{\displaystyle y_{k}}
will equal one and
1
−
p
k
{\displaystyle 1-p_{k}}
are the probabilities that they will be zero (see Bernoulli distribution). We wish to find the values of
β
0
{\displaystyle \beta _{0}}
and
β
1
{\displaystyle \beta _{1}}
which give the "best fit" to the data. In the case of linear regression, the sum of the squared deviations of the fit from the data points (yk), the squared error loss, is taken as a measure of the goodness of fit, and the best fit is obtained when that function is minimized.
The log loss for the k-th point
ℓ
k
{\displaystyle \ell _{k}}
is:
ℓ
k
=
{
−
ln
p
k
if
y
k
=
1
,
−
ln
(
1
−
p
k
)
if
y
k
=
0.
{\displaystyle \ell _{k}={\begin{cases}-\ln p_{k}&{\text{ if }}y_{k}=1,\\-\ln(1-p_{k})&{\text{ if }}y_{k}=0.\end{cases}}}
The log loss can be interpreted as the "surprisal" of the actual outcome
y
k
{\displaystyle y_{k}}
relative to the prediction
p
k
{\displaystyle p_{k}}
, and is a measure of information content. Log loss is always greater than or equal to 0, equals 0 only in case of a perfect prediction (i.e., when
p
k
=
1
{\displaystyle p_{k}=1}
and
y
k
=
1
{\displaystyle y_{k}=1}
, or
p
k
=
0
{\displaystyle p_{k}=0}
and
y
k
=
0
{\displaystyle y_{k}=0}
), and approaches infinity as the prediction gets worse (i.e., when
y
k
=
1
{\displaystyle y_{k}=1}
and
p
k
→
0
{\displaystyle p_{k}\to 0}
or
y
k
=
0
{\displaystyle y_{k}=0}
and
p
k
→
1
{\displaystyle p_{k}\to 1}
), meaning the actual outcome is "more surprising". Since the value of the logistic function is always strictly between zero and one, the log loss is always greater than zero and less than infinity. Unlike in a linear regression, where the model can have zero loss at a point by passing through a data point (and zero loss overall if all points are on a line), in a logistic regression it is not possible to have zero loss at any points, since
y
k
{\displaystyle y_{k}}
is either 0 or 1, but
0
<
p
k
<
1
{\displaystyle 0<p_{k}<1}
.
These can be combined into a single expression:
ℓ
k
=
−
y
k
ln
p
k
−
(
1
−
y
k
)
ln
(
1
−
p
k
)
.
{\displaystyle \ell _{k}=-y_{k}\ln p_{k}-(1-y_{k})\ln(1-p_{k}).}
This expression is more formally known as the cross-entropy of the predicted distribution
(
p
k
,
(
1
−
p
k
)
)
{\displaystyle {\big (}p_{k},(1-p_{k}){\big )}}
from the actual distribution
(
y
k
,
(
1
−
y
k
)
)
{\displaystyle {\big (}y_{k},(1-y_{k}){\big )}}
, as probability distributions on the two-element space of (pass, fail).
The sum of these, the total loss, is the overall negative log-likelihood
−
ℓ
{\displaystyle -\ell }
, and the best fit is obtained for those choices of
β
0
{\displaystyle \beta _{0}}
and
β
1
{\displaystyle \beta _{1}}
for which
−
ℓ
{\displaystyle -\ell }
is minimized.
Alternatively, instead of minimizing the loss, one can maximize its inverse, the (positive) log-likelihood:
ℓ
=
∑
k
:
y
k
=
1
ln
(
p
k
)
+
∑
k
:
y
k
=
0
ln
(
1
−
p
k
)
=
∑
k
=
1
K
(
y
k
ln
(
p
k
)
+
(
1
−
y
k
)
ln
(
1
−
p
k
)
)
{\displaystyle \ell =\sum _{k:y_{k}=1}\ln(p_{k})+\sum _{k:y_{k}=0}\ln(1-p_{k})=\sum _{k=1}^{K}\left(\,y_{k}\ln(p_{k})+(1-y_{k})\ln(1-p_{k})\right)}
or equivalently maximize the likelihood function itself, which is the probability that the given data set is produced by a particular logistic function:
L
=
∏
k
:
y
k
=
1
p
k
∏
k
:
y
k
=
0
(
1
−
p
k
)
{\displaystyle L=\prod _{k:y_{k}=1}p_{k}\,\prod _{k:y_{k}=0}(1-p_{k})}
This method is known as maximum likelihood estimation.
=== Parameter estimation ===
Since ℓ is nonlinear in
β
0
{\displaystyle \beta _{0}}
and
β
1
{\displaystyle \beta _{1}}
, determining their optimum values will require numerical methods. One method of maximizing ℓ is to require the derivatives of ℓ with respect to
β
0
{\displaystyle \beta _{0}}
and
β
1
{\displaystyle \beta _{1}}
to be zero:
0
=
∂
ℓ
∂
β
0
=
∑
k
=
1
K
(
y
k
−
p
k
)
{\displaystyle 0={\frac {\partial \ell }{\partial \beta _{0}}}=\sum _{k=1}^{K}(y_{k}-p_{k})}
0
=
∂
ℓ
∂
β
1
=
∑
k
=
1
K
(
y
k
−
p
k
)
x
k
{\displaystyle 0={\frac {\partial \ell }{\partial \beta _{1}}}=\sum _{k=1}^{K}(y_{k}-p_{k})x_{k}}
and the maximization procedure can be accomplished by solving the above two equations for
β
0
{\displaystyle \beta _{0}}
and
β
1
{\displaystyle \beta _{1}}
, which, again, will generally require the use of numerical methods.
The values of
β
0
{\displaystyle \beta _{0}}
and
β
1
{\displaystyle \beta _{1}}
which maximize ℓ and L using the above data are found to be:
β
0
≈
−
4.1
{\displaystyle \beta _{0}\approx -4.1}
β
1
≈
1.5
{\displaystyle \beta _{1}\approx 1.5}
which yields a value for μ and s of:
μ
=
−
β
0
/
β
1
≈
2.7
{\displaystyle \mu =-\beta _{0}/\beta _{1}\approx 2.7}
s
=
1
/
β
1
≈
0.67
{\displaystyle s=1/\beta _{1}\approx 0.67}
=== Predictions ===
The
β
0
{\displaystyle \beta _{0}}
and
β
1
{\displaystyle \beta _{1}}
coefficients may be entered into the logistic regression equation to estimate the probability of passing the exam.
For example, for a student who studies 2 hours, entering the value
x
=
2
{\displaystyle x=2}
into the equation gives the estimated probability of passing the exam of 0.25:
t
=
β
0
+
2
β
1
≈
−
4.1
+
2
⋅
1.5
=
−
1.1
{\displaystyle t=\beta _{0}+2\beta _{1}\approx -4.1+2\cdot 1.5=-1.1}
p
=
1
1
+
e
−
t
≈
0.25
=
Probability of passing exam
{\displaystyle p={\frac {1}{1+e^{-t}}}\approx 0.25={\text{Probability of passing exam}}}
Similarly, for a student who studies 4 hours, the estimated probability of passing the exam is 0.87:
t
=
β
0
+
4
β
1
≈
−
4.1
+
4
⋅
1.5
=
1.9
{\displaystyle t=\beta _{0}+4\beta _{1}\approx -4.1+4\cdot 1.5=1.9}
p
=
1
1
+
e
−
t
≈
0.87
=
Probability of passing exam
{\displaystyle p={\frac {1}{1+e^{-t}}}\approx 0.87={\text{Probability of passing exam}}}
This table shows the estimated probability of passing the exam for several values of hours studying.
=== Model evaluation ===
The logistic regression analysis gives the following output.
By the Wald test, the output indicates that hours studying is significantly associated with the probability of passing the exam (
p
=
0.017
{\displaystyle p=0.017}
). Rather than the Wald method, the recommended method to calculate the p-value for logistic regression is the likelihood-ratio test (LRT), which for these data give
p
≈
0.00064
{\displaystyle p\approx 0.00064}
(see § Deviance and likelihood ratio tests below).
=== Generalizations ===
This simple model is an example of binary logistic regression, and has one explanatory variable and a binary categorical variable which can assume one of two categorical values. Multinomial logistic regression is the generalization of binary logistic regression to include any number of explanatory variables and any number of categories.
== Background ==
=== Definition of the logistic function ===
An explanation of logistic regression can begin with an explanation of the standard logistic function. The logistic function is a sigmoid function, which takes any real input
t
{\displaystyle t}
, and outputs a value between zero and one. For the logit, this is interpreted as taking input log-odds and having output probability. The standard logistic function
σ
:
R
→
(
0
,
1
)
{\displaystyle \sigma :\mathbb {R} \rightarrow (0,1)}
is defined as follows:
σ
(
t
)
=
e
t
e
t
+
1
=
1
1
+
e
−
t
{\displaystyle \sigma (t)={\frac {e^{t}}{e^{t}+1}}={\frac {1}{1+e^{-t}}}}
A graph of the logistic function on the t-interval (−6,6) is shown in Figure 1.
Let us assume that
t
{\displaystyle t}
is a linear function of a single explanatory variable
x
{\displaystyle x}
(the case where
t
{\displaystyle t}
is a linear combination of multiple explanatory variables is treated similarly). We can then express
t
{\displaystyle t}
as follows:
t
=
β
0
+
β
1
x
{\displaystyle t=\beta _{0}+\beta _{1}x}
And the general logistic function
p
:
R
→
(
0
,
1
)
{\displaystyle p:\mathbb {R} \rightarrow (0,1)}
can now be written as:
p
(
x
)
=
σ
(
t
)
=
1
1
+
e
−
(
β
0
+
β
1
x
)
{\displaystyle p(x)=\sigma (t)={\frac {1}{1+e^{-(\beta _{0}+\beta _{1}x)}}}}
In the logistic model,
p
(
x
)
{\displaystyle p(x)}
is interpreted as the probability of the dependent variable
Y
{\displaystyle Y}
equaling a success/case rather than a failure/non-case. It is clear that the response variables
Y
i
{\displaystyle Y_{i}}
are not identically distributed:
P
(
Y
i
=
1
∣
X
)
{\displaystyle P(Y_{i}=1\mid X)}
differs from one data point
X
i
{\displaystyle X_{i}}
to another, though they are independent given design matrix
X
{\displaystyle X}
and shared parameters
β
{\displaystyle \beta }
.
=== Definition of the inverse of the logistic function ===
We can now define the logit (log odds) function as the inverse
g
=
σ
−
1
{\displaystyle g=\sigma ^{-1}}
of the standard logistic function. It is easy to see that it satisfies:
g
(
p
(
x
)
)
=
σ
−
1
(
p
(
x
)
)
=
logit
p
(
x
)
=
ln
(
p
(
x
)
1
−
p
(
x
)
)
=
β
0
+
β
1
x
,
{\displaystyle g(p(x))=\sigma ^{-1}(p(x))=\operatorname {logit} p(x)=\ln \left({\frac {p(x)}{1-p(x)}}\right)=\beta _{0}+\beta _{1}x,}
and equivalently, after exponentiating both sides we have the odds:
p
(
x
)
1
−
p
(
x
)
=
e
β
0
+
β
1
x
.
{\displaystyle {\frac {p(x)}{1-p(x)}}=e^{\beta _{0}+\beta _{1}x}.}
=== Interpretation of these terms ===
In the above equations, the terms are as follows:
g
{\displaystyle g}
is the logit function. The equation for
g
(
p
(
x
)
)
{\displaystyle g(p(x))}
illustrates that the logit (i.e., log-odds or natural logarithm of the odds) is equivalent to the linear regression expression.
ln
{\displaystyle \ln }
denotes the natural logarithm.
p
(
x
)
{\displaystyle p(x)}
is the probability that the dependent variable equals a case, given some linear combination of the predictors. The formula for
p
(
x
)
{\displaystyle p(x)}
illustrates that the probability of the dependent variable equaling a case is equal to the value of the logistic function of the linear regression expression. This is important in that it shows that the value of the linear regression expression can vary from negative to positive infinity and yet, after transformation, the resulting expression for the probability
p
(
x
)
{\displaystyle p(x)}
ranges between 0 and 1.
β
0
{\displaystyle \beta _{0}}
is the intercept from the linear regression equation (the value of the criterion when the predictor is equal to zero).
β
1
x
{\displaystyle \beta _{1}x}
is the regression coefficient multiplied by some value of the predictor.
base
e
{\displaystyle e}
denotes the exponential function.
=== Definition of the odds ===
The odds of the dependent variable equaling a case (given some linear combination
x
{\displaystyle x}
of the predictors) is equivalent to the exponential function of the linear regression expression. This illustrates how the logit serves as a link function between the probability and the linear regression expression. Given that the logit ranges between negative and positive infinity, it provides an adequate criterion upon which to conduct linear regression and the logit is easily converted back into the odds.
So we define odds of the dependent variable equaling a case (given some linear combination
x
{\displaystyle x}
of the predictors) as follows:
odds
=
e
β
0
+
β
1
x
.
{\displaystyle {\text{odds}}=e^{\beta _{0}+\beta _{1}x}.}
=== The odds ratio ===
For a continuous independent variable the odds ratio can be defined as:
O
R
=
odds
(
x
+
1
)
odds
(
x
)
=
(
p
(
x
+
1
)
1
−
p
(
x
+
1
)
)
(
p
(
x
)
1
−
p
(
x
)
)
=
e
β
0
+
β
1
(
x
+
1
)
e
β
0
+
β
1
x
=
e
β
1
{\displaystyle \mathrm {OR} ={\frac {\operatorname {odds} (x+1)}{\operatorname {odds} (x)}}={\frac {\left({\frac {p(x+1)}{1-p(x+1)}}\right)}{\left({\frac {p(x)}{1-p(x)}}\right)}}={\frac {e^{\beta _{0}+\beta _{1}(x+1)}}{e^{\beta _{0}+\beta _{1}x}}}=e^{\beta _{1}}}
This exponential relationship provides an interpretation for
β
1
{\displaystyle \beta _{1}}
: The odds multiply by
e
β
1
{\displaystyle e^{\beta _{1}}}
for every 1-unit increase in x.
For a binary independent variable the odds ratio is defined as
a
d
b
c
{\displaystyle {\frac {ad}{bc}}}
where a, b, c and d are cells in a 2×2 contingency table.
=== Multiple explanatory variables ===
If there are multiple explanatory variables, the above expression
β
0
+
β
1
x
{\displaystyle \beta _{0}+\beta _{1}x}
can be revised to
β
0
+
β
1
x
1
+
β
2
x
2
+
⋯
+
β
m
x
m
=
β
0
+
∑
i
=
1
m
β
i
x
i
{\displaystyle \beta _{0}+\beta _{1}x_{1}+\beta _{2}x_{2}+\cdots +\beta _{m}x_{m}=\beta _{0}+\sum _{i=1}^{m}\beta _{i}x_{i}}
. Then when this is used in the equation relating the log odds of a success to the values of the predictors, the linear regression will be a multiple regression with m explanators; the parameters
β
i
{\displaystyle \beta _{i}}
for all
i
=
0
,
1
,
2
,
…
,
m
{\displaystyle i=0,1,2,\dots ,m}
are all estimated.
Again, the more traditional equations are:
log
p
1
−
p
=
β
0
+
β
1
x
1
+
β
2
x
2
+
⋯
+
β
m
x
m
{\displaystyle \log {\frac {p}{1-p}}=\beta _{0}+\beta _{1}x_{1}+\beta _{2}x_{2}+\cdots +\beta _{m}x_{m}}
and
p
=
1
1
+
b
−
(
β
0
+
β
1
x
1
+
β
2
x
2
+
⋯
+
β
m
x
m
)
{\displaystyle p={\frac {1}{1+b^{-(\beta _{0}+\beta _{1}x_{1}+\beta _{2}x_{2}+\cdots +\beta _{m}x_{m})}}}}
where usually
b
=
e
{\displaystyle b=e}
.
== Definition ==
A dataset contains N points. Each point i consists of a set of m input variables x1,i ... xm,i (also called independent variables, explanatory variables, predictor variables, features, or attributes), and a binary outcome variable Yi (also known as a dependent variable, response variable, output variable, or class), i.e. it can assume only the two possible values 0 (often meaning "no" or "failure") or 1 (often meaning "yes" or "success"). The goal of logistic regression is to use the dataset to create a predictive model of the outcome variable.
As in linear regression, the outcome variables Yi are assumed to depend on the explanatory variables x1,i ... xm,i.
Explanatory variables
The explanatory variables may be of any type: real-valued, binary, categorical, etc. The main distinction is between continuous variables and discrete variables.
(Discrete variables referring to more than two possible choices are typically coded using dummy variables (or indicator variables), that is, separate explanatory variables taking the value 0 or 1 are created for each possible value of the discrete variable, with a 1 meaning "variable does have the given value" and a 0 meaning "variable does not have that value".)
Outcome variables
Formally, the outcomes Yi are described as being Bernoulli-distributed data, where each outcome is determined by an unobserved probability pi that is specific to the outcome at hand, but related to the explanatory variables. This can be expressed in any of the following equivalent forms:
Y
i
∣
x
1
,
i
,
…
,
x
m
,
i
∼
Bernoulli
(
p
i
)
E
[
Y
i
∣
x
1
,
i
,
…
,
x
m
,
i
]
=
p
i
Pr
(
Y
i
=
y
∣
x
1
,
i
,
…
,
x
m
,
i
)
=
{
p
i
if
y
=
1
1
−
p
i
if
y
=
0
Pr
(
Y
i
=
y
∣
x
1
,
i
,
…
,
x
m
,
i
)
=
p
i
y
(
1
−
p
i
)
(
1
−
y
)
{\displaystyle {\begin{aligned}Y_{i}\mid x_{1,i},\ldots ,x_{m,i}\ &\sim \operatorname {Bernoulli} (p_{i})\\[5pt]\operatorname {\mathbb {E} } [Y_{i}\mid x_{1,i},\ldots ,x_{m,i}]&=p_{i}\\[5pt]\Pr(Y_{i}=y\mid x_{1,i},\ldots ,x_{m,i})&={\begin{cases}p_{i}&{\text{if }}y=1\\1-p_{i}&{\text{if }}y=0\end{cases}}\\[5pt]\Pr(Y_{i}=y\mid x_{1,i},\ldots ,x_{m,i})&=p_{i}^{y}(1-p_{i})^{(1-y)}\end{aligned}}}
The meanings of these four lines are:
The first line expresses the probability distribution of each Yi : conditioned on the explanatory variables, it follows a Bernoulli distribution with parameters pi, the probability of the outcome of 1 for trial i. As noted above, each separate trial has its own probability of success, just as each trial has its own explanatory variables. The probability of success pi is not observed, only the outcome of an individual Bernoulli trial using that probability.
The second line expresses the fact that the expected value of each Yi is equal to the probability of success pi, which is a general property of the Bernoulli distribution. In other words, if we run a large number of Bernoulli trials using the same probability of success pi, then take the average of all the 1 and 0 outcomes, then the result would be close to pi. This is because doing an average this way simply computes the proportion of successes seen, which we expect to converge to the underlying probability of success.
The third line writes out the probability mass function of the Bernoulli distribution, specifying the probability of seeing each of the two possible outcomes.
The fourth line is another way of writing the probability mass function, which avoids having to write separate cases and is more convenient for certain types of calculations. This relies on the fact that Yi can take only the value 0 or 1. In each case, one of the exponents will be 1, "choosing" the value under it, while the other is 0, "canceling out" the value under it. Hence, the outcome is either pi or 1 − pi, as in the previous line.
Linear predictor function
The basic idea of logistic regression is to use the mechanism already developed for linear regression by modeling the probability pi using a linear predictor function, i.e. a linear combination of the explanatory variables and a set of regression coefficients that are specific to the model at hand but the same for all trials. The linear predictor function
f
(
i
)
{\displaystyle f(i)}
for a particular data point i is written as:
f
(
i
)
=
β
0
+
β
1
x
1
,
i
+
⋯
+
β
m
x
m
,
i
,
{\displaystyle f(i)=\beta _{0}+\beta _{1}x_{1,i}+\cdots +\beta _{m}x_{m,i},}
where
β
0
,
…
,
β
m
{\displaystyle \beta _{0},\ldots ,\beta _{m}}
are regression coefficients indicating the relative effect of a particular explanatory variable on the outcome.
The model is usually put into a more compact form as follows:
The regression coefficients β0, β1, ..., βm are grouped into a single vector β of size m + 1.
For each data point i, an additional explanatory pseudo-variable x0,i is added, with a fixed value of 1, corresponding to the intercept coefficient β0.
The resulting explanatory variables x0,i, x1,i, ..., xm,i are then grouped into a single vector Xi of size m + 1.
This makes it possible to write the linear predictor function as follows:
f
(
i
)
=
β
⋅
X
i
,
{\displaystyle f(i)={\boldsymbol {\beta }}\cdot \mathbf {X} _{i},}
using the notation for a dot product between two vectors.
=== Many explanatory variables, two categories ===
The above example of binary logistic regression on one explanatory variable can be generalized to binary logistic regression on any number of explanatory variables x1, x2,... and any number of categorical values
y
=
0
,
1
,
2
,
…
{\displaystyle y=0,1,2,\dots }
.
To begin with, we may consider a logistic model with M explanatory variables, x1, x2 ... xM and, as in the example above, two categorical values (y = 0 and 1). For the simple binary logistic regression model, we assumed a linear relationship between the predictor variable and the log-odds (also called logit) of the event that
y
=
1
{\displaystyle y=1}
. This linear relationship may be extended to the case of M explanatory variables:
t
=
log
b
p
1
−
p
=
β
0
+
β
1
x
1
+
β
2
x
2
+
⋯
+
β
M
x
M
{\displaystyle t=\log _{b}{\frac {p}{1-p}}=\beta _{0}+\beta _{1}x_{1}+\beta _{2}x_{2}+\cdots +\beta _{M}x_{M}}
where t is the log-odds and
β
i
{\displaystyle \beta _{i}}
are parameters of the model. An additional generalization has been introduced in which the base of the model (b) is not restricted to Euler's number e. In most applications, the base
b
{\displaystyle b}
of the logarithm is usually taken to be e. However, in some cases it can be easier to communicate results by working in base 2 or base 10.
For a more compact notation, we will specify the explanatory variables and the β coefficients as
(
M
+
1
)
{\displaystyle (M+1)}
-dimensional vectors:
x
=
{
x
0
,
x
1
,
x
2
,
…
,
x
M
}
{\displaystyle {\boldsymbol {x}}=\{x_{0},x_{1},x_{2},\dots ,x_{M}\}}
β
=
{
β
0
,
β
1
,
β
2
,
…
,
β
M
}
{\displaystyle {\boldsymbol {\beta }}=\{\beta _{0},\beta _{1},\beta _{2},\dots ,\beta _{M}\}}
with an added explanatory variable x0 =1. The logit may now be written as:
t
=
∑
m
=
0
M
β
m
x
m
=
β
⋅
x
{\displaystyle t=\sum _{m=0}^{M}\beta _{m}x_{m}={\boldsymbol {\beta }}\cdot x}
Solving for the probability p that
y
=
1
{\displaystyle y=1}
yields:
p
(
x
)
=
b
β
⋅
x
1
+
b
β
⋅
x
=
1
1
+
b
−
β
⋅
x
=
S
b
(
t
)
{\displaystyle p({\boldsymbol {x}})={\frac {b^{{\boldsymbol {\beta }}\cdot {\boldsymbol {x}}}}{1+b^{{\boldsymbol {\beta }}\cdot {\boldsymbol {x}}}}}={\frac {1}{1+b^{-{\boldsymbol {\beta }}\cdot {\boldsymbol {x}}}}}=S_{b}(t)}
,
where
S
b
{\displaystyle S_{b}}
is the sigmoid function with base
b
{\displaystyle b}
. The above formula shows that once the
β
m
{\displaystyle \beta _{m}}
are fixed, we can easily compute either the log-odds that
y
=
1
{\displaystyle y=1}
for a given observation, or the probability that
y
=
1
{\displaystyle y=1}
for a given observation. The main use-case of a logistic model is to be given an observation
x
{\displaystyle {\boldsymbol {x}}}
, and estimate the probability
p
(
x
)
{\displaystyle p({\boldsymbol {x}})}
that
y
=
1
{\displaystyle y=1}
. The optimum beta coefficients may again be found by maximizing the log-likelihood. For K measurements, defining
x
k
{\displaystyle {\boldsymbol {x}}_{k}}
as the explanatory vector of the k-th measurement, and
y
k
{\displaystyle y_{k}}
as the categorical outcome of that measurement, the log likelihood may be written in a form very similar to the simple
M
=
1
{\displaystyle M=1}
case above:
ℓ
=
∑
k
=
1
K
y
k
log
b
(
p
(
x
k
)
)
+
∑
k
=
1
K
(
1
−
y
k
)
log
b
(
1
−
p
(
x
k
)
)
{\displaystyle \ell =\sum _{k=1}^{K}y_{k}\log _{b}(p({\boldsymbol {x_{k}}}))+\sum _{k=1}^{K}(1-y_{k})\log _{b}(1-p({\boldsymbol {x_{k}}}))}
As in the simple example above, finding the optimum β parameters will require numerical methods. One useful technique is to equate the derivatives of the log likelihood with respect to each of the β parameters to zero yielding a set of equations which will hold at the maximum of the log likelihood:
∂
ℓ
∂
β
m
=
0
=
∑
k
=
1
K
y
k
x
m
k
−
∑
k
=
1
K
p
(
x
k
)
x
m
k
{\displaystyle {\frac {\partial \ell }{\partial \beta _{m}}}=0=\sum _{k=1}^{K}y_{k}x_{mk}-\sum _{k=1}^{K}p({\boldsymbol {x}}_{k})x_{mk}}
where xmk is the value of the xm explanatory variable from the k-th measurement.
Consider an example with
M
=
2
{\displaystyle M=2}
explanatory variables,
b
=
10
{\displaystyle b=10}
, and coefficients
β
0
=
−
3
{\displaystyle \beta _{0}=-3}
,
β
1
=
1
{\displaystyle \beta _{1}=1}
, and
β
2
=
2
{\displaystyle \beta _{2}=2}
which have been determined by the above method. To be concrete, the model is:
t
=
log
10
p
1
−
p
=
−
3
+
x
1
+
2
x
2
{\displaystyle t=\log _{10}{\frac {p}{1-p}}=-3+x_{1}+2x_{2}}
p
=
b
β
⋅
x
1
+
b
β
⋅
x
=
b
β
0
+
β
1
x
1
+
β
2
x
2
1
+
b
β
0
+
β
1
x
1
+
β
2
x
2
=
1
1
+
b
−
(
β
0
+
β
1
x
1
+
β
2
x
2
)
{\displaystyle p={\frac {b^{{\boldsymbol {\beta }}\cdot {\boldsymbol {x}}}}{1+b^{{\boldsymbol {\beta }}\cdot x}}}={\frac {b^{\beta _{0}+\beta _{1}x_{1}+\beta _{2}x_{2}}}{1+b^{\beta _{0}+\beta _{1}x_{1}+\beta _{2}x_{2}}}}={\frac {1}{1+b^{-(\beta _{0}+\beta _{1}x_{1}+\beta _{2}x_{2})}}}}
,
where p is the probability of the event that
y
=
1
{\displaystyle y=1}
. This can be interpreted as follows:
β
0
=
−
3
{\displaystyle \beta _{0}=-3}
is the y-intercept. It is the log-odds of the event that
y
=
1
{\displaystyle y=1}
, when the predictors
x
1
=
x
2
=
0
{\displaystyle x_{1}=x_{2}=0}
. By exponentiating, we can see that when
x
1
=
x
2
=
0
{\displaystyle x_{1}=x_{2}=0}
the odds of the event that
y
=
1
{\displaystyle y=1}
are 1-to-1000, or
10
−
3
{\displaystyle 10^{-3}}
. Similarly, the probability of the event that
y
=
1
{\displaystyle y=1}
when
x
1
=
x
2
=
0
{\displaystyle x_{1}=x_{2}=0}
can be computed as
1
/
(
1000
+
1
)
=
1
/
1001.
{\displaystyle 1/(1000+1)=1/1001.}
β
1
=
1
{\displaystyle \beta _{1}=1}
means that increasing
x
1
{\displaystyle x_{1}}
by 1 increases the log-odds by
1
{\displaystyle 1}
. So if
x
1
{\displaystyle x_{1}}
increases by 1, the odds that
y
=
1
{\displaystyle y=1}
increase by a factor of
10
1
{\displaystyle 10^{1}}
. The probability of
y
=
1
{\displaystyle y=1}
has also increased, but it has not increased by as much as the odds have increased.
β
2
=
2
{\displaystyle \beta _{2}=2}
means that increasing
x
2
{\displaystyle x_{2}}
by 1 increases the log-odds by
2
{\displaystyle 2}
. So if
x
2
{\displaystyle x_{2}}
increases by 1, the odds that
y
=
1
{\displaystyle y=1}
increase by a factor of
10
2
.
{\displaystyle 10^{2}.}
Note how the effect of
x
2
{\displaystyle x_{2}}
on the log-odds is twice as great as the effect of
x
1
{\displaystyle x_{1}}
, but the effect on the odds is 10 times greater. But the effect on the probability of
y
=
1
{\displaystyle y=1}
is not as much as 10 times greater, it's only the effect on the odds that is 10 times greater.
=== Multinomial logistic regression: Many explanatory variables and many categories ===
In the above cases of two categories (binomial logistic regression), the categories were indexed by "0" and "1", and we had two probabilities: The probability that the outcome was in category 1 was given by
p
(
x
)
{\displaystyle p({\boldsymbol {x}})}
and the probability that the outcome was in category 0 was given by
1
−
p
(
x
)
{\displaystyle 1-p({\boldsymbol {x}})}
. The sum of these probabilities equals 1, which must be true, since "0" and "1" are the only possible categories in this setup.
In general, if we have
M
+
1
{\displaystyle M+1}
explanatory variables (including x0) and
N
+
1
{\displaystyle N+1}
categories, we will need
N
+
1
{\displaystyle N+1}
separate probabilities, one for each category, indexed by n, which describe the probability that the categorical outcome y will be in category y=n, conditional on the vector of covariates x. The sum of these probabilities over all categories must equal 1. Using the mathematically convenient base e, these probabilities are:
p
n
(
x
)
=
e
β
n
⋅
x
1
+
∑
u
=
1
N
e
β
u
⋅
x
{\displaystyle p_{n}({\boldsymbol {x}})={\frac {e^{{\boldsymbol {\beta }}_{n}\cdot {\boldsymbol {x}}}}{1+\sum _{u=1}^{N}e^{{\boldsymbol {\beta }}_{u}\cdot {\boldsymbol {x}}}}}}
for
n
=
1
,
2
,
…
,
N
{\displaystyle n=1,2,\dots ,N}
p
0
(
x
)
=
1
−
∑
n
=
1
N
p
n
(
x
)
=
1
1
+
∑
u
=
1
N
e
β
u
⋅
x
{\displaystyle p_{0}({\boldsymbol {x}})=1-\sum _{n=1}^{N}p_{n}({\boldsymbol {x}})={\frac {1}{1+\sum _{u=1}^{N}e^{{\boldsymbol {\beta }}_{u}\cdot {\boldsymbol {x}}}}}}
Each of the probabilities except
p
0
(
x
)
{\displaystyle p_{0}({\boldsymbol {x}})}
will have their own set of regression coefficients
β
n
{\displaystyle {\boldsymbol {\beta }}_{n}}
. It can be seen that, as required, the sum of the
p
n
(
x
)
{\displaystyle p_{n}({\boldsymbol {x}})}
over all categories n is 1. The selection of
p
0
(
x
)
{\displaystyle p_{0}({\boldsymbol {x}})}
to be defined in terms of the other probabilities is artificial. Any of the probabilities could have been selected to be so defined. This special value of n is termed the "pivot index", and the log-odds (tn) are expressed in terms of the pivot probability and are again expressed as a linear combination of the explanatory variables:
t
n
=
ln
(
p
n
(
x
)
p
0
(
x
)
)
=
β
n
⋅
x
{\displaystyle t_{n}=\ln \left({\frac {p_{n}({\boldsymbol {x}})}{p_{0}({\boldsymbol {x}})}}\right)={\boldsymbol {\beta }}_{n}\cdot {\boldsymbol {x}}}
Note also that for the simple case of
N
=
1
{\displaystyle N=1}
, the two-category case is recovered, with
p
(
x
)
=
p
1
(
x
)
{\displaystyle p({\boldsymbol {x}})=p_{1}({\boldsymbol {x}})}
and
p
0
(
x
)
=
1
−
p
1
(
x
)
{\displaystyle p_{0}({\boldsymbol {x}})=1-p_{1}({\boldsymbol {x}})}
.
The log-likelihood that a particular set of K measurements or data points will be generated by the above probabilities can now be calculated. Indexing each measurement by k, let the k-th set of measured explanatory variables be denoted by
x
k
{\displaystyle {\boldsymbol {x}}_{k}}
and their categorical outcomes be denoted by
y
k
{\displaystyle y_{k}}
which can be equal to any integer in [0,N]. The log-likelihood is then:
ℓ
=
∑
k
=
1
K
∑
n
=
0
N
Δ
(
n
,
y
k
)
ln
(
p
n
(
x
k
)
)
{\displaystyle \ell =\sum _{k=1}^{K}\sum _{n=0}^{N}\Delta (n,y_{k})\,\ln(p_{n}({\boldsymbol {x}}_{k}))}
where
Δ
(
n
,
y
k
)
{\displaystyle \Delta (n,y_{k})}
is an indicator function which equals 1 if yk = n and zero otherwise. In the case of two explanatory variables, this indicator function was defined as yk when n = 1 and 1-yk when n = 0. This was convenient, but not necessary. Again, the optimum beta coefficients may be found by maximizing the log-likelihood function generally using numerical methods. A possible method of solution is to set the derivatives of the log-likelihood with respect to each beta coefficient equal to zero and solve for the beta coefficients:
∂
ℓ
∂
β
n
m
=
0
=
∑
k
=
1
K
Δ
(
n
,
y
k
)
x
m
k
−
∑
k
=
1
K
p
n
(
x
k
)
x
m
k
{\displaystyle {\frac {\partial \ell }{\partial \beta _{nm}}}=0=\sum _{k=1}^{K}\Delta (n,y_{k})x_{mk}-\sum _{k=1}^{K}p_{n}({\boldsymbol {x}}_{k})x_{mk}}
where
β
n
m
{\displaystyle \beta _{nm}}
is the m-th coefficient of the
β
n
{\displaystyle {\boldsymbol {\beta }}_{n}}
vector and
x
m
k
{\displaystyle x_{mk}}
is the m-th explanatory variable of the k-th measurement. Once the beta coefficients have been estimated from the data, we will be able to estimate the probability that any subsequent set of explanatory variables will result in any of the possible outcome categories.
== Interpretations ==
There are various equivalent specifications and interpretations of logistic regression, which fit into different types of more general models, and allow different generalizations.
=== As a generalized linear model ===
The particular model used by logistic regression, which distinguishes it from standard linear regression and from other types of regression analysis used for binary-valued outcomes, is the way the probability of a particular outcome is linked to the linear predictor function:
logit
(
E
[
Y
i
∣
x
1
,
i
,
…
,
x
m
,
i
]
)
=
logit
(
p
i
)
=
ln
(
p
i
1
−
p
i
)
=
β
0
+
β
1
x
1
,
i
+
⋯
+
β
m
x
m
,
i
{\displaystyle \operatorname {logit} (\operatorname {\mathbb {E} } [Y_{i}\mid x_{1,i},\ldots ,x_{m,i}])=\operatorname {logit} (p_{i})=\ln \left({\frac {p_{i}}{1-p_{i}}}\right)=\beta _{0}+\beta _{1}x_{1,i}+\cdots +\beta _{m}x_{m,i}}
Written using the more compact notation described above, this is:
logit
(
E
[
Y
i
∣
X
i
]
)
=
logit
(
p
i
)
=
ln
(
p
i
1
−
p
i
)
=
β
⋅
X
i
{\displaystyle \operatorname {logit} (\operatorname {\mathbb {E} } [Y_{i}\mid \mathbf {X} _{i}])=\operatorname {logit} (p_{i})=\ln \left({\frac {p_{i}}{1-p_{i}}}\right)={\boldsymbol {\beta }}\cdot \mathbf {X} _{i}}
This formulation expresses logistic regression as a type of generalized linear model, which predicts variables with various types of probability distributions by fitting a linear predictor function of the above form to some sort of arbitrary transformation of the expected value of the variable.
The intuition for transforming using the logit function (the natural log of the odds) was explained above. It also has the practical effect of converting the probability (which is bounded to be between 0 and 1) to a variable that ranges over
(
−
∞
,
+
∞
)
{\displaystyle (-\infty ,+\infty )}
— thereby matching the potential range of the linear prediction function on the right side of the equation.
Both the probabilities pi and the regression coefficients are unobserved, and the means of determining them is not part of the model itself. They are typically determined by some sort of optimization procedure, e.g. maximum likelihood estimation, that finds values that best fit the observed data (i.e. that give the most accurate predictions for the data already observed), usually subject to regularization conditions that seek to exclude unlikely values, e.g. extremely large values for any of the regression coefficients. The use of a regularization condition is equivalent to doing maximum a posteriori (MAP) estimation, an extension of maximum likelihood. (Regularization is most commonly done using a squared regularizing function, which is equivalent to placing a zero-mean Gaussian prior distribution on the coefficients, but other regularizers are also possible.) Whether or not regularization is used, it is usually not possible to find a closed-form solution; instead, an iterative numerical method must be used, such as iteratively reweighted least squares (IRLS) or, more commonly these days, a quasi-Newton method such as the L-BFGS method.
The interpretation of the βj parameter estimates is as the additive effect on the log of the odds for a unit change in the j the explanatory variable. In the case of a dichotomous explanatory variable, for instance, gender
e
β
{\displaystyle e^{\beta }}
is the estimate of the odds of having the outcome for, say, males compared with females.
An equivalent formula uses the inverse of the logit function, which is the logistic function, i.e.:
E
[
Y
i
∣
X
i
]
=
p
i
=
logit
−
1
(
β
⋅
X
i
)
=
1
1
+
e
−
β
⋅
X
i
{\displaystyle \operatorname {\mathbb {E} } [Y_{i}\mid \mathbf {X} _{i}]=p_{i}=\operatorname {logit} ^{-1}({\boldsymbol {\beta }}\cdot \mathbf {X} _{i})={\frac {1}{1+e^{-{\boldsymbol {\beta }}\cdot \mathbf {X} _{i}}}}}
The formula can also be written as a probability distribution (specifically, using a probability mass function):
Pr
(
Y
i
=
y
∣
X
i
)
=
p
i
y
(
1
−
p
i
)
1
−
y
=
(
e
β
⋅
X
i
1
+
e
β
⋅
X
i
)
y
(
1
−
e
β
⋅
X
i
1
+
e
β
⋅
X
i
)
1
−
y
=
e
β
⋅
X
i
⋅
y
1
+
e
β
⋅
X
i
{\displaystyle \Pr(Y_{i}=y\mid \mathbf {X} _{i})={p_{i}}^{y}(1-p_{i})^{1-y}=\left({\frac {e^{{\boldsymbol {\beta }}\cdot \mathbf {X} _{i}}}{1+e^{{\boldsymbol {\beta }}\cdot \mathbf {X} _{i}}}}\right)^{y}\left(1-{\frac {e^{{\boldsymbol {\beta }}\cdot \mathbf {X} _{i}}}{1+e^{{\boldsymbol {\beta }}\cdot \mathbf {X} _{i}}}}\right)^{1-y}={\frac {e^{{\boldsymbol {\beta }}\cdot \mathbf {X} _{i}\cdot y}}{1+e^{{\boldsymbol {\beta }}\cdot \mathbf {X} _{i}}}}}
=== As a latent-variable model ===
The logistic model has an equivalent formulation as a latent-variable model. This formulation is common in the theory of discrete choice models and makes it easier to extend to certain more complicated models with multiple, correlated choices, as well as to compare logistic regression to the closely related probit model.
Imagine that, for each trial i, there is a continuous latent variable Yi* (i.e. an unobserved random variable) that is distributed as follows:
Y
i
∗
=
β
⋅
X
i
+
ε
i
{\displaystyle Y_{i}^{\ast }={\boldsymbol {\beta }}\cdot \mathbf {X} _{i}+\varepsilon _{i}\,}
where
ε
i
∼
Logistic
(
0
,
1
)
{\displaystyle \varepsilon _{i}\sim \operatorname {Logistic} (0,1)\,}
i.e. the latent variable can be written directly in terms of the linear predictor function and an additive random error variable that is distributed according to a standard logistic distribution.
Then Yi can be viewed as an indicator for whether this latent variable is positive:
Y
i
=
{
1
if
Y
i
∗
>
0
i.e.
−
ε
i
<
β
⋅
X
i
,
0
otherwise.
{\displaystyle Y_{i}={\begin{cases}1&{\text{if }}Y_{i}^{\ast }>0\ {\text{ i.e. }}{-\varepsilon _{i}}<{\boldsymbol {\beta }}\cdot \mathbf {X} _{i},\\0&{\text{otherwise.}}\end{cases}}}
The choice of modeling the error variable specifically with a standard logistic distribution, rather than a general logistic distribution with the location and scale set to arbitrary values, seems restrictive, but in fact, it is not. It must be kept in mind that we can choose the regression coefficients ourselves, and very often can use them to offset changes in the parameters of the error variable's distribution. For example, a logistic error-variable distribution with a non-zero location parameter μ (which sets the mean) is equivalent to a distribution with a zero location parameter, where μ has been added to the intercept coefficient. Both situations produce the same value for Yi* regardless of settings of explanatory variables. Similarly, an arbitrary scale parameter s is equivalent to setting the scale parameter to 1 and then dividing all regression coefficients by s. In the latter case, the resulting value of Yi* will be smaller by a factor of s than in the former case, for all sets of explanatory variables — but critically, it will always remain on the same side of 0, and hence lead to the same Yi choice.
(This predicts that the irrelevancy of the scale parameter may not carry over into more complex models where more than two choices are available.)
It turns out that this formulation is exactly equivalent to the preceding one, phrased in terms of the generalized linear model and without any latent variables. This can be shown as follows, using the fact that the cumulative distribution function (CDF) of the standard logistic distribution is the logistic function, which is the inverse of the logit function, i.e.
Pr
(
ε
i
<
x
)
=
logit
−
1
(
x
)
{\displaystyle \Pr(\varepsilon _{i}<x)=\operatorname {logit} ^{-1}(x)}
Then:
Pr
(
Y
i
=
1
∣
X
i
)
=
Pr
(
Y
i
∗
>
0
∣
X
i
)
=
Pr
(
β
⋅
X
i
+
ε
i
>
0
)
=
Pr
(
ε
i
>
−
β
⋅
X
i
)
=
Pr
(
ε
i
<
β
⋅
X
i
)
(because the logistic distribution is symmetric)
=
logit
−
1
(
β
⋅
X
i
)
=
p
i
(see above)
{\displaystyle {\begin{aligned}\Pr(Y_{i}=1\mid \mathbf {X} _{i})&=\Pr(Y_{i}^{\ast }>0\mid \mathbf {X} _{i})\\[5pt]&=\Pr({\boldsymbol {\beta }}\cdot \mathbf {X} _{i}+\varepsilon _{i}>0)\\[5pt]&=\Pr(\varepsilon _{i}>-{\boldsymbol {\beta }}\cdot \mathbf {X} _{i})\\[5pt]&=\Pr(\varepsilon _{i}<{\boldsymbol {\beta }}\cdot \mathbf {X} _{i})&&{\text{(because the logistic distribution is symmetric)}}\\[5pt]&=\operatorname {logit} ^{-1}({\boldsymbol {\beta }}\cdot \mathbf {X} _{i})&\\[5pt]&=p_{i}&&{\text{(see above)}}\end{aligned}}}
This formulation—which is standard in discrete choice models—makes clear the relationship between logistic regression (the "logit model") and the probit model, which uses an error variable distributed according to a standard normal distribution instead of a standard logistic distribution. Both the logistic and normal distributions are symmetric with a basic unimodal, "bell curve" shape. The only difference is that the logistic distribution has somewhat heavier tails, which means that it is less sensitive to outlying data (and hence somewhat more robust to model mis-specifications or erroneous data).
=== Two-way latent-variable model ===
Yet another formulation uses two separate latent variables:
Y
i
0
∗
=
β
0
⋅
X
i
+
ε
0
Y
i
1
∗
=
β
1
⋅
X
i
+
ε
1
{\displaystyle {\begin{aligned}Y_{i}^{0\ast }&={\boldsymbol {\beta }}_{0}\cdot \mathbf {X} _{i}+\varepsilon _{0}\,\\Y_{i}^{1\ast }&={\boldsymbol {\beta }}_{1}\cdot \mathbf {X} _{i}+\varepsilon _{1}\,\end{aligned}}}
where
ε
0
∼
EV
1
(
0
,
1
)
ε
1
∼
EV
1
(
0
,
1
)
{\displaystyle {\begin{aligned}\varepsilon _{0}&\sim \operatorname {EV} _{1}(0,1)\\\varepsilon _{1}&\sim \operatorname {EV} _{1}(0,1)\end{aligned}}}
where EV1(0,1) is a standard type-1 extreme value distribution: i.e.
Pr
(
ε
0
=
x
)
=
Pr
(
ε
1
=
x
)
=
e
−
x
e
−
e
−
x
{\displaystyle \Pr(\varepsilon _{0}=x)=\Pr(\varepsilon _{1}=x)=e^{-x}e^{-e^{-x}}}
Then
Y
i
=
{
1
if
Y
i
1
∗
>
Y
i
0
∗
,
0
otherwise.
{\displaystyle Y_{i}={\begin{cases}1&{\text{if }}Y_{i}^{1\ast }>Y_{i}^{0\ast },\\0&{\text{otherwise.}}\end{cases}}}
This model has a separate latent variable and a separate set of regression coefficients for each possible outcome of the dependent variable. The reason for this separation is that it makes it easy to extend logistic regression to multi-outcome categorical variables, as in the multinomial logit model. In such a model, it is natural to model each possible outcome using a different set of regression coefficients. It is also possible to motivate each of the separate latent variables as the theoretical utility associated with making the associated choice, and thus motivate logistic regression in terms of utility theory. (In terms of utility theory, a rational actor always chooses the choice with the greatest associated utility.) This is the approach taken by economists when formulating discrete choice models, because it both provides a theoretically strong foundation and facilitates intuitions about the model, which in turn makes it easy to consider various sorts of extensions. (See the example below.)
The choice of the type-1 extreme value distribution seems fairly arbitrary, but it makes the mathematics work out, and it may be possible to justify its use through rational choice theory.
It turns out that this model is equivalent to the previous model, although this seems non-obvious, since there are now two sets of regression coefficients and error variables, and the error variables have a different distribution. In fact, this model reduces directly to the previous one with the following substitutions:
β
=
β
1
−
β
0
{\displaystyle {\boldsymbol {\beta }}={\boldsymbol {\beta }}_{1}-{\boldsymbol {\beta }}_{0}}
ε
=
ε
1
−
ε
0
{\displaystyle \varepsilon =\varepsilon _{1}-\varepsilon _{0}}
An intuition for this comes from the fact that, since we choose based on the maximum of two values, only their difference matters, not the exact values — and this effectively removes one degree of freedom. Another critical fact is that the difference of two type-1 extreme-value-distributed variables is a logistic distribution, i.e.
ε
=
ε
1
−
ε
0
∼
Logistic
(
0
,
1
)
.
{\displaystyle \varepsilon =\varepsilon _{1}-\varepsilon _{0}\sim \operatorname {Logistic} (0,1).}
We can demonstrate the equivalent as follows:
Pr
(
Y
i
=
1
∣
X
i
)
=
Pr
(
Y
i
1
∗
>
Y
i
0
∗
∣
X
i
)
=
Pr
(
Y
i
1
∗
−
Y
i
0
∗
>
0
∣
X
i
)
=
Pr
(
β
1
⋅
X
i
+
ε
1
−
(
β
0
⋅
X
i
+
ε
0
)
>
0
)
=
Pr
(
(
β
1
⋅
X
i
−
β
0
⋅
X
i
)
+
(
ε
1
−
ε
0
)
>
0
)
=
Pr
(
(
β
1
−
β
0
)
⋅
X
i
+
(
ε
1
−
ε
0
)
>
0
)
=
Pr
(
(
β
1
−
β
0
)
⋅
X
i
+
ε
>
0
)
(substitute
ε
as above)
=
Pr
(
β
⋅
X
i
+
ε
>
0
)
(substitute
β
as above)
=
Pr
(
ε
>
−
β
⋅
X
i
)
(now, same as above model)
=
Pr
(
ε
<
β
⋅
X
i
)
=
logit
−
1
(
β
⋅
X
i
)
=
p
i
{\displaystyle {\begin{aligned}\Pr(Y_{i}=1\mid \mathbf {X} _{i})={}&\Pr \left(Y_{i}^{1\ast }>Y_{i}^{0\ast }\mid \mathbf {X} _{i}\right)&\\[5pt]={}&\Pr \left(Y_{i}^{1\ast }-Y_{i}^{0\ast }>0\mid \mathbf {X} _{i}\right)&\\[5pt]={}&\Pr \left({\boldsymbol {\beta }}_{1}\cdot \mathbf {X} _{i}+\varepsilon _{1}-\left({\boldsymbol {\beta }}_{0}\cdot \mathbf {X} _{i}+\varepsilon _{0}\right)>0\right)&\\[5pt]={}&\Pr \left(({\boldsymbol {\beta }}_{1}\cdot \mathbf {X} _{i}-{\boldsymbol {\beta }}_{0}\cdot \mathbf {X} _{i})+(\varepsilon _{1}-\varepsilon _{0})>0\right)&\\[5pt]={}&\Pr(({\boldsymbol {\beta }}_{1}-{\boldsymbol {\beta }}_{0})\cdot \mathbf {X} _{i}+(\varepsilon _{1}-\varepsilon _{0})>0)&\\[5pt]={}&\Pr(({\boldsymbol {\beta }}_{1}-{\boldsymbol {\beta }}_{0})\cdot \mathbf {X} _{i}+\varepsilon >0)&&{\text{(substitute }}\varepsilon {\text{ as above)}}\\[5pt]={}&\Pr({\boldsymbol {\beta }}\cdot \mathbf {X} _{i}+\varepsilon >0)&&{\text{(substitute }}{\boldsymbol {\beta }}{\text{ as above)}}\\[5pt]={}&\Pr(\varepsilon >-{\boldsymbol {\beta }}\cdot \mathbf {X} _{i})&&{\text{(now, same as above model)}}\\[5pt]={}&\Pr(\varepsilon <{\boldsymbol {\beta }}\cdot \mathbf {X} _{i})&\\[5pt]={}&\operatorname {logit} ^{-1}({\boldsymbol {\beta }}\cdot \mathbf {X} _{i})\\[5pt]={}&p_{i}\end{aligned}}}
==== Example ====
As an example, consider a province-level election where the choice is between a right-of-center party, a left-of-center party, and a secessionist party (e.g. the Parti Québécois, which wants Quebec to secede from Canada). We would then use three latent variables, one for each choice. Then, in accordance with utility theory, we can then interpret the latent variables as expressing the utility that results from making each of the choices. We can also interpret the regression coefficients as indicating the strength that the associated factor (i.e. explanatory variable) has in contributing to the utility — or more correctly, the amount by which a unit change in an explanatory variable changes the utility of a given choice. A voter might expect that the right-of-center party would lower taxes, especially on rich people. This would give low-income people no benefit, i.e. no change in utility (since they usually don't pay taxes); would cause moderate benefit (i.e. somewhat more money, or moderate utility increase) for middle-incoming people; would cause significant benefits for high-income people. On the other hand, the left-of-center party might be expected to raise taxes and offset it with increased welfare and other assistance for the lower and middle classes. This would cause significant positive benefit to low-income people, perhaps a weak benefit to middle-income people, and significant negative benefit to high-income people. Finally, the secessionist party would take no direct actions on the economy, but simply secede. A low-income or middle-income voter might expect basically no clear utility gain or loss from this, but a high-income voter might expect negative utility since he/she is likely to own companies, which will have a harder time doing business in such an environment and probably lose money.
These intuitions can be expressed as follows:
This clearly shows that
Separate sets of regression coefficients need to exist for each choice. When phrased in terms of utility, this can be seen very easily. Different choices have different effects on net utility; furthermore, the effects vary in complex ways that depend on the characteristics of each individual, so there need to be separate sets of coefficients for each characteristic, not simply a single extra per-choice characteristic.
Even though income is a continuous variable, its effect on utility is too complex for it to be treated as a single variable. Either it needs to be directly split up into ranges, or higher powers of income need to be added so that polynomial regression on income is effectively done.
=== As a "log-linear" model ===
Yet another formulation combines the two-way latent variable formulation above with the original formulation higher up without latent variables, and in the process provides a link to one of the standard formulations of the multinomial logit.
Here, instead of writing the logit of the probabilities pi as a linear predictor, we separate the linear predictor into two, one for each of the two outcomes:
ln
Pr
(
Y
i
=
0
)
=
β
0
⋅
X
i
−
ln
Z
ln
Pr
(
Y
i
=
1
)
=
β
1
⋅
X
i
−
ln
Z
{\displaystyle {\begin{aligned}\ln \Pr(Y_{i}=0)&={\boldsymbol {\beta }}_{0}\cdot \mathbf {X} _{i}-\ln Z\\\ln \Pr(Y_{i}=1)&={\boldsymbol {\beta }}_{1}\cdot \mathbf {X} _{i}-\ln Z\end{aligned}}}
Two separate sets of regression coefficients have been introduced, just as in the two-way latent variable model, and the two equations appear a form that writes the logarithm of the associated probability as a linear predictor, with an extra term
−
ln
Z
{\displaystyle -\ln Z}
at the end. This term, as it turns out, serves as the normalizing factor ensuring that the result is a distribution. This can be seen by exponentiating both sides:
Pr
(
Y
i
=
0
)
=
1
Z
e
β
0
⋅
X
i
Pr
(
Y
i
=
1
)
=
1
Z
e
β
1
⋅
X
i
{\displaystyle {\begin{aligned}\Pr(Y_{i}=0)&={\frac {1}{Z}}e^{{\boldsymbol {\beta }}_{0}\cdot \mathbf {X} _{i}}\\[5pt]\Pr(Y_{i}=1)&={\frac {1}{Z}}e^{{\boldsymbol {\beta }}_{1}\cdot \mathbf {X} _{i}}\end{aligned}}}
In this form it is clear that the purpose of Z is to ensure that the resulting distribution over Yi is in fact a probability distribution, i.e. it sums to 1. This means that Z is simply the sum of all un-normalized probabilities, and by dividing each probability by Z, the probabilities become "normalized". That is:
Z
=
e
β
0
⋅
X
i
+
e
β
1
⋅
X
i
{\displaystyle Z=e^{{\boldsymbol {\beta }}_{0}\cdot \mathbf {X} _{i}}+e^{{\boldsymbol {\beta }}_{1}\cdot \mathbf {X} _{i}}}
and the resulting equations are
Pr
(
Y
i
=
0
)
=
e
β
0
⋅
X
i
e
β
0
⋅
X
i
+
e
β
1
⋅
X
i
Pr
(
Y
i
=
1
)
=
e
β
1
⋅
X
i
e
β
0
⋅
X
i
+
e
β
1
⋅
X
i
.
{\displaystyle {\begin{aligned}\Pr(Y_{i}=0)&={\frac {e^{{\boldsymbol {\beta }}_{0}\cdot \mathbf {X} _{i}}}{e^{{\boldsymbol {\beta }}_{0}\cdot \mathbf {X} _{i}}+e^{{\boldsymbol {\beta }}_{1}\cdot \mathbf {X} _{i}}}}\\[5pt]\Pr(Y_{i}=1)&={\frac {e^{{\boldsymbol {\beta }}_{1}\cdot \mathbf {X} _{i}}}{e^{{\boldsymbol {\beta }}_{0}\cdot \mathbf {X} _{i}}+e^{{\boldsymbol {\beta }}_{1}\cdot \mathbf {X} _{i}}}}.\end{aligned}}}
Or generally:
Pr
(
Y
i
=
c
)
=
e
β
c
⋅
X
i
∑
h
e
β
h
⋅
X
i
{\displaystyle \Pr(Y_{i}=c)={\frac {e^{{\boldsymbol {\beta }}_{c}\cdot \mathbf {X} _{i}}}{\sum _{h}e^{{\boldsymbol {\beta }}_{h}\cdot \mathbf {X} _{i}}}}}
This shows clearly how to generalize this formulation to more than two outcomes, as in multinomial logit.
This general formulation is exactly the softmax function as in
Pr
(
Y
i
=
c
)
=
softmax
(
c
,
β
0
⋅
X
i
,
β
1
⋅
X
i
,
…
)
.
{\displaystyle \Pr(Y_{i}=c)=\operatorname {softmax} (c,{\boldsymbol {\beta }}_{0}\cdot \mathbf {X} _{i},{\boldsymbol {\beta }}_{1}\cdot \mathbf {X} _{i},\dots ).}
In order to prove that this is equivalent to the previous model, the above model is overspecified, in that
Pr
(
Y
i
=
0
)
{\displaystyle \Pr(Y_{i}=0)}
and
Pr
(
Y
i
=
1
)
{\displaystyle \Pr(Y_{i}=1)}
cannot be independently specified: rather
Pr
(
Y
i
=
0
)
+
Pr
(
Y
i
=
1
)
=
1
{\displaystyle \Pr(Y_{i}=0)+\Pr(Y_{i}=1)=1}
so knowing one automatically determines the other. As a result, the model is nonidentifiable, in that multiple combinations of β0 and β1 will produce the same probabilities for all possible explanatory variables. In fact, it can be seen that adding any constant vector to both of them will produce the same probabilities:
Pr
(
Y
i
=
1
)
=
e
(
β
1
+
C
)
⋅
X
i
e
(
β
0
+
C
)
⋅
X
i
+
e
(
β
1
+
C
)
⋅
X
i
=
e
β
1
⋅
X
i
e
C
⋅
X
i
e
β
0
⋅
X
i
e
C
⋅
X
i
+
e
β
1
⋅
X
i
e
C
⋅
X
i
=
e
C
⋅
X
i
e
β
1
⋅
X
i
e
C
⋅
X
i
(
e
β
0
⋅
X
i
+
e
β
1
⋅
X
i
)
=
e
β
1
⋅
X
i
e
β
0
⋅
X
i
+
e
β
1
⋅
X
i
.
{\displaystyle {\begin{aligned}\Pr(Y_{i}=1)&={\frac {e^{({\boldsymbol {\beta }}_{1}+\mathbf {C} )\cdot \mathbf {X} _{i}}}{e^{({\boldsymbol {\beta }}_{0}+\mathbf {C} )\cdot \mathbf {X} _{i}}+e^{({\boldsymbol {\beta }}_{1}+\mathbf {C} )\cdot \mathbf {X} _{i}}}}\\[5pt]&={\frac {e^{{\boldsymbol {\beta }}_{1}\cdot \mathbf {X} _{i}}e^{\mathbf {C} \cdot \mathbf {X} _{i}}}{e^{{\boldsymbol {\beta }}_{0}\cdot \mathbf {X} _{i}}e^{\mathbf {C} \cdot \mathbf {X} _{i}}+e^{{\boldsymbol {\beta }}_{1}\cdot \mathbf {X} _{i}}e^{\mathbf {C} \cdot \mathbf {X} _{i}}}}\\[5pt]&={\frac {e^{\mathbf {C} \cdot \mathbf {X} _{i}}e^{{\boldsymbol {\beta }}_{1}\cdot \mathbf {X} _{i}}}{e^{\mathbf {C} \cdot \mathbf {X} _{i}}(e^{{\boldsymbol {\beta }}_{0}\cdot \mathbf {X} _{i}}+e^{{\boldsymbol {\beta }}_{1}\cdot \mathbf {X} _{i}})}}\\[5pt]&={\frac {e^{{\boldsymbol {\beta }}_{1}\cdot \mathbf {X} _{i}}}{e^{{\boldsymbol {\beta }}_{0}\cdot \mathbf {X} _{i}}+e^{{\boldsymbol {\beta }}_{1}\cdot \mathbf {X} _{i}}}}.\end{aligned}}}
As a result, we can simplify matters, and restore identifiability, by picking an arbitrary value for one of the two vectors. We choose to set
β
0
=
0
.
{\displaystyle {\boldsymbol {\beta }}_{0}=\mathbf {0} .}
Then,
e
β
0
⋅
X
i
=
e
0
⋅
X
i
=
1
{\displaystyle e^{{\boldsymbol {\beta }}_{0}\cdot \mathbf {X} _{i}}=e^{\mathbf {0} \cdot \mathbf {X} _{i}}=1}
and so
Pr
(
Y
i
=
1
)
=
e
β
1
⋅
X
i
1
+
e
β
1
⋅
X
i
=
1
1
+
e
−
β
1
⋅
X
i
=
p
i
{\displaystyle \Pr(Y_{i}=1)={\frac {e^{{\boldsymbol {\beta }}_{1}\cdot \mathbf {X} _{i}}}{1+e^{{\boldsymbol {\beta }}_{1}\cdot \mathbf {X} _{i}}}}={\frac {1}{1+e^{-{\boldsymbol {\beta }}_{1}\cdot \mathbf {X} _{i}}}}=p_{i}}
which shows that this formulation is indeed equivalent to the previous formulation. (As in the two-way latent variable formulation, any settings where
β
=
β
1
−
β
0
{\displaystyle {\boldsymbol {\beta }}={\boldsymbol {\beta }}_{1}-{\boldsymbol {\beta }}_{0}}
will produce equivalent results.)
Most treatments of the multinomial logit model start out either by extending the "log-linear" formulation presented here or the two-way latent variable formulation presented above, since both clearly show the way that the model could be extended to multi-way outcomes. In general, the presentation with latent variables is more common in econometrics and political science, where discrete choice models and utility theory reign, while the "log-linear" formulation here is more common in computer science, e.g. machine learning and natural language processing.
=== As a single-layer perceptron ===
The model has an equivalent formulation
p
i
=
1
1
+
e
−
(
β
0
+
β
1
x
1
,
i
+
⋯
+
β
k
x
k
,
i
)
.
{\displaystyle p_{i}={\frac {1}{1+e^{-(\beta _{0}+\beta _{1}x_{1,i}+\cdots +\beta _{k}x_{k,i})}}}.\,}
This functional form is commonly called a single-layer perceptron or single-layer artificial neural network. A single-layer neural network computes a continuous output instead of a step function. The derivative of pi with respect to X = (x1, ..., xk) is computed from the general form:
y
=
1
1
+
e
−
f
(
X
)
{\displaystyle y={\frac {1}{1+e^{-f(X)}}}}
where f(X) is an analytic function in X. With this choice, the single-layer neural network is identical to the logistic regression model. This function has a continuous derivative, which allows it to be used in backpropagation. This function is also preferred because its derivative is easily calculated:
d
y
d
X
=
y
(
1
−
y
)
d
f
d
X
.
{\displaystyle {\frac {\mathrm {d} y}{\mathrm {d} X}}=y(1-y){\frac {\mathrm {d} f}{\mathrm {d} X}}.\,}
=== In terms of binomial data ===
A closely related model assumes that each i is associated not with a single Bernoulli trial but with ni independent identically distributed trials, where the observation Yi is the number of successes observed (the sum of the individual Bernoulli-distributed random variables), and hence follows a binomial distribution:
Y
i
∼
Bin
(
n
i
,
p
i
)
,
for
i
=
1
,
…
,
n
{\displaystyle Y_{i}\,\sim \operatorname {Bin} (n_{i},p_{i}),{\text{ for }}i=1,\dots ,n}
An example of this distribution is the fraction of seeds (pi) that germinate after ni are planted.
In terms of expected values, this model is expressed as follows:
p
i
=
E
[
Y
i
n
i
|
X
i
]
,
{\displaystyle p_{i}=\operatorname {\mathbb {E} } \left[\left.{\frac {Y_{i}}{n_{i}}}\,\right|\,\mathbf {X} _{i}\right]\,,}
so that
logit
(
E
[
Y
i
n
i
|
X
i
]
)
=
logit
(
p
i
)
=
ln
(
p
i
1
−
p
i
)
=
β
⋅
X
i
,
{\displaystyle \operatorname {logit} \left(\operatorname {\mathbb {E} } \left[\left.{\frac {Y_{i}}{n_{i}}}\,\right|\,\mathbf {X} _{i}\right]\right)=\operatorname {logit} (p_{i})=\ln \left({\frac {p_{i}}{1-p_{i}}}\right)={\boldsymbol {\beta }}\cdot \mathbf {X} _{i}\,,}
Or equivalently:
Pr
(
Y
i
=
y
∣
X
i
)
=
(
n
i
y
)
p
i
y
(
1
−
p
i
)
n
i
−
y
=
(
n
i
y
)
(
1
1
+
e
−
β
⋅
X
i
)
y
(
1
−
1
1
+
e
−
β
⋅
X
i
)
n
i
−
y
.
{\displaystyle \Pr(Y_{i}=y\mid \mathbf {X} _{i})={n_{i} \choose y}p_{i}^{y}(1-p_{i})^{n_{i}-y}={n_{i} \choose y}\left({\frac {1}{1+e^{-{\boldsymbol {\beta }}\cdot \mathbf {X} _{i}}}}\right)^{y}\left(1-{\frac {1}{1+e^{-{\boldsymbol {\beta }}\cdot \mathbf {X} _{i}}}}\right)^{n_{i}-y}\,.}
This model can be fit using the same sorts of methods as the above more basic model.
== Model fitting ==
=== Maximum likelihood estimation (MLE) ===
The regression coefficients are usually estimated using maximum likelihood estimation. Unlike linear regression with normally distributed residuals, it is not possible to find a closed-form expression for the coefficient values that maximize the likelihood function so an iterative process must be used instead; for example Newton's method. This process begins with a tentative solution, revises it slightly to see if it can be improved, and repeats this revision until no more improvement is made, at which point the process is said to have converged.
In some instances, the model may not reach convergence. Non-convergence of a model indicates that the coefficients are not meaningful because the iterative process was unable to find appropriate solutions. A failure to converge may occur for a number of reasons: having a large ratio of predictors to cases, multicollinearity, sparseness, or complete separation.
Having a large ratio of variables to cases results in an overly conservative Wald statistic (discussed below) and can lead to non-convergence. Regularized logistic regression is specifically intended to be used in this situation.
Multicollinearity refers to unacceptably high correlations between predictors. As multicollinearity increases, coefficients remain unbiased but standard errors increase and the likelihood of model convergence decreases. To detect multicollinearity amongst the predictors, one can conduct a linear regression analysis with the predictors of interest for the sole purpose of examining the tolerance statistic used to assess whether multicollinearity is unacceptably high.
Sparseness in the data refers to having a large proportion of empty cells (cells with zero counts). Zero cell counts are particularly problematic with categorical predictors. With continuous predictors, the model can infer values for the zero cell counts, but this is not the case with categorical predictors. The model will not converge with zero cell counts for categorical predictors because the natural logarithm of zero is an undefined value so that the final solution to the model cannot be reached. To remedy this problem, researchers may collapse categories in a theoretically meaningful way or add a constant to all cells.
Another numerical problem that may lead to a lack of convergence is complete separation, which refers to the instance in which the predictors perfectly predict the criterion – all cases are accurately classified and the likelihood maximized with infinite coefficients. In such instances, one should re-examine the data, as there may be some kind of error.
One can also take semi-parametric or non-parametric approaches, e.g., via local-likelihood or nonparametric quasi-likelihood methods, which avoid assumptions of a parametric form for the index function and is robust to the choice of the link function (e.g., probit or logit).
=== Iteratively reweighted least squares (IRLS) ===
Binary logistic regression (
y
=
0
{\displaystyle y=0}
or
y
=
1
{\displaystyle y=1}
) can, for example, be calculated using iteratively reweighted least squares (IRLS), which is equivalent to maximizing the log-likelihood of a Bernoulli distributed process using Newton's method. If the problem is written in vector matrix form, with parameters
w
T
=
[
β
0
,
β
1
,
β
2
,
…
]
{\displaystyle \mathbf {w} ^{T}=[\beta _{0},\beta _{1},\beta _{2},\ldots ]}
, explanatory variables
x
(
i
)
=
[
1
,
x
1
(
i
)
,
x
2
(
i
)
,
…
]
T
{\displaystyle \mathbf {x} (i)=[1,x_{1}(i),x_{2}(i),\ldots ]^{T}}
and expected value of the Bernoulli distribution
μ
(
i
)
=
1
1
+
e
−
w
T
x
(
i
)
{\displaystyle \mu (i)={\frac {1}{1+e^{-\mathbf {w} ^{T}\mathbf {x} (i)}}}}
, the parameters
w
{\displaystyle \mathbf {w} }
can be found using the following iterative algorithm:
w
k
+
1
=
(
X
T
S
k
X
)
−
1
X
T
(
S
k
X
w
k
+
y
−
μ
k
)
{\displaystyle \mathbf {w} _{k+1}=\left(\mathbf {X} ^{T}\mathbf {S} _{k}\mathbf {X} \right)^{-1}\mathbf {X} ^{T}\left(\mathbf {S} _{k}\mathbf {X} \mathbf {w} _{k}+\mathbf {y} -\mathbf {\boldsymbol {\mu }} _{k}\right)}
where
S
=
diag
(
μ
(
i
)
(
1
−
μ
(
i
)
)
)
{\displaystyle \mathbf {S} =\operatorname {diag} (\mu (i)(1-\mu (i)))}
is a diagonal weighting matrix,
μ
=
[
μ
(
1
)
,
μ
(
2
)
,
…
]
{\displaystyle {\boldsymbol {\mu }}=[\mu (1),\mu (2),\ldots ]}
the vector of expected values,
X
=
[
1
x
1
(
1
)
x
2
(
1
)
…
1
x
1
(
2
)
x
2
(
2
)
…
⋮
⋮
⋮
]
{\displaystyle \mathbf {X} ={\begin{bmatrix}1&x_{1}(1)&x_{2}(1)&\ldots \\1&x_{1}(2)&x_{2}(2)&\ldots \\\vdots &\vdots &\vdots \end{bmatrix}}}
The regressor matrix and
y
(
i
)
=
[
y
(
1
)
,
y
(
2
)
,
…
]
T
{\displaystyle \mathbf {y} (i)=[y(1),y(2),\ldots ]^{T}}
the vector of response variables. More details can be found in the literature.
=== Bayesian ===
In a Bayesian statistics context, prior distributions are normally placed on the regression coefficients, for example in the form of Gaussian distributions. There is no conjugate prior of the likelihood function in logistic regression. When Bayesian inference was performed analytically, this made the posterior distribution difficult to calculate except in very low dimensions. Now, though, automatic software such as OpenBUGS, JAGS, PyMC, Stan or Turing.jl allows these posteriors to be computed using simulation, so lack of conjugacy is not a concern. However, when the sample size or the number of parameters is large, full Bayesian simulation can be slow, and people often use approximate methods such as variational Bayesian methods and expectation propagation.
=== "Rule of ten" ===
Widely used, the "one in ten rule", states that logistic regression models give stable values for the explanatory variables if based on a minimum of about 10 events per explanatory variable (EPV); where event denotes the cases belonging to the less frequent category in the dependent variable. Thus a study designed to use
k
{\displaystyle k}
explanatory variables for an event (e.g. myocardial infarction) expected to occur in a proportion
p
{\displaystyle p}
of participants in the study will require a total of
10
k
/
p
{\displaystyle 10k/p}
participants. However, there is considerable debate about the reliability of this rule, which is based on simulation studies and lacks a secure theoretical underpinning. According to some authors the rule is overly conservative in some circumstances, with the authors stating, "If we (somewhat subjectively) regard confidence interval coverage less than 93 percent, type I error greater than 7 percent, or relative bias greater than 15 percent as problematic, our results indicate that problems are fairly frequent with 2–4 EPV, uncommon with 5–9 EPV, and still observed with 10–16 EPV. The worst instances of each problem were not severe with 5–9 EPV and usually comparable to those with 10–16 EPV".
Others have found results that are not consistent with the above, using different criteria. A useful criterion is whether the fitted model will be expected to achieve the same predictive discrimination in a new sample as it appeared to achieve in the model development sample. For that criterion, 20 events per candidate variable may be required. Also, one can argue that 96 observations are needed only to estimate the model's intercept precisely enough that the margin of error in predicted probabilities is ±0.1 with a 0.95 confidence level.
== Error and significance of fit ==
=== Deviance and likelihood ratio test ─ a simple case ===
In any fitting procedure, the addition of another fitting parameter to a model (e.g. the beta parameters in a logistic regression model) will almost always improve the ability of the model to predict the measured outcomes. This will be true even if the additional term has no predictive value, since the model will simply be "overfitting" to the noise in the data. The question arises as to whether the improvement gained by the addition of another fitting parameter is significant enough to recommend the inclusion of the additional term, or whether the improvement is simply that which may be expected from overfitting.
In short, for logistic regression, a statistic known as the deviance is defined which is a measure of the error between the logistic model fit and the outcome data. In the limit of a large number of data points, the deviance is chi-squared distributed, which allows a chi-squared test to be implemented in order to determine the significance of the explanatory variables.
Linear regression and logistic regression have many similarities. For example, in simple linear regression, a set of K data points (xk, yk) are fitted to a proposed model function of the form
y
=
b
0
+
b
1
x
{\displaystyle y=b_{0}+b_{1}x}
. The fit is obtained by choosing the b parameters which minimize the sum of the squares of the residuals (the squared error term) for each data point:
ε
2
=
∑
k
=
1
K
(
b
0
+
b
1
x
k
−
y
k
)
2
.
{\displaystyle \varepsilon ^{2}=\sum _{k=1}^{K}(b_{0}+b_{1}x_{k}-y_{k})^{2}.}
The minimum value which constitutes the fit will be denoted by
ε
^
2
{\displaystyle {\hat {\varepsilon }}^{2}}
The idea of a null model may be introduced, in which it is assumed that the x variable is of no use in predicting the yk outcomes: The data points are fitted to a null model function of the form y = b0 with a squared error term:
ε
2
=
∑
k
=
1
K
(
b
0
−
y
k
)
2
.
{\displaystyle \varepsilon ^{2}=\sum _{k=1}^{K}(b_{0}-y_{k})^{2}.}
The fitting process consists of choosing a value of b0 which minimizes
ε
2
{\displaystyle \varepsilon ^{2}}
of the fit to the null model, denoted by
ε
φ
2
{\displaystyle \varepsilon _{\varphi }^{2}}
where the
φ
{\displaystyle \varphi }
subscript denotes the null model. It is seen that the null model is optimized by
b
0
=
y
¯
{\displaystyle b_{0}={\overline {y}}}
where
y
¯
{\displaystyle {\overline {y}}}
is the mean of the yk values, and the optimized
ε
φ
2
{\displaystyle \varepsilon _{\varphi }^{2}}
is:
ε
^
φ
2
=
∑
k
=
1
K
(
y
¯
−
y
k
)
2
{\displaystyle {\hat {\varepsilon }}_{\varphi }^{2}=\sum _{k=1}^{K}({\overline {y}}-y_{k})^{2}}
which is proportional to the square of the (uncorrected) sample standard deviation of the yk data points.
We can imagine a case where the yk data points are randomly assigned to the various xk, and then fitted using the proposed model. Specifically, we can consider the fits of the proposed model to every permutation of the yk outcomes. It can be shown that the optimized error of any of these fits will never be less than the optimum error of the null model, and that the difference between these minimum error will follow a chi-squared distribution, with degrees of freedom equal those of the proposed model minus those of the null model which, in this case, will be
2
−
1
=
1
{\displaystyle 2-1=1}
. Using the chi-squared test, we may then estimate how many of these permuted sets of yk will yield a minimum error less than or equal to the minimum error using the original yk, and so we can estimate how significant an improvement is given by the inclusion of the x variable in the proposed model.
For logistic regression, the measure of goodness-of-fit is the likelihood function L, or its logarithm, the log-likelihood ℓ. The likelihood function L is analogous to the
ε
2
{\displaystyle \varepsilon ^{2}}
in the linear regression case, except that the likelihood is maximized rather than minimized. Denote the maximized log-likelihood of the proposed model by
ℓ
^
{\displaystyle {\hat {\ell }}}
.
In the case of simple binary logistic regression, the set of K data points are fitted in a probabilistic sense to a function of the form:
p
(
x
)
=
1
1
+
e
−
t
{\displaystyle p(x)={\frac {1}{1+e^{-t}}}}
where
p
(
x
)
{\displaystyle p(x)}
is the probability that
y
=
1
{\displaystyle y=1}
. The log-odds are given by:
t
=
β
0
+
β
1
x
{\displaystyle t=\beta _{0}+\beta _{1}x}
and the log-likelihood is:
ℓ
=
∑
k
=
1
K
(
y
k
ln
(
p
(
x
k
)
)
+
(
1
−
y
k
)
ln
(
1
−
p
(
x
k
)
)
)
{\displaystyle \ell =\sum _{k=1}^{K}\left(y_{k}\ln(p(x_{k}))+(1-y_{k})\ln(1-p(x_{k}))\right)}
For the null model, the probability that
y
=
1
{\displaystyle y=1}
is given by:
p
φ
(
x
)
=
1
1
+
e
−
t
φ
{\displaystyle p_{\varphi }(x)={\frac {1}{1+e^{-t_{\varphi }}}}}
The log-odds for the null model are given by:
t
φ
=
β
0
{\displaystyle t_{\varphi }=\beta _{0}}
and the log-likelihood is:
ℓ
φ
=
∑
k
=
1
K
(
y
k
ln
(
p
φ
)
+
(
1
−
y
k
)
ln
(
1
−
p
φ
)
)
{\displaystyle \ell _{\varphi }=\sum _{k=1}^{K}\left(y_{k}\ln(p_{\varphi })+(1-y_{k})\ln(1-p_{\varphi })\right)}
Since we have
p
φ
=
y
¯
{\displaystyle p_{\varphi }={\overline {y}}}
at the maximum of L, the maximum log-likelihood for the null model is
ℓ
^
φ
=
K
(
y
¯
ln
(
y
¯
)
+
(
1
−
y
¯
)
ln
(
1
−
y
¯
)
)
{\displaystyle {\hat {\ell }}_{\varphi }=K(\,{\overline {y}}\ln({\overline {y}})+(1-{\overline {y}})\ln(1-{\overline {y}}))}
The optimum
β
0
{\displaystyle \beta _{0}}
is:
β
0
=
ln
(
y
¯
1
−
y
¯
)
{\displaystyle \beta _{0}=\ln \left({\frac {\overline {y}}{1-{\overline {y}}}}\right)}
where
y
¯
{\displaystyle {\overline {y}}}
is again the mean of the yk values. Again, we can conceptually consider the fit of the proposed model to every permutation of the yk and it can be shown that the maximum log-likelihood of these permutation fits will never be smaller than that of the null model:
ℓ
^
≥
ℓ
^
φ
{\displaystyle {\hat {\ell }}\geq {\hat {\ell }}_{\varphi }}
Also, as an analog to the error of the linear regression case, we may define the deviance of a logistic regression fit as:
D
=
ln
(
L
^
2
L
^
φ
2
)
=
2
(
ℓ
^
−
ℓ
^
φ
)
{\displaystyle D=\ln \left({\frac {{\hat {L}}^{2}}{{\hat {L}}_{\varphi }^{2}}}\right)=2({\hat {\ell }}-{\hat {\ell }}_{\varphi })}
which will always be positive or zero. The reason for this choice is that not only is the deviance a good measure of the goodness of fit, it is also approximately chi-squared distributed, with the approximation improving as the number of data points (K) increases, becoming exactly chi-square distributed in the limit of an infinite number of data points. As in the case of linear regression, we may use this fact to estimate the probability that a random set of data points will give a better fit than the fit obtained by the proposed model, and so have an estimate how significantly the model is improved by including the xk data points in the proposed model.
For the simple model of student test scores described above, the maximum value of the log-likelihood of the null model is
ℓ
^
φ
=
−
13.8629
…
{\displaystyle {\hat {\ell }}_{\varphi }=-13.8629\ldots }
The maximum value of the log-likelihood for the simple model is
ℓ
^
=
−
8.02988
…
{\displaystyle {\hat {\ell }}=-8.02988\ldots }
so that the deviance is
D
=
2
(
ℓ
^
−
ℓ
^
φ
)
=
11.6661
…
{\displaystyle D=2({\hat {\ell }}-{\hat {\ell }}_{\varphi })=11.6661\ldots }
Using the chi-squared test of significance, the integral of the chi-squared distribution with one degree of freedom from 11.6661... to infinity is equal to 0.00063649...
This effectively means that about 6 out of a 10,000 fits to random yk can be expected to have a better fit (smaller deviance) than the given yk and so we can conclude that the inclusion of the x variable and data in the proposed model is a very significant improvement over the null model. In other words, we reject the null hypothesis with
1
−
D
≈
99.94
%
{\displaystyle 1-D\approx 99.94\%}
confidence.
=== Goodness of fit summary ===
Goodness of fit in linear regression models is generally measured using R2. Since this has no direct analog in logistic regression, various methods: ch.21 including the following can be used instead.
==== Deviance and likelihood ratio tests ====
In linear regression analysis, one is concerned with partitioning variance via the sum of squares calculations – variance in the criterion is essentially divided into variance accounted for by the predictors and residual variance. In logistic regression analysis, deviance is used in lieu of a sum of squares calculations. Deviance is analogous to the sum of squares calculations in linear regression and is a measure of the lack of fit to the data in a logistic regression model. When a "saturated" model is available (a model with a theoretically perfect fit), deviance is calculated by comparing a given model with the saturated model. This computation gives the likelihood-ratio test:
D
=
−
2
ln
likelihood of the fitted model
likelihood of the saturated model
.
{\displaystyle D=-2\ln {\frac {\text{likelihood of the fitted model}}{\text{likelihood of the saturated model}}}.}
In the above equation, D represents the deviance and ln represents the natural logarithm. The log of this likelihood ratio (the ratio of the fitted model to the saturated model) will produce a negative value, hence the need for a negative sign. D can be shown to follow an approximate chi-squared distribution. Smaller values indicate better fit as the fitted model deviates less from the saturated model. When assessed upon a chi-square distribution, nonsignificant chi-square values indicate very little unexplained variance and thus, good model fit. Conversely, a significant chi-square value indicates that a significant amount of the variance is unexplained.
When the saturated model is not available (a common case), deviance is calculated simply as −2·(log likelihood of the fitted model), and the reference to the saturated model's log likelihood can be removed from all that follows without harm.
Two measures of deviance are particularly important in logistic regression: null deviance and model deviance. The null deviance represents the difference between a model with only the intercept (which means "no predictors") and the saturated model. The model deviance represents the difference between a model with at least one predictor and the saturated model. In this respect, the null model provides a baseline upon which to compare predictor models. Given that deviance is a measure of the difference between a given model and the saturated model, smaller values indicate better fit. Thus, to assess the contribution of a predictor or set of predictors, one can subtract the model deviance from the null deviance and assess the difference on a
χ
s
−
p
2
,
{\displaystyle \chi _{s-p}^{2},}
chi-square distribution with degrees of freedom equal to the difference in the number of parameters estimated.
Let
D
null
=
−
2
ln
likelihood of null model
likelihood of the saturated model
D
fitted
=
−
2
ln
likelihood of fitted model
likelihood of the saturated model
.
{\displaystyle {\begin{aligned}D_{\text{null}}&=-2\ln {\frac {\text{likelihood of null model}}{\text{likelihood of the saturated model}}}\\[6pt]D_{\text{fitted}}&=-2\ln {\frac {\text{likelihood of fitted model}}{\text{likelihood of the saturated model}}}.\end{aligned}}}
Then the difference of both is:
D
null
−
D
fitted
=
−
2
(
ln
likelihood of null model
likelihood of the saturated model
−
ln
likelihood of fitted model
likelihood of the saturated model
)
=
−
2
ln
(
likelihood of null model
likelihood of the saturated model
)
(
likelihood of fitted model
likelihood of the saturated model
)
=
−
2
ln
likelihood of the null model
likelihood of fitted model
.
{\displaystyle {\begin{aligned}D_{\text{null}}-D_{\text{fitted}}&=-2\left(\ln {\frac {\text{likelihood of null model}}{\text{likelihood of the saturated model}}}-\ln {\frac {\text{likelihood of fitted model}}{\text{likelihood of the saturated model}}}\right)\\[6pt]&=-2\ln {\frac {\left({\dfrac {\text{likelihood of null model}}{\text{likelihood of the saturated model}}}\right)}{\left({\dfrac {\text{likelihood of fitted model}}{\text{likelihood of the saturated model}}}\right)}}\\[6pt]&=-2\ln {\frac {\text{likelihood of the null model}}{\text{likelihood of fitted model}}}.\end{aligned}}}
If the model deviance is significantly smaller than the null deviance then one can conclude that the predictor or set of predictors significantly improve the model's fit. This is analogous to the F-test used in linear regression analysis to assess the significance of prediction.
==== Pseudo-R-squared ====
In linear regression the squared multiple correlation, R2 is used to assess goodness of fit as it represents the proportion of variance in the criterion that is explained by the predictors. In logistic regression analysis, there is no agreed upon analogous measure, but there are several competing measures each with limitations.
Four of the most commonly used indices and one less commonly used one are examined on this page:
Likelihood ratio R2L
Cox and Snell R2CS
Nagelkerke R2N
McFadden R2McF
Tjur R2T
==== Hosmer–Lemeshow test ====
The Hosmer–Lemeshow test uses a test statistic that asymptotically follows a
χ
2
{\displaystyle \chi ^{2}}
distribution to assess whether or not the observed event rates match expected event rates in subgroups of the model population. This test is considered to be obsolete by some statisticians because of its dependence on arbitrary binning of predicted probabilities and relative low power.
=== Coefficient significance ===
After fitting the model, it is likely that researchers will want to examine the contribution of individual predictors. To do so, they will want to examine the regression coefficients. In linear regression, the regression coefficients represent the change in the criterion for each unit change in the predictor. In logistic regression, however, the regression coefficients represent the change in the logit for each unit change in the predictor. Given that the logit is not intuitive, researchers are likely to focus on a predictor's effect on the exponential function of the regression coefficient – the odds ratio (see definition). In linear regression, the significance of a regression coefficient is assessed by computing a t test. In logistic regression, there are several different tests designed to assess the significance of an individual predictor, most notably the likelihood ratio test and the Wald statistic.
==== Likelihood ratio test ====
The likelihood-ratio test discussed above to assess model fit is also the recommended procedure to assess the contribution of individual "predictors" to a given model. In the case of a single predictor model, one simply compares the deviance of the predictor model with that of the null model on a chi-square distribution with a single degree of freedom. If the predictor model has significantly smaller deviance (c.f. chi-square using the difference in degrees of freedom of the two models), then one can conclude that there is a significant association between the "predictor" and the outcome. Although some common statistical packages (e.g. SPSS) do provide likelihood ratio test statistics, without this computationally intensive test it would be more difficult to assess the contribution of individual predictors in the multiple logistic regression case. To assess the contribution of individual predictors one can enter the predictors hierarchically, comparing each new model with the previous to determine the contribution of each predictor. There is some debate among statisticians about the appropriateness of so-called "stepwise" procedures. The fear is that they may not preserve nominal statistical properties and may become misleading.
==== Wald statistic ====
Alternatively, when assessing the contribution of individual predictors in a given model, one may examine the significance of the Wald statistic. The Wald statistic, analogous to the t-test in linear regression, is used to assess the significance of coefficients. The Wald statistic is the ratio of the square of the regression coefficient to the square of the standard error of the coefficient and is asymptotically distributed as a chi-square distribution.
W
j
=
β
j
2
S
E
β
j
2
{\displaystyle W_{j}={\frac {\beta _{j}^{2}}{SE_{\beta _{j}}^{2}}}}
Although several statistical packages (e.g., SPSS, SAS) report the Wald statistic to assess the contribution of individual predictors, the Wald statistic has limitations. When the regression coefficient is large, the standard error of the regression coefficient also tends to be larger increasing the probability of Type-II error. The Wald statistic also tends to be biased when data are sparse.
==== Case-control sampling ====
Suppose cases are rare. Then we might wish to sample them more frequently than their prevalence in the population. For example, suppose there is a disease that affects 1 person in 10,000 and to collect our data we need to do a complete physical. It may be too expensive to do thousands of physicals of healthy people in order to obtain data for only a few diseased individuals. Thus, we may evaluate more diseased individuals, perhaps all of the rare outcomes. This is also retrospective sampling, or equivalently it is called unbalanced data. As a rule of thumb, sampling controls at a rate of five times the number of cases will produce sufficient control data.
Logistic regression is unique in that it may be estimated on unbalanced data, rather than randomly sampled data, and still yield correct coefficient estimates of the effects of each independent variable on the outcome. That is to say, if we form a logistic model from such data, if the model is correct in the general population, the
β
j
{\displaystyle \beta _{j}}
parameters are all correct except for
β
0
{\displaystyle \beta _{0}}
. We can correct
β
0
{\displaystyle \beta _{0}}
if we know the true prevalence as follows:
β
^
0
∗
=
β
^
0
+
log
π
1
−
π
−
log
π
~
1
−
π
~
{\displaystyle {\widehat {\beta }}_{0}^{*}={\widehat {\beta }}_{0}+\log {\frac {\pi }{1-\pi }}-\log {{\tilde {\pi }} \over {1-{\tilde {\pi }}}}}
where
π
{\displaystyle \pi }
is the true prevalence and
π
~
{\displaystyle {\tilde {\pi }}}
is the prevalence in the sample.
== Discussion ==
Like other forms of regression analysis, logistic regression makes use of one or more predictor variables that may be either continuous or categorical. Unlike ordinary linear regression, however, logistic regression is used for predicting dependent variables that take membership in one of a limited number of categories (treating the dependent variable in the binomial case as the outcome of a Bernoulli trial) rather than a continuous outcome. Given this difference, the assumptions of linear regression are violated. In particular, the residuals cannot be normally distributed. In addition, linear regression may make nonsensical predictions for a binary dependent variable. What is needed is a way to convert a binary variable into a continuous one that can take on any real value (negative or positive). To do that, binomial logistic regression first calculates the odds of the event happening for different levels of each independent variable, and then takes its logarithm to create a continuous criterion as a transformed version of the dependent variable. The logarithm of the odds is the logit of the probability, the logit is defined as follows:
logit
p
=
ln
p
1
−
p
for
0
<
p
<
1
.
{\displaystyle \operatorname {logit} p=\ln {\frac {p}{1-p}}\quad {\text{for }}0<p<1\,.}
Although the dependent variable in logistic regression is Bernoulli, the logit is on an unrestricted scale. The logit function is the link function in this kind of generalized linear model, i.e.
logit
E
(
Y
)
=
β
0
+
β
1
x
{\displaystyle \operatorname {logit} \operatorname {\mathcal {E}} (Y)=\beta _{0}+\beta _{1}x}
Y is the Bernoulli-distributed response variable and x is the predictor variable; the β values are the linear parameters.
The logit of the probability of success is then fitted to the predictors. The predicted value of the logit is converted back into predicted odds, via the inverse of the natural logarithm – the exponential function. Thus, although the observed dependent variable in binary logistic regression is a 0-or-1 variable, the logistic regression estimates the odds, as a continuous variable, that the dependent variable is a 'success'. In some applications, the odds are all that is needed. In others, a specific yes-or-no prediction is needed for whether the dependent variable is or is not a 'success'; this categorical prediction can be based on the computed odds of success, with predicted odds above some chosen cutoff value being translated into a prediction of success.
== Maximum entropy ==
Of all the functional forms used for estimating the probabilities of a particular categorical outcome which optimize the fit by maximizing the likelihood function (e.g. probit regression, Poisson regression, etc.), the logistic regression solution is unique in that it is a maximum entropy solution. This is a case of a general property: an exponential family of distributions maximizes entropy, given an expected value. In the case of the logistic model, the logistic function is the natural parameter of the Bernoulli distribution (it is in "canonical form", and the logistic function is the canonical link function), while other sigmoid functions are non-canonical link functions; this underlies its mathematical elegance and ease of optimization. See Exponential family § Maximum entropy derivation for details.
=== Proof ===
In order to show this, we use the method of Lagrange multipliers. The Lagrangian is equal to the entropy plus the sum of the products of Lagrange multipliers times various constraint expressions. The general multinomial case will be considered, since the proof is not made that much simpler by considering simpler cases. Equating the derivative of the Lagrangian with respect to the various probabilities to zero yields a functional form for those probabilities which corresponds to those used in logistic regression.
As in the above section on multinomial logistic regression, we will consider
M
+
1
{\displaystyle M+1}
explanatory variables denoted
x
m
{\displaystyle x_{m}}
and which include
x
0
=
1
{\displaystyle x_{0}=1}
. There will be a total of K data points, indexed by
k
=
{
1
,
2
,
…
,
K
}
{\displaystyle k=\{1,2,\dots ,K\}}
, and the data points are given by
x
m
k
{\displaystyle x_{mk}}
and
y
k
{\displaystyle y_{k}}
. The xmk will also be represented as an
(
M
+
1
)
{\displaystyle (M+1)}
-dimensional vector
x
k
=
{
x
0
k
,
x
1
k
,
…
,
x
M
k
}
{\displaystyle {\boldsymbol {x}}_{k}=\{x_{0k},x_{1k},\dots ,x_{Mk}\}}
. There will be
N
+
1
{\displaystyle N+1}
possible values of the categorical variable y ranging from 0 to N.
Let pn(x) be the probability, given explanatory variable vector x, that the outcome will be
y
=
n
{\displaystyle y=n}
. Define
p
n
k
=
p
n
(
x
k
)
{\displaystyle p_{nk}=p_{n}({\boldsymbol {x}}_{k})}
which is the probability that for the k-th measurement, the categorical outcome is n.
The Lagrangian will be expressed as a function of the probabilities pnk and will minimized by equating the derivatives of the Lagrangian with respect to these probabilities to zero. An important point is that the probabilities are treated equally and the fact that they sum to 1 is part of the Lagrangian formulation, rather than being assumed from the beginning.
The first contribution to the Lagrangian is the entropy:
L
e
n
t
=
−
∑
k
=
1
K
∑
n
=
0
N
p
n
k
ln
(
p
n
k
)
{\displaystyle {\mathcal {L}}_{ent}=-\sum _{k=1}^{K}\sum _{n=0}^{N}p_{nk}\ln(p_{nk})}
The log-likelihood is:
ℓ
=
∑
k
=
1
K
∑
n
=
0
N
Δ
(
n
,
y
k
)
ln
(
p
n
k
)
{\displaystyle \ell =\sum _{k=1}^{K}\sum _{n=0}^{N}\Delta (n,y_{k})\ln(p_{nk})}
Assuming the multinomial logistic function, the derivative of the log-likelihood with respect the beta coefficients was found to be:
∂
ℓ
∂
β
n
m
=
∑
k
=
1
K
(
p
n
k
x
m
k
−
Δ
(
n
,
y
k
)
x
m
k
)
{\displaystyle {\frac {\partial \ell }{\partial \beta _{nm}}}=\sum _{k=1}^{K}(p_{nk}x_{mk}-\Delta (n,y_{k})x_{mk})}
A very important point here is that this expression is (remarkably) not an explicit function of the beta coefficients. It is only a function of the probabilities pnk and the data. Rather than being specific to the assumed multinomial logistic case, it is taken to be a general statement of the condition at which the log-likelihood is maximized and makes no reference to the functional form of pnk. There are then (M+1)(N+1) fitting constraints and the fitting constraint term in the Lagrangian is then:
L
f
i
t
=
∑
n
=
0
N
∑
m
=
0
M
λ
n
m
∑
k
=
1
K
(
p
n
k
x
m
k
−
Δ
(
n
,
y
k
)
x
m
k
)
{\displaystyle {\mathcal {L}}_{fit}=\sum _{n=0}^{N}\sum _{m=0}^{M}\lambda _{nm}\sum _{k=1}^{K}(p_{nk}x_{mk}-\Delta (n,y_{k})x_{mk})}
where the λnm are the appropriate Lagrange multipliers. There are K normalization constraints which may be written:
∑
n
=
0
N
p
n
k
=
1
{\displaystyle \sum _{n=0}^{N}p_{nk}=1}
so that the normalization term in the Lagrangian is:
L
n
o
r
m
=
∑
k
=
1
K
α
k
(
1
−
∑
n
=
1
N
p
n
k
)
{\displaystyle {\mathcal {L}}_{norm}=\sum _{k=1}^{K}\alpha _{k}\left(1-\sum _{n=1}^{N}p_{nk}\right)}
where the αk are the appropriate Lagrange multipliers. The Lagrangian is then the sum of the above three terms:
L
=
L
e
n
t
+
L
f
i
t
+
L
n
o
r
m
{\displaystyle {\mathcal {L}}={\mathcal {L}}_{ent}+{\mathcal {L}}_{fit}+{\mathcal {L}}_{norm}}
Setting the derivative of the Lagrangian with respect to one of the probabilities to zero yields:
∂
L
∂
p
n
′
k
′
=
0
=
−
ln
(
p
n
′
k
′
)
−
1
+
∑
m
=
0
M
(
λ
n
′
m
x
m
k
′
)
−
α
k
′
{\displaystyle {\frac {\partial {\mathcal {L}}}{\partial p_{n'k'}}}=0=-\ln(p_{n'k'})-1+\sum _{m=0}^{M}(\lambda _{n'm}x_{mk'})-\alpha _{k'}}
Using the more condensed vector notation:
∑
m
=
0
M
λ
n
m
x
m
k
=
λ
n
⋅
x
k
{\displaystyle \sum _{m=0}^{M}\lambda _{nm}x_{mk}={\boldsymbol {\lambda }}_{n}\cdot {\boldsymbol {x}}_{k}}
and dropping the primes on the n and k indices, and then solving for
p
n
k
{\displaystyle p_{nk}}
yields:
p
n
k
=
e
λ
n
⋅
x
k
/
Z
k
{\displaystyle p_{nk}=e^{{\boldsymbol {\lambda }}_{n}\cdot {\boldsymbol {x}}_{k}}/Z_{k}}
where:
Z
k
=
e
1
+
α
k
{\displaystyle Z_{k}=e^{1+\alpha _{k}}}
Imposing the normalization constraint, we can solve for the Zk and write the probabilities as:
p
n
k
=
e
λ
n
⋅
x
k
∑
u
=
0
N
e
λ
u
⋅
x
k
{\displaystyle p_{nk}={\frac {e^{{\boldsymbol {\lambda }}_{n}\cdot {\boldsymbol {x}}_{k}}}{\sum _{u=0}^{N}e^{{\boldsymbol {\lambda }}_{u}\cdot {\boldsymbol {x}}_{k}}}}}
The
λ
n
{\displaystyle {\boldsymbol {\lambda }}_{n}}
are not all independent. We can add any constant
(
M
+
1
)
{\displaystyle (M+1)}
-dimensional vector to each of the
λ
n
{\displaystyle {\boldsymbol {\lambda }}_{n}}
without changing the value of the
p
n
k
{\displaystyle p_{nk}}
probabilities so that there are only N rather than
N
+
1
{\displaystyle N+1}
independent
λ
n
{\displaystyle {\boldsymbol {\lambda }}_{n}}
. In the multinomial logistic regression section above, the
λ
0
{\displaystyle {\boldsymbol {\lambda }}_{0}}
was subtracted from each
λ
n
{\displaystyle {\boldsymbol {\lambda }}_{n}}
which set the exponential term involving
λ
0
{\displaystyle {\boldsymbol {\lambda }}_{0}}
to 1, and the beta coefficients were given by
β
n
=
λ
n
−
λ
0
{\displaystyle {\boldsymbol {\beta }}_{n}={\boldsymbol {\lambda }}_{n}-{\boldsymbol {\lambda }}_{0}}
.
=== Other approaches ===
In machine learning applications where logistic regression is used for binary classification, the MLE minimises the cross-entropy loss function.
Logistic regression is an important machine learning algorithm. The goal is to model the probability of a random variable
Y
{\displaystyle Y}
being 0 or 1 given experimental data.
Consider a generalized linear model function parameterized by
θ
{\displaystyle \theta }
,
h
θ
(
X
)
=
1
1
+
e
−
θ
T
X
=
Pr
(
Y
=
1
∣
X
;
θ
)
{\displaystyle h_{\theta }(X)={\frac {1}{1+e^{-\theta ^{T}X}}}=\Pr(Y=1\mid X;\theta )}
Therefore,
Pr
(
Y
=
0
∣
X
;
θ
)
=
1
−
h
θ
(
X
)
{\displaystyle \Pr(Y=0\mid X;\theta )=1-h_{\theta }(X)}
and since
Y
∈
{
0
,
1
}
{\displaystyle Y\in \{0,1\}}
, we see that
Pr
(
y
∣
X
;
θ
)
{\displaystyle \Pr(y\mid X;\theta )}
is given by
Pr
(
y
∣
X
;
θ
)
=
h
θ
(
X
)
y
(
1
−
h
θ
(
X
)
)
(
1
−
y
)
.
{\displaystyle \Pr(y\mid X;\theta )=h_{\theta }(X)^{y}(1-h_{\theta }(X))^{(1-y)}.}
We now calculate the likelihood function assuming that all the observations in the sample are independently Bernoulli distributed,
L
(
θ
∣
y
;
x
)
=
Pr
(
Y
∣
X
;
θ
)
=
∏
i
Pr
(
y
i
∣
x
i
;
θ
)
=
∏
i
h
θ
(
x
i
)
y
i
(
1
−
h
θ
(
x
i
)
)
(
1
−
y
i
)
{\displaystyle {\begin{aligned}L(\theta \mid y;x)&=\Pr(Y\mid X;\theta )\\&=\prod _{i}\Pr(y_{i}\mid x_{i};\theta )\\&=\prod _{i}h_{\theta }(x_{i})^{y_{i}}(1-h_{\theta }(x_{i}))^{(1-y_{i})}\end{aligned}}}
Typically, the log likelihood is maximized,
N
−
1
log
L
(
θ
∣
y
;
x
)
=
N
−
1
∑
i
=
1
N
log
Pr
(
y
i
∣
x
i
;
θ
)
{\displaystyle N^{-1}\log L(\theta \mid y;x)=N^{-1}\sum _{i=1}^{N}\log \Pr(y_{i}\mid x_{i};\theta )}
which is maximized using optimization techniques such as gradient descent.
Assuming the
(
x
,
y
)
{\displaystyle (x,y)}
pairs are drawn uniformly from the underlying distribution, then in the limit of large N,
lim
N
→
+
∞
N
−
1
∑
i
=
1
N
log
Pr
(
y
i
∣
x
i
;
θ
)
=
∑
x
∈
X
∑
y
∈
Y
Pr
(
X
=
x
,
Y
=
y
)
log
Pr
(
Y
=
y
∣
X
=
x
;
θ
)
=
∑
x
∈
X
∑
y
∈
Y
Pr
(
X
=
x
,
Y
=
y
)
(
−
log
Pr
(
Y
=
y
∣
X
=
x
)
Pr
(
Y
=
y
∣
X
=
x
;
θ
)
+
log
Pr
(
Y
=
y
∣
X
=
x
)
)
=
−
D
KL
(
Y
∥
Y
θ
)
−
H
(
Y
∣
X
)
{\displaystyle {\begin{aligned}&\lim \limits _{N\rightarrow +\infty }N^{-1}\sum _{i=1}^{N}\log \Pr(y_{i}\mid x_{i};\theta )=\sum _{x\in {\mathcal {X}}}\sum _{y\in {\mathcal {Y}}}\Pr(X=x,Y=y)\log \Pr(Y=y\mid X=x;\theta )\\[6pt]={}&\sum _{x\in {\mathcal {X}}}\sum _{y\in {\mathcal {Y}}}\Pr(X=x,Y=y)\left(-\log {\frac {\Pr(Y=y\mid X=x)}{\Pr(Y=y\mid X=x;\theta )}}+\log \Pr(Y=y\mid X=x)\right)\\[6pt]={}&-D_{\text{KL}}(Y\parallel Y_{\theta })-H(Y\mid X)\end{aligned}}}
where
H
(
Y
∣
X
)
{\displaystyle H(Y\mid X)}
is the conditional entropy and
D
KL
{\displaystyle D_{\text{KL}}}
is the Kullback–Leibler divergence. This leads to the intuition that by maximizing the log-likelihood of a model, you are minimizing the KL divergence of your model from the maximal entropy distribution. Intuitively searching for the model that makes the fewest assumptions in its parameters.
== Comparison with linear regression ==
Logistic regression can be seen as a special case of the generalized linear model and thus analogous to linear regression. The model of logistic regression, however, is based on quite different assumptions (about the relationship between the dependent and independent variables) from those of linear regression. In particular, the key differences between these two models can be seen in the following two features of logistic regression. First, the conditional distribution
y
∣
x
{\displaystyle y\mid x}
is a Bernoulli distribution rather than a Gaussian distribution, because the dependent variable is binary. Second, the predicted values are probabilities and are therefore restricted to (0,1) through the logistic distribution function because logistic regression predicts the probability of particular outcomes rather than the outcomes themselves.
== Alternatives ==
A common alternative to the logistic model (logit model) is the probit model, as the related names suggest. From the perspective of generalized linear models, these differ in the choice of link function: the logistic model uses the logit function (inverse logistic function), while the probit model uses the probit function (inverse error function). Equivalently, in the latent variable interpretations of these two methods, the first assumes a standard logistic distribution of errors and the second a standard normal distribution of errors. Other sigmoid functions or error distributions can be used instead.
Logistic regression is an alternative to Fisher's 1936 method, linear discriminant analysis. If the assumptions of linear discriminant analysis hold, the conditioning can be reversed to produce logistic regression. The converse is not true, however, because logistic regression does not require the multivariate normal assumption of discriminant analysis.
The assumption of linear predictor effects can easily be relaxed using techniques such as spline functions.
== History ==
A detailed history of the logistic regression is given in Cramer (2002). The logistic function was developed as a model of population growth and named "logistic" by Pierre François Verhulst in the 1830s and 1840s, under the guidance of Adolphe Quetelet; see Logistic function § History for details. In his earliest paper (1838), Verhulst did not specify how he fit the curves to the data. In his more detailed paper (1845), Verhulst determined the three parameters of the model by making the curve pass through three observed points, which yielded poor predictions.
The logistic function was independently developed in chemistry as a model of autocatalysis (Wilhelm Ostwald, 1883). An autocatalytic reaction is one in which one of the products is itself a catalyst for the same reaction, while the supply of one of the reactants is fixed. This naturally gives rise to the logistic equation for the same reason as population growth: the reaction is self-reinforcing but constrained.
The logistic function was independently rediscovered as a model of population growth in 1920 by Raymond Pearl and Lowell Reed, published as Pearl & Reed (1920), which led to its use in modern statistics. They were initially unaware of Verhulst's work and presumably learned about it from L. Gustave du Pasquier, but they gave him little credit and did not adopt his terminology. Verhulst's priority was acknowledged and the term "logistic" revived by Udny Yule in 1925 and has been followed since. Pearl and Reed first applied the model to the population of the United States, and also initially fitted the curve by making it pass through three points; as with Verhulst, this again yielded poor results.
In the 1930s, the probit model was developed and systematized by Chester Ittner Bliss, who coined the term "probit" in Bliss (1934), and by John Gaddum in Gaddum (1933), and the model fit by maximum likelihood estimation by Ronald A. Fisher in Fisher (1935), as an addendum to Bliss's work. The probit model was principally used in bioassay, and had been preceded by earlier work dating to 1860; see Probit model § History. The probit model influenced the subsequent development of the logit model and these models competed with each other.
The logistic model was likely first used as an alternative to the probit model in bioassay by Edwin Bidwell Wilson and his student Jane Worcester in Wilson & Worcester (1943). However, the development of the logistic model as a general alternative to the probit model was principally due to the work of Joseph Berkson over many decades, beginning in Berkson (1944), where he coined "logit", by analogy with "probit", and continuing through Berkson (1951) and following years. The logit model was initially dismissed as inferior to the probit model, but "gradually achieved an equal footing with the probit", particularly between 1960 and 1970. By 1970, the logit model achieved parity with the probit model in use in statistics journals and thereafter surpassed it. This relative popularity was due to the adoption of the logit outside of bioassay, rather than displacing the probit within bioassay, and its informal use in practice; the logit's popularity is credited to the logit model's computational simplicity, mathematical properties, and generality, allowing its use in varied fields.
Various refinements occurred during that time, notably by David Cox, as in Cox (1958).
The multinomial logit model was introduced independently in Cox (1966) and Theil (1969), which greatly increased the scope of application and the popularity of the logit model. In 1973 Daniel McFadden linked the multinomial logit to the theory of discrete choice, specifically Luce's choice axiom, showing that the multinomial logit followed from the assumption of independence of irrelevant alternatives and interpreting odds of alternatives as relative preferences; this gave a theoretical foundation for the logistic regression.
== Extensions ==
There are large numbers of extensions:
Multinomial logistic regression (or multinomial logit) handles the case of a multi-way categorical dependent variable (with unordered values, also called "classification"). The general case of having dependent variables with more than two values is termed polytomous regression.
Ordered logistic regression (or ordered logit) handles ordinal dependent variables (ordered values).
Mixed logit is an extension of multinomial logit that allows for correlations among the choices of the dependent variable.
An extension of the logistic model to sets of interdependent variables is the conditional random field.
Conditional logistic regression handles matched or stratified data when the strata are small. It is mostly used in the analysis of observational studies.
== See also ==
Logistic function
Discrete choice
Jarrow–Turnbull model
Limited dependent variable
Multinomial logit model
Ordered logit
Hosmer–Lemeshow test
Brier score
mlpack - contains a C++ implementation of logistic regression
Local case-control sampling
Logistic model tree
== References ==
== Sources ==
== External links ==
Media related to Logistic regression at Wikimedia Commons
Econometrics Lecture (topic: Logit model) on YouTube by Mark Thoma
Logistic Regression tutorial
mlelr: software in C for teaching purposes | Wikipedia/Logit_model |
The Monod equation is a mathematical model for the growth of microorganisms. It is named for Jacques Monod (1910–1976, a French biochemist, Nobel Prize in Physiology or Medicine in 1965), who proposed using an equation of this form to relate microbial growth rates in an aqueous environment to the concentration of a limiting nutrient. The Monod equation has the same form as the Michaelis–Menten equation, but differs in that it is empirical while the latter is based on theoretical considerations.
The Monod equation is commonly used in environmental engineering. For example, it is used in the activated sludge model for sewage treatment.
== Equation ==
The empirical Monod equation is
μ
=
μ
max
[
S
]
K
s
+
[
S
]
{\displaystyle \mu =\mu _{\max }{\frac {[S]}{K_{s}+[S]}}}
where:
μ is the growth rate of a considered microorganism,
μmax is the maximum growth rate of this microorganism,
[S] is the concentration of the limiting substrate S for growth,
Ks is the "half-velocity constant"—the value of [S] when μ/μmax = 0.5.
μmax and Ks are empirical (experimental) coefficients to the Monod equation. They will differ between microorganism species and will also depend on the ambient environmental conditions, e.g., on the temperature, on the pH of the solution, and on the composition of the culture medium.
== Application notes ==
The rate of substrate utilization is related to the specific growth rate as
r
s
=
μ
X
/
Y
,
{\displaystyle r_{s}=\mu X/Y,}
where
X is the total biomass (since the specific growth rate μ is normalized to the total biomass),
Y is the yield coefficient.
rs is negative by convention.
In some applications, several terms of the form [S] / (Ks + [S]) are multiplied together where more than one nutrient or growth factor has the potential to be limiting (e.g. organic matter and oxygen are both necessary to heterotrophic bacteria). When the yield coefficient, being the ratio of mass of microorganisms to mass of substrate utilized, becomes very large, this signifies that there is deficiency of substrate available for utilization.
== Graphical determination of constants ==
As with the Michaelis–Menten equation graphical methods may be used to fit the coefficients of the Monod equation:
Eadie–Hofstee diagram
Hanes–Woolf plot
Lineweaver–Burk plot
== See also ==
Activated sludge model (uses the Monod equation to model bacterial growth and substrate utilization)
Bacterial growth
Hill equation (biochemistry)
Hill contribution to Langmuir equation
Langmuir adsorption model (equation with the same mathematical form)
Michaelis–Menten kinetics (equation with the same mathematical form)
Gompertz function
Victor Henri, who first wrote the general equation form in 1901
Von Bertalanffy function
== References == | Wikipedia/Monod_equation |
Dorland's is the brand name of a family of medical reference works (including dictionaries, spellers and word books, and spell-check software) in various media spanning printed books, CD-ROMs, and online content. The flagship products are Dorland's Illustrated Medical Dictionary (currently in its 33rd edition, published in 2019) and Dorland's Pocket Medical Dictionary (currently in its 30th edition). The principal dictionary was first published in 1890 as the American Illustrated Medical Dictionary, including 770 pages. The pocket edition, called the American Pocket Medical Dictionary, was first published in 1898, consisting of just over 500 pages.
With the death of the editor William Alexander Newman Dorland, AM, MD in 1956, the dictionaries were retitled to incorporate his name, which was how they had generally come to be known. The illustrated dictionary had grown to 2144 pages for the 33rd edition.
The dictionaries were historically published by Saunders.
== List of products ==
=== English-language originals published by Saunders ===
American Illustrated Medical Dictionary
American Pocket Medical Dictionary (until 1956)
Dorland's Illustrated Medical Dictionary (currently in its 33rd edition)
Dorland's Illustrated Medical Dictionary on CD-ROM
Dorland's Illustrated Medical Dictionary online
Dorland's Pocket Medical Dictionary (currently in its 30th edition)
Dorland's Pocket Medical Dictionary on CD-ROM
Dorland's Electronic Medical Speller CD-ROM (various release versions)
Dorland's Alternative Medicine Word Book for Medical Transcriptionists (2003) (ISBN 0721695221)
Dorland's Dentistry Word Book for Medical Transcriptionists (2003) (ISBN 0721693938)
Dorland's Pediatrics Word Book for Medical Transcriptionists (2003) (ISBN 0721695248)
Dorland's Psychiatry Word Book for Medical Transcriptionists (2003) (ISBN 072169523X)
Dorland's Dermatology Word Book for Medical Transcriptionists (2002) (ISBN 0721695264)
Dorland's Laboratory/Pathology Word Book for Medical Transcriptionists (2002) (ISBN 0721695256)
Dorland's Medical Equipment Word Book for Medical Transcriptionists (2002) (ISBN 0721695213)
Dorland's Gastroenterology Word Book for Medical Transcriptionists (2001) (ISBN 072169389X)
Dorland's Immun. & Endocrinology Word Book for Medical Transcriptionists (2001) (ISBN 072169392X)
Dorland's OB/GYN Word Book for Medical Transcriptionists (2001) (ISBN 0721693911)
Dorland's Orthopedic Word Book for Medical Transcriptionists (2001) (ISBN 0721693903)
Dorland's Plastic Surgery Word Book for Medical Transcriptionists (2001) (ISBN 0721693954)
Dorland's Cardiology Word Book for Medical Transcriptionists (2000) (ISBN 072169151X)
Dorland's Neurology Word Book for Medical Transcriptionists (2000) (ISBN 0721690785)
Dorland's Radiology/Oncology Word Book for Medical Transcriptionists (2000) (ISBN 0721691501)
Dorland's Dentistry Speller (1994)
Dorland's Medical Speller (1992)
Dorland's Cardiology Speller (1992)
Dorland's Medical Abbreviations (1992)
=== Translated co-editions published by partners ===
In addition to the Saunders titles in English, there have also been numerous translated co-editions around the world. Listed below are the latest translated co-editions of the flagship product Dorland's Illustrated Medical Dictionary, together with the languages for the translations and the names of the publishers:
Chinese (28th Edition)—Xi'an World Publishing Corp., Xi'an, China
Indonesian (26th Edition)—E.G.C. Medical Publishers, Jakarta, Indonesia
Italian (28th Edition)—Edizioni Scientifiche Internazionali (ESI), Milan, Italy
Japanese (28th Edition)—Hirokawa Publishing Company, Tokyo, Japan
Portuguese (28th Edition)—Editiora Manole Ltda., São Paulo, Brazil
Spanish (30th Edition)—Elsevier España, S.A., Madrid, Spain
Vietnamese (30th Edition)—Medical Publishing House One Member Company Limited, Hanoi, Vietnam
== Publisher ==
Dorland's was published for over a century by the W.B. Saunders Company, which was an independent medical publisher during most of that time. In the 1980s and 1990s, W.B. Saunders was acquired first by CBS and then by Harcourt. In 2001, the company was absorbed into Elsevier, where the name Saunders (without the W.B.) was used as an imprint name. The 2020 33rd edition imprint is Elsevier.
Contexo Media's Dorland Healthcare Information, publisher of Dorland's Medical Directory, appears to be unrelated to Elsevier, Saunders, and the Dorland's family of medical reference works.
== See also ==
Medical dictionary
== References ==
== External links ==
Dorland's Medical Dictionary Online – subscription only
Version provided by the Free Dictionary – "The main sources of TheFreeDictionary's Medical dictionary are The American Heritage® Stedman's Medical Dictionary, Second Edition and Dorland's Medical Dictionary for Health Care Consumers [...]." | Wikipedia/Dorland's_Illustrated_Medical_Dictionary |
The Langmuir adsorption model explains adsorption by assuming an adsorbate behaves as an ideal gas at isothermal conditions. According to the model, adsorption and desorption are reversible processes. This model even explains the effect of pressure; i.e., at these conditions the adsorbate's partial pressure
p
A
{\displaystyle p_{A}}
is related to its volume V adsorbed onto a solid adsorbent. The adsorbent, as indicated in the figure, is assumed to be an ideal solid surface composed of a series of distinct sites capable of binding the adsorbate. The adsorbate binding is treated as a chemical reaction between the adsorbate gaseous molecule
A
g
{\displaystyle A_{\text{g}}}
and an empty sorption site S. This reaction yields an adsorbed species
A
ad
{\displaystyle A_{\text{ad}}}
with an associated equilibrium constant
K
eq
{\displaystyle K_{\text{eq}}}
:
A
g
+
S
↽
−
−
⇀
A
ad
{\displaystyle {\ce {A_{g}{}+ S <=> A_{ad}}}}
.
From these basic hypotheses the mathematical formulation of the Langmuir adsorption isotherm can be derived in various independent and complementary ways: by the kinetics, the thermodynamics, and the statistical mechanics approaches respectively (see below for the different demonstrations).
The Langmuir adsorption equation is
θ
A
=
V
V
m
=
K
eq
A
p
A
1
+
K
eq
A
p
A
,
{\displaystyle \theta _{A}={\frac {V}{V_{\text{m}}}}={\frac {K_{\text{eq}}^{A}\,p_{A}}{1+K_{\text{eq}}^{A}\,p_{A}}},}
where
θ
A
{\displaystyle \theta _{A}}
is the fractional occupancy of the adsorption sites, i.e., the ratio of the volume V of gas adsorbed onto the solid to the volume
V
m
{\displaystyle V_{\text{m}}}
of a gas molecules monolayer covering the whole surface of the solid and completely occupied by the adsorbate. A continuous monolayer of adsorbate molecules covering a homogeneous flat solid surface is the conceptual basis for this adsorption model.
== Background and experiments ==
In 1916, Irving Langmuir presented his model for the adsorption of species onto simple surfaces. Langmuir was awarded the Nobel Prize in 1932 for his work concerning surface chemistry. He hypothesized that a given surface has a certain number of equivalent sites to which a species can "stick", either by physisorption or chemisorption. His theory began when he postulated that gaseous molecules do not rebound elastically from a surface, but are held by it in a similar way to groups of molecules in solid bodies.
Langmuir published two papers that confirmed the assumption that adsorbed films do not exceed one molecule in thickness. The first experiment involved observing electron emission from heated filaments in gases. The second, a more direct evidence, examined and measured the films of liquid onto an adsorbent surface layer. He also noted that generally the attractive strength between the surface and the first layer of adsorbed substance is much greater than the strength between the first and second layer. However, there are instances where the subsequent layers may condense given the right combination of temperature and pressure.
== Basic assumptions of the model ==
Inherent within this model, the following assumptions are valid specifically for the simplest case: the adsorption of a single adsorbate onto a series of equivalent sites onto the surface of the solid.
The surface containing the adsorbing sites is a perfectly flat plane with no corrugations (assume the surface is homogeneous). However, chemically heterogeneous surfaces can be considered to be homogeneous if the adsorbate is bound to only one type of functional groups on the surface.
The adsorbing gas adsorbs into an immobile state.
All sites are energetically equivalent, and the energy of adsorption is equal for all sites.
Each site can hold at most one molecule (mono-layer coverage only).
No (or ideal) interactions between adsorbate molecules on adjacent sites. When the interactions are ideal, the energy of side-to-side interactions is equal for all sites regardless of the surface occupancy.
== Derivations of the Langmuir adsorption isotherm ==
The mathematical expression of the Langmuir adsorption isotherm involving only one sorbing species can be demonstrated in different ways: the kinetics approach, the thermodynamics approach, and the statistical mechanics approach respectively. In case of two competing adsorbed species, the competitive adsorption model is required, while when a sorbed species dissociates into two distinct entities, the dissociative adsorption model need to be used.
=== Kinetic derivation ===
This section provides a kinetic derivation for a single-adsorbate case. The kinetic derivation applies to gas-phase adsorption. The multiple-adsorbate case is covered in the competitive adsorption sub-section.
The model assumes adsorption and desorption as being elementary processes, where the rate of adsorption rad and the rate of desorption rd are given by
r
ad
=
k
ad
p
A
[
S
]
,
{\displaystyle r_{\text{ad}}=k_{\text{ad}}p_{A}[S],}
r
d
=
k
d
[
A
ad
]
,
{\displaystyle r_{\text{d}}=k_{d}[A_{\text{ad}}],}
where pA is the partial pressure of A over the surface, [S] is the concentration of free sites in number/m2, [Aad] is the surface concentration of A in molecules/m2 (concentration of occupied sites), and kad and kd are constants of forward adsorption reaction and backward desorption reaction in the above reactions.
At equilibrium, the rate of adsorption equals the rate of desorption. Setting rad = rd and rearranging, we obtain
[
A
ad
]
p
A
[
S
]
=
k
ad
k
d
=
K
eq
A
.
{\displaystyle {\frac {[A_{\text{ad}}]}{p_{A}[S]}}={\frac {k_{\text{ad}}}{k_{\text{d}}}}=K_{\text{eq}}^{A}.}
The concentration of sites is given by dividing the total number of sites (S0) covering the whole surface by the area of the adsorbent (a):
[
S
0
]
=
S
0
/
a
.
{\displaystyle [S_{0}]=S_{0}/a.}
We can then calculate the concentration of all sites by summing the concentration of free sites [S] and occupied sites:
[
S
0
]
=
[
S
]
+
[
A
ad
]
.
{\displaystyle [S_{0}]=[S]+[A_{\text{ad}}].}
Combining this with the equilibrium equation, we get
[
S
0
]
=
[
A
ad
]
K
eq
A
p
A
+
[
A
ad
]
=
1
+
K
eq
A
p
A
K
eq
A
p
A
[
A
ad
]
.
{\displaystyle [S_{0}]={\frac {[A_{\text{ad}}]}{K_{\text{eq}}^{A}p_{A}}}+[A_{\text{ad}}]={\frac {1+K_{\text{eq}}^{A}p_{A}}{K_{\text{eq}}^{A}p_{A}}}[A_{\text{ad}}].}
We define now the fraction of the surface sites covered with A as
θ
A
=
[
A
ad
]
[
S
0
]
.
{\displaystyle \theta _{A}={\frac {[A_{\text{ad}}]}{[S_{0}]}}.}
This, applied to the previous equation that combined site balance and equilibrium, yields the Langmuir adsorption isotherm:
θ
A
=
K
eq
A
p
A
1
+
K
eq
A
p
A
.
{\displaystyle \theta _{A}={\frac {K_{\text{eq}}^{A}p_{A}}{1+K_{\text{eq}}^{A}p_{A}}}.}
=== Thermodynamic derivation ===
In condensed phases (solutions), adsorption to a solid surface is a competitive process between the solvent (A) and the solute (B) to occupy the binding site. The thermodynamic equilibrium is described as
Solvent (bound) + Solute (free) ↔ Solvent (free) + Solute (bound).
If we designate the solvent by the subscript "1" and the solute by "2", and the bound state by the superscript "s" (surface/bound) and the free state by the "b" (bulk solution / free), then the equilibrium constant can be written as a ratio between the activities of products over reactants:
K
=
a
1
b
×
a
2
s
a
2
b
×
a
1
s
.
{\displaystyle K={\frac {a_{1}^{\text{b}}\times a_{2}^{\text{s}}}{a_{2}^{\text{b}}\times a_{1}^{\text{s}}}}.}
For dilute solutions the activity of the solvent in bulk solution
a
1
b
≃
1
,
{\displaystyle a_{1}^{\text{b}}\simeq 1,}
and the activity coefficients (
γ
{\displaystyle \gamma }
) are also assumed to ideal on the surface. Thus,
a
2
s
=
X
2
s
=
θ
,
{\displaystyle a_{2}^{\text{s}}=X_{2}^{\text{s}}=\theta ,}
a
1
s
=
X
1
s
,
{\displaystyle a_{1}^{\text{s}}=X_{1}^{\text{s}},}
, and
X
1
s
+
X
2
s
=
1
,
{\displaystyle X_{1}^{\text{s}}+X_{2}^{\text{s}}=1,}
where
X
i
{\displaystyle X_{i}}
are mole fractions.
Re-writing the equilibrium constant and solving for
θ
{\displaystyle \theta }
yields
θ
=
K
a
2
b
1
+
K
a
2
b
.
{\displaystyle \theta ={\frac {Ka_{2}^{\text{b}}}{1+Ka_{2}^{\text{b}}}}.}
Note that the concentration of the solute adsorbate can be used instead of the activity coefficient. However, the equilibrium constant will no longer be dimensionless and will have units of reciprocal concentration instead. The difference between the kinetic and thermodynamic derivations of the Langmuir model is that the thermodynamic uses activities as a starting point while the kinetic derivation uses rates of reaction. The thermodynamic derivation allows for the activity coefficients of adsorbates in their bound and free states to be included. The thermodynamic derivation is usually referred to as the "Langmuir-like equation".
=== Statistical mechanical derivation ===
This derivation
based on statistical mechanics was originally provided by Volmer and Mahnert in 1925. The partition function of the finite number of adsorbents adsorbed on a surface, in a canonical ensemble, is given by
Z
(
N
A
)
=
[
ζ
L
N
A
N
S
!
(
N
S
−
N
A
)
!
]
1
N
A
!
,
{\displaystyle Z(N_{A})=\left[\zeta _{L}^{N_{A}}{\frac {N_{S}!}{(N_{S}-N_{A})!}}\right]{\frac {1}{N_{A}!}},}
where
ζ
L
{\displaystyle \zeta _{L}}
is the partition function of a single adsorbed molecule,
N
S
{\displaystyle N_{S}}
is the number of adsorption sites (both occupied and unoccupied), and
N
A
{\displaystyle N_{A}}
is the number of adsorbed molecules which should be less than or equal to
N
S
{\displaystyle N_{S}}
. The terms in the bracket give the total partition function of the
N
A
{\displaystyle N_{A}}
adsorbed molecules by taking a product of the individual partition functions (refer to Partition function of subsystems). The
1
/
N
A
!
{\displaystyle 1/N_{A}!}
factor accounts for the overcounting arising due to the indistinguishable nature of the adsorbates. The grand canonical partition function is given by
Z
(
μ
A
)
=
∑
N
A
=
0
N
S
exp
(
N
A
μ
A
k
B
T
)
ζ
L
N
A
N
A
!
N
S
!
(
N
S
−
N
A
)
!
.
{\displaystyle {\mathcal {Z}}(\mu _{A})=\sum _{N_{A}=0}^{N_{S}}\exp \left({\frac {N_{A}\mu _{A}}{k_{\text{B}}T}}\right){\frac {\zeta _{L}^{N_{A}}}{N_{A}!}}\,{\frac {N_{S}!}{(N_{S}-N_{A})!}}.}
μ
A
{\displaystyle \mu _{A}}
is the chemical potential of an adsorbed molecule. As it has the form of binomial series, the summation is reduced to
Z
(
μ
A
)
=
(
1
+
x
)
N
S
,
{\displaystyle {\mathcal {Z}}(\mu _{A})=(1+x)^{N_{S}},}
where
x
=
ζ
L
exp
(
μ
A
k
B
T
)
.
{\displaystyle x=\zeta _{L}\exp \left({\frac {\mu _{A}}{k_{\rm {B}}T}}\right).}
The grand canonical potential is
Ω
=
−
k
B
T
ln
(
Z
)
=
−
k
B
T
N
S
ln
(
1
+
x
)
,
{\displaystyle \Omega =-k_{\rm {B}}T\ln({\mathcal {Z}})=-k_{\rm {B}}TN_{S}\ln(1+x),}
based on which the average number of occupied sites is calculated
⟨
N
A
⟩
=
−
(
∂
Ω
∂
μ
A
)
T
,
area
,
{\displaystyle \langle N_{A}\rangle =-\left({\frac {\partial \Omega }{\partial \mu _{A}}}\right)_{T,{\text{area}}},}
which gives the coverage
θ
A
=
⟨
N
A
⟩
N
S
=
x
1
+
x
.
{\displaystyle \theta _{A}={\frac {\langle N_{A}\rangle }{N_{S}}}={\frac {x}{1+x}}.}
Now, invoking the condition that the system is in equilibrium, that is, the chemical potential of the adsorbed molecules is equal to that of the molecules in gas phase, we have
μ
A
=
μ
g
,
{\displaystyle \mu _{A}=\mu _{\text{g}},}
The chemical potential of an ideal gas is
μ
g
=
(
∂
A
g
∂
N
)
T
,
V
{\displaystyle \mu _{\text{g}}=\left({\frac {\partial A_{\text{g}}}{\partial N}}\right)_{T,V}}
where
A
g
=
−
k
B
T
ln
Z
g
{\displaystyle A_{g}=-k_{\rm {B}}T\ln Z_{g}}
is the Helmholtz free energy of an ideal gas with its partition function
Z
g
=
q
N
N
!
.
{\displaystyle Z_{g}={\frac {q^{N}}{N!}}.}
q
{\displaystyle q}
is the partition function of a single particle in the volume of
V
{\displaystyle V}
(only consider the translational freedom here).
q
=
V
(
2
π
m
k
B
T
h
2
)
3
/
2
.
{\displaystyle q=V\left({\frac {2\pi mk_{\rm {B}}T}{h^{2}}}\right)^{3/2}.}
We thus have
μ
g
=
−
k
B
T
ln
(
q
/
N
)
{\displaystyle \mu _{g}=-k_{\rm {B}}T\ln(q/N)}
, where we use Stirling's approximation.
Plugging
μ
g
{\displaystyle \mu _{g}}
to the expression of
x
{\displaystyle x}
, we have
θ
A
1
−
θ
A
=
x
=
ζ
L
N
q
{\displaystyle {\frac {\theta _{A}}{1-\theta _{A}}}=x=\zeta _{L}{\frac {N}{q}}}
which gives the coverage
θ
A
=
ζ
L
/
(
q
/
N
)
1
+
ζ
L
/
(
q
/
N
)
{\displaystyle \theta _{A}={\frac {\zeta _{L}/(q/N)}{1+\zeta _{L}/(q/N)}}}
By defining
P
0
=
k
B
T
ζ
L
(
2
π
m
k
B
T
h
2
)
3
/
2
{\displaystyle P_{0}={\frac {k_{\text{B}}T}{\zeta _{L}}}\left({\frac {2\pi mk_{\text{B}}T}{h^{2}}}\right)^{3/2}}
and using the identity
P
V
=
N
k
B
T
{\displaystyle PV=Nk_{\rm {B}}T}
, finally, we have
θ
A
=
P
P
+
P
0
.
{\displaystyle \theta _{A}={\frac {P}{P+P_{0}}}.}
It is plotted in the figure alongside demonstrating that the surface coverage increases quite rapidly with the partial pressure of the adsorbants, but levels off after P reaches P0.
=== Competitive adsorption ===
The previous derivations assumed that there is only one species, A, adsorbing onto the surface. This section considers the case when there are two distinct adsorbates present in the system. Consider two species A and B that compete for the same adsorption sites. The following hypotheses are made here:
All the sites are equivalent.
Each site can hold at most one molecule of A, or one molecule of B, but not both simultaneously.
There are no interactions between adsorbate molecules on adjacent sites.
As derived using kinetic considerations, the equilibrium constants for both A and B are given by
[
A
ad
]
p
A
[
S
]
=
K
eq
A
{\displaystyle {\frac {[A_{\text{ad}}]}{p_{A}\,[S]}}=K_{\text{eq}}^{A}}
and
[
B
ad
]
p
B
[
S
]
=
K
eq
B
.
{\displaystyle {\frac {[B_{\text{ad}}]}{p_{B}\,[S]}}=K_{\text{eq}}^{B}.}
The site balance states that the concentration of total sites [S0] is equal to the sum of free sites, sites occupied by A and sites occupied by B:
[
S
0
]
=
[
S
]
+
[
A
ad
]
+
[
B
ad
]
.
{\displaystyle [S_{0}]=[S]+[A_{\text{ad}}]+[B_{\text{ad}}].}
Inserting the equilibrium equations and rearranging in the same way we did for the single-species adsorption, we get similar expressions for both θA and θB:
θ
A
=
K
eq
A
p
A
1
+
K
eq
A
p
A
+
K
eq
B
p
B
,
{\displaystyle \theta _{A}={\frac {K_{\text{eq}}^{A}\,p_{A}}{1+K_{\text{eq}}^{A}\,p_{A}+K_{\text{eq}}^{B}\,p_{B}}},}
θ
B
=
K
eq
B
p
B
1
+
K
eq
A
p
A
+
K
eq
B
p
B
.
{\displaystyle \theta _{B}={\frac {K_{\text{eq}}^{B}\,p_{B}}{1+K_{\text{eq}}^{A}\,p_{A}+K_{\text{eq}}^{B}\,p_{B}}}.}
=== Dissociative adsorption ===
The other case of special importance is when a molecule D2 dissociates into two atoms upon adsorption. Here, the following assumptions would be held to be valid:
D2 completely dissociates to two molecules of D upon adsorption.
The D atoms adsorb onto distinct sites on the surface of the solid and then move around and equilibrate.
All sites are equivalent.
Each site can hold at most one atom of D.
There are no interactions between adsorbate molecules on adjacent sites.
Using similar kinetic considerations, we get
[
D
ad
]
p
D
2
1
/
2
[
S
]
=
K
eq
D
.
{\displaystyle {\frac {[D_{\text{ad}}]}{p_{D_{2}}^{1/2}[S]}}=K_{\text{eq}}^{D}.}
The 1/2 exponent on pD2 arises because one gas phase molecule produces two adsorbed species. Applying the site balance as done above,
θ
D
=
(
K
eq
D
p
D
2
)
1
/
2
1
+
(
K
eq
D
p
D
2
)
1
/
2
.
{\displaystyle \theta _{D}={\frac {(K_{\text{eq}}^{D}\,p_{D_{2}})^{1/2}}{1+(K_{\text{eq}}^{D}\,p_{D_{2}})^{1/2}}}.}
== Entropic considerations ==
The formation of Langmuir monolayers by adsorption onto a surface dramatically reduces the entropy of the molecular system.
To find the entropy decrease, we find the entropy of the molecule when in the adsorbed condition.
S
=
S
configurational
+
S
vibrational
,
{\displaystyle S=S_{\text{configurational}}+S_{\text{vibrational}},}
S
conf
=
k
B
ln
Ω
conf
,
{\displaystyle S_{\text{conf}}=k_{\rm {B}}\ln \Omega _{\text{conf}},}
Ω
conf
=
N
S
!
N
!
(
N
S
−
N
)
!
.
{\displaystyle \Omega _{\text{conf}}={\frac {N_{S}!}{N!(N_{S}-N)!}}.}
Using Stirling's approximation, we have
ln
N
!
≈
N
ln
N
−
N
,
{\displaystyle \ln N!\approx N\ln N-N,}
S
conf
/
k
B
≈
−
θ
A
ln
(
θ
A
)
−
(
1
−
θ
A
)
ln
(
1
−
θ
A
)
.
{\displaystyle S_{\text{conf}}/k_{\rm {B}}\approx -\theta _{A}\ln(\theta _{A})-(1-\theta _{A})\ln(1-\theta _{A}).}
On the other hand, the entropy of a molecule of an ideal gas is
S
gas
N
k
B
=
ln
(
k
B
T
P
λ
3
)
+
5
/
2
,
{\displaystyle {\frac {S_{\text{gas}}}{Nk_{\text{B}}}}=\ln \left({\frac {k_{\text{B}}T}{P\lambda ^{3}}}\right)+5/2,}
where
λ
{\displaystyle \lambda }
is the thermal de Broglie wavelength of the gas molecule.
== Limitations of the model ==
The Langmuir adsorption model deviates significantly in many cases, primarily because it fails to account for the surface roughness of the adsorbent. Rough inhomogeneous surfaces have multiple site types available for adsorption, with some parameters varying from site to site, such as the heat of adsorption. Moreover, specific surface area is a scale-dependent quantity, and no single true value exists for this parameter. Thus, the use of alternative probe molecules can often result in different obtained numerical values for surface area, rendering comparison problematic.
The model also ignores adsorbate–adsorbate interactions. Experimentally, there is clear evidence for adsorbate–adsorbate interactions in heat of adsorption data. There are two kinds of adsorbate–adsorbate interactions: direct interaction and indirect interaction. Direct interactions are between adjacent adsorbed molecules, which could make adsorbing near another adsorbate molecule more or less favorable and greatly affects high-coverage behavior. In indirect interactions, the adsorbate changes the surface around the adsorbed site, which in turn affects the adsorption of other adsorbate molecules nearby.
== Modifications ==
The modifications try to account for the points mentioned in above section like surface roughness, inhomogeneity, and adsorbate–adsorbate interactions.
=== Two-mechanism Langmuir-like equation (TMLLE) ===
Also known as the two-site Langmuir equation. This equation describes the adsorption of one adsorbate to two or more distinct types of adsorption sites. Each binding site can be described with its own Langmuir expression, as long as the adsorption at each binding site type is independent from the rest.
q
total
=
q
1
max
K
1
a
2
b
1
+
K
1
a
2
b
+
q
2
max
K
2
a
2
b
1
+
K
2
a
2
b
+
…
,
{\displaystyle q_{\text{total}}={\frac {q_{1}^{\text{max}}K_{1}a_{2}^{\text{b}}}{1+K_{1}a_{2}^{\text{b}}}}+{\frac {q_{2}^{\text{max}}K_{2}a_{2}^{\text{b}}}{1+K_{2}a_{2}^{\text{b}}}}+\dots ,}
where
q
total
{\displaystyle q_{\text{total}}}
– total amount adsorbed at a given adsorbate concentration,
q
1
max
{\displaystyle q_{1}^{\text{max}}}
– maximum capacity of site type 1,
q
2
max
{\displaystyle q_{2}^{\text{max}}}
– maximum capacity of site type 2,
K
1
{\displaystyle K_{1}}
– equilibrium (affinity) constant of site type 1,
K
2
{\displaystyle K_{2}}
– equilibrium (affinity) constant of site type 2,
a
2
b
{\displaystyle a_{2}^{\text{b}}}
– adsorbate activity in solution at equilibrium
This equation works well for adsorption of some drug molecules to activated carbon in which some adsorbate molecules interact with hydrogen bonding while others interact with a different part of the surface by hydrophobic interactions (hydrophobic effect). The equation was modified to account for the hydrophobic effect (also known as entropy-driven adsorption):
q
total
=
q
1
max
K
1
a
2
b
1
+
K
1
a
2
b
+
q
HB
.
{\displaystyle q_{\text{total}}={\frac {q_{1}^{\text{max}}K_{1}a_{2}^{\text{b}}}{1+K_{1}a_{2}^{\text{b}}}}+q_{\text{HB}}.}
The hydrophobic effect is independent of concentration, since
K
2
a
2
b
≫
1.
{\displaystyle K_{2}a_{2}^{\text{b}}\gg 1.}
Therefore, the capacity of the adsorbent for hydrophobic interactions
q
HB
{\displaystyle q_{\text{HB}}}
can obtained from fitting to experimental data. The entropy-driven adsorption originates from the restriction of translational motion of bulk water molecules by the adsorbate, which is alleviated upon adsorption.
=== Freundlich adsorption isotherm ===
The Freundlich isotherm is the most important multi-site adsorption isotherm for rough surfaces.
θ
A
=
α
F
p
C
F
,
{\displaystyle \theta _{A}=\alpha _{F}p^{C_{\text{F}}},}
where αF and CF are fitting parameters. This equation implies that if one makes a log–log plot of adsorption data, the data will fit a straight line. The Freundlich isotherm has two parameters, while Langmuir's equations has only one: as a result, it often fits the data on rough surfaces better than the Langmuir isotherm. However, the Freundlich equation is not unique; consequently, a good fit of the data points does not offer sufficient proof that the surface is heterogeneous. The heterogeneity of the surface can be confirmed with calorimetry. Homogeneous surfaces (or heterogeneous surfaces that exhibit homogeneous adsorption (single-site)) have a constant
Δ
H
{\displaystyle \Delta H}
of adsorption as a function of the occupied-sites fraction. On the other hand, heterogeneous adsorbents (multi-site) have a variable
Δ
H
{\displaystyle \Delta H}
of adsorption depending on the sites occupation. When the adsorbate pressure (or concentration) is low, the fractional occupation is small and as a result, only low-energy sites are occupied, since these are the most stable. As the pressure increases, the higher-energy sites become occupied, resulting in a smaller
Δ
H
{\displaystyle \Delta H}
of adsorption, given that adsorption is an exothermic process.
A related equation is the Toth equation. Rearranging the Langmuir equation, one can obtain
θ
A
=
p
A
1
K
eq
A
+
p
A
.
{\displaystyle \theta _{A}={\frac {p_{A}}{{\frac {1}{K_{\text{eq}}^{A}}}+p_{A}}}.}
J. Toth modified this equation by adding two parameters αT0 and CT0 to formulate the Toth equation:
θ
C
T
0
=
α
T
0
p
A
C
T
0
1
K
eq
A
+
p
A
C
T
0
.
{\displaystyle \theta ^{C_{T_{0}}}={\frac {\alpha _{T_{0}}p_{A}^{C_{T_{0}}}}{{\frac {1}{K_{\text{eq}}^{A}}}+p_{A}^{C_{T_{0}}}}}.}
=== Temkin adsorption isotherm ===
This isotherm takes into account indirect adsorbate–adsorbate interactions on adsorption isotherms. Temkin noted experimentally that heats of adsorption would more often decrease than increase with increasing coverage.
The heat of adsorption ΔHad is defined as
[
A
ad
]
p
A
[
S
]
=
K
eq
A
∝
e
−
Δ
G
ad
/
R
T
=
e
Δ
S
ad
/
R
e
−
Δ
H
ad
/
R
T
.
{\displaystyle {\frac {[A_{\text{ad}}]}{p_{A}[S]}}=K_{\text{eq}}^{A}\propto \mathrm {e} ^{-\Delta G_{\text{ad}}/RT}=\mathrm {e} ^{\Delta S_{\text{ad}}/R}\,\mathrm {e} ^{-\Delta H_{\text{ad}}/RT}.}
He derived a model assuming that as the surface is loaded up with adsorbate, the heat of adsorption of all the molecules in the layer would decrease linearly with coverage due to adsorbate–adsorbate interactions:
Δ
H
ad
=
Δ
H
ad
0
(
1
−
α
T
θ
)
,
{\displaystyle \Delta H_{\text{ad}}=\Delta H_{\text{ad}}^{0}(1-\alpha _{T}\theta ),}
where αT is a fitting parameter. Assuming the Langmuir adsorption isotherm still applied to the adsorbed layer,
K
eq
A
{\displaystyle K_{\text{eq}}^{A}}
is expected to vary with coverage as follows:
K
eq
A
=
K
eq
A
,
0
e
Δ
H
ad
0
(
1
−
α
T
θ
)
/
k
T
.
{\displaystyle K_{\text{eq}}^{A}=K_{\text{eq}}^{A,0}\mathrm {e} ^{\Delta H_{\text{ad}}^{0}(1-\alpha _{T}\theta )/kT}.}
Langmuir's isotherm can be rearranged to
K
eq
A
p
A
=
θ
1
−
θ
.
{\displaystyle K_{\text{eq}}^{A}p_{A}={\frac {\theta }{1-\theta }}.}
Substituting the expression of the equilibrium constant and taking the natural logarithm:
ln
(
K
eq
A
,
0
p
A
)
=
−
Δ
H
ad
0
α
T
θ
k
T
+
ln
θ
1
−
θ
.
{\displaystyle \ln {\big (}K_{\text{eq}}^{A,0}p_{A}{\big )}={\frac {-\Delta H_{\text{ad}}^{0}\alpha _{T}\theta }{kT}}+\ln {\frac {\theta }{1-\theta }}.}
=== BET equation ===
Brunauer, Emmett and Teller (BET) derived the first isotherm for multilayer adsorption. It assumes a random distribution of sites that are empty or that are covered with by one monolayer, two layers and so on, as illustrated alongside. The main equation of this model is
[
A
]
S
0
=
c
B
x
B
(
1
−
x
B
)
[
1
+
(
c
B
−
1
)
x
B
]
,
{\displaystyle {\frac {[A]}{S_{0}}}={\frac {c_{B}x_{B}}{(1-x_{B})[1+(c_{B}-1)x_{B}]}},}
where
x
B
=
p
A
K
m
,
c
B
=
K
1
K
m
,
{\displaystyle x_{B}=p_{A}K_{m},\quad c_{B}={\frac {K_{1}}{K_{m}}},}
and [A] is the total concentration of molecules on the surface, given by
[
A
]
=
∑
i
=
1
∞
i
[
A
]
i
=
∑
i
=
1
∞
i
K
1
K
m
i
−
1
p
A
i
[
A
]
0
,
{\displaystyle [A]=\sum _{i=1}^{\infty }i[A]_{i}=\sum _{i=1}^{\infty }iK_{1}K_{m}^{i-1}p_{A}^{i}[A]_{0},}
where
K
i
=
[
A
]
i
p
A
[
A
]
i
−
1
,
{\displaystyle K_{i}={\frac {[A]_{i}}{p_{A}[A]_{i-1}}},}
in which [A]0 is the number of bare sites, and [A]i is the number of surface sites covered by i molecules.
== Adsorption of a binary liquid on a solid ==
This section describes the surface coverage when the adsorbate is in liquid phase and is a binary mixture.
For ideal both phases[clarification needed] – no lateral interactions, homogeneous surface – the composition of a surface phase for a binary liquid system in contact with solid surface is given by a classic Everett isotherm equation (being a simple analogue of Langmuir equation), where the components are interchangeable (i.e. "1" may be exchanged to "2") without change of equation form:
x
1
s
=
K
x
1
l
1
+
(
K
−
1
)
x
1
l
,
{\displaystyle x_{1}^{s}={\frac {Kx_{1}^{l}}{1+(K-1)x_{1}^{l}}},}
where the normal definition of multi-component system is valid as follows:
∑
i
=
1
k
x
i
s
=
1
,
∑
i
=
1
k
x
i
l
=
1.
{\displaystyle \sum _{i=1}^{k}x_{i}^{s}=1,\quad \sum _{i=1}^{k}x_{i}^{l}=1.}
By simple rearrangement, we get
x
1
s
=
K
[
x
1
l
/
(
1
−
x
1
l
)
]
1
+
K
[
x
1
l
/
(
1
−
x
1
l
)
]
.
{\displaystyle x_{1}^{s}={\frac {K[x_{1}^{l}/(1-x_{1}^{l})]}{1+K[x_{1}^{l}/(1-x_{1}^{l})]}}.}
This equation describes competition of components "1" and "2".
== See also ==
Hill equation (biochemistry)
Michaelis–Menten kinetics (equation with the same mathematical form)
Monod equation (equation with the same mathematical form)
Reactions on surfaces
== References ==
The constitution and fundamental properties of solids and liquids. part i. solids. Irving Langmuir; J. Am. Chem. Soc. 38, 2221-95 1916
== External links ==
Langmuir isotherm from Queen Mary, University of London
LMMpro, Langmuir equation-fitting software | Wikipedia/Langmuir_adsorption_model |
The administration of drugs to whole populations irrespective of disease status is referred to as mass drug administration (MDA) or mass dispensing.
This article describes the administration of antimalarial drugs to whole populations, an intervention which has been used as a malaria-control measure for more than 70 years. Recent proposals to eliminate, or even to eradicate, malaria have led to a renewed interest in mass drug administrations in areas with very high malaria endemicity.
Drugs have been administered either directly as a full therapeutic course of treatment, or indirectly through the fortification of salt. Mass drug administrations were generally unsuccessful in interrupting transmission, but, in some cases, had a marked effect on parasite prevalence and on the incidence of clinical malaria. MDAs are likely to encourage the spread of drug-resistant parasites and so have only a limited role in malaria control. They may have a part to play in the management of epidemics and in the control of malaria in areas with a very short transmission season. In order to reduce the risk of spreading drug resistance, MDAs should use more than one drug and, preferably include a drug, such as an artemisinin, which has an effect on gametocytes. MDAs have low acceptance in areas with low malaria endemicity.
Another example of mass drug administration is mass deworming of children to remove helminth infections (intestinal worms).
== Background and history ==
Reports of attempts to control malaria through mass treatment with antimalarial drugs date back to at least 1932. In the 1950s, the WHO included mass drug administration (MDA) of antimalarial drugs as a tool for malaria eradication ‘in exceptional conditions when conventional control techniques have failed. In 1971, the WHO expert committee on malaria still recommended MDA in special circumstances. Subsequently, MDA was linked to the emergence of drug resistance and its overall benefit was questioned. Concomitantly, the goal of malaria eradication was replaced by one of prevention of malaria morbidity and mortality through the provision of effective treatment. Considering the short lasting benefit of mass drug administration. one modification has been to repeat mass drug administrations which has led to the development of intermittent preventive therapy.
== Methods ==
Two methods of mass drug treatment (MDA), direct and indirect, have been used. In direct MDA, a therapeutic dose of the antimalarial drug, usually in the form of tablets, is given to an entire population. In indirect MDA, the antimalarial drug is added to food, such as the fortification of salt.
=== Direct drug administration ===
The first, well documented use of direct MDA took place in a rubber plantation in Liberia in 1931. Two doses of the 8-aminoquinoline plasmoquine were given weekly to workers and their families in two camps. The prevalences of malaria parasite infections in humans and anopheline mosquitoes before and after treatment were studied. The authors concluded that "the fall in the mosquito infection rate of the two plasmoquine treated camps was so large as to indicate a local disappearance, or at least a great reduction, in gametocyte carriers in the treated population". No long-term follow up data were provided for this study or most of the trials reported subsequently. The next documented use of MDA in sub-Saharan Africa took place in 1948 and 1949 in tea estates in Kericho, Kenya. Ten thousand inhabitants of the tea estates received twice weekly proguanil from April to July 1948. The intervention was supplemented with DDT spraying in March and June of the following year. Before the intervention the mean malaria incidence in July, the peak of the malaria transmission season, was 56 cases per 1000 population. Following the intervention 4 malaria cases were detected in July 1949. The author therefore recommended continuation of twice weekly proguanil prophylaxis on the estates.
The Nandi district of Kenya was the scene of a large MDA in 1953 and 1954. The target population of 83,000 received a single dose of pyrimethamine at the beginning of the malaria season in 1953 and 1954. The coverage was estimated to be around 95%. Before the intervention severe malaria epidemics had been reported in the area. Following the intervention the parasite prevalence dropped from 23% to 2.3%. The author states that in a control area parasite prevalence rose over the same period to over 50%. It was felt that the MDA was effective in curbing severe malaria epidemics. In the following three years, 1955 to 1957, pyrimethamine administration was replaced with Dieldrin spraying to consolidate malaria control, which makes an assessment of the long-term effect of this MDA impossible.
During a pilot programme in Uganda in 1959 mass administration of chloroquine / pyrimethamine was combined with spraying of residual insecticides (DDT). The success of the pilot programme led to a larger study targeted at a population of 16,000. Because of logistic problems, only half of the target population received the first round of MDA. According to the investigators, the intervention resulted in the eradication of the vector and rapid elimination of malaria from the area.
Two large trials of MDA combined with household spraying with DDT were conducted in Cameroun and Upper Volta (Burkina Faso) in 1960–1961. In both trials, substantial reductions in the prevalence of parasitaemia were achieved but transmission was not interrupted. In Bobo-Dioulasso, where primaquine was used in combination with either chloroquine or amodiaquine, the prevalence of gametocytes and Anopheles gambiae sporozoites were reduced substantially. A MDA was also combined with DDT spraying in Zanzibar (Dola 1974). After the MDA, the parasite prevalence in children decreased, but the overall parasite prevalence increased slightly, thus failing to deplete the reservoir of infection.
Two trials in Northern Nigeria combined multiple rounds of MDA and insecticide spraying. The first trial, in Kankiya, included 11 rounds of MDA combined with 8 rounds of DDT indoor spraying. The study was based on computer-aided models that showed that MDA could eradicate malaria in the study area if combined with an appropriate 'insecticide attack'. Following MDAs, parasite prevalence dropped from 19% to 1%. The investigators did not consider this a success because parasite prevalence increased again after the interventions were stopped. Entomological indices also showed only a temporary reduction in transmission, which was completely reversed after the control measures ceased. Because the investigators felt that the failure of the trial to interrupt transmission was due to operational inadequacies, they recommended a much larger and more sophisticated evaluation of insecticide spraying combined with MDA. This recommendation helped to launch the Garki project, also in Northern Nigeria, in 1969. In the Garki project, all 164 study villages in the catchment area were sprayed with propoxur, a residual insecticide. In addition, in 60 villages, MDA with sulfalene / pyrimethamine was given at 10-week intervals for two years. In two small village clusters, house spraying was supplemented with larvicide and MDA every two weeks. With biweekly MDA, parasite prevalence fell to 1% in the dry season and to 5% in the rainy season. MDA given every 10 weeks resulted in a parasite prevalence of 2% in the dry season and 28% in the rainy season. Transmission was not interrupted with either MDA regime. The authors concluded that spraying of residual insecticides and MDA did not result in a sustainable interruption of malaria transmission.
In 1999 in The Gambia residents living in 33 of 42 villages in the catchment area received a single dose of sulfadoxine / pyrimethamine (SP) combined with artesunate while the residents of nine control villages received placebo. Following the MDA, 1388 children ≤10 years of age living in nine control villages and in nine matched villages which had been allocated active treatment were kept under surveillance for clinical malaria throughout the transmission season. Initially, during July and August, the mean malaria incidence rate in treated villages was significantly lower than in the control villages. In subsequent months, the incidence was slightly higher in the MDA villages. The difference between the two groups was not statistically significant. Overall no benefit of the mass drug administration was detected over the course of the malaria transmission season.
A mass drug administration campaign using S/P, artesunate and primaquine was completed in Moshi district, Tanzania in 2008. The findings have yet to be published.
Outside of sub-Saharan Africa one of the larger reported malaria-control projects using MDA took place in Nicaragua in 1981 following the overthrow of the Somoza regime. An estimated 70% of Nicaragua's total population (1.9 million people) received chloroquine and primaquine during the peak period of disease transmission (November). An estimated 9200 cases of malaria were prevented. The campaign had better results in preventing and curing malaria infections than in interrupting transmission. However, the mass administration of antimalarials was not sustainable and, as with other malaria-control efforts, collapsed following the return of politically conservative forces.
In three malaria-control projects conducted in the Indian states of Andhra Pradesh, Uttar Pradesh, and Orissa in the early 1960s, MDA had an ancillary role and was mentioned only briefly in reports on these interventions. More detailed information is available following a focal outbreak in two villages in Gujarat State during 1978–1979. Here a mass administration of chloroquine was part of a programme of intensified surveillance, case management, health education, and residual spraying. The incidence of malaria decreased so that, by the end of 1979, the authors considered the intervention to be a success. In 1980, in areas of Andhra Pradesh State in India, residual spraying was combined with a MDA. During the period of lowest malaria incidence a single dose of chloroquine plus primaquine was distributed to the whole population in eight villages. A second dose was given after an interval of 2–3 months. This project failed to reduce malaria incidence and was considered to be a failure.
In 1984, MDA was added to the distribution of insecticide-impregnated bed nets (ITNs) in Sabah (Malaysia), but this failed to interrupt malaria transmission. A MDA in Sumatra, Indonesia, in 1987 focused on schoolchildren. Eight months after the MDA, Plasmodium falciparum prevalence had decreased from 14% to 1%.
The only reported project with an MDA component which succeeded in permanently interrupting malaria transmission took place on the island of Aneityum, Vanuatu. Starting in September 1991, three malaria-control activities were employed – permethrin-impregnated bed nets, larvivorous fish and the administration of three antimalarials. This MDA comprised 300 mg chloroquine base and 45 mg pyrimethamine weekly for nine weeks. An additional 300 mg chloroquine and 75 mg pyrimethamine plus 1500 mg sulfadoxine was added to this regimen in the first, fifth, and ninth week. Children received an adjusted equivalent of the adult dose. Follow-up consisted of yearly parasite surveillance. During the seven surveillance years following the MDA, no P.falciparum infections were detected.
MDA is included in the malaria-control policy of the People's Republic of China. Following the first malaria-control phase from 1955 to 1962, which was mostly focused on malaria surveys, mass administrations were added to vector control measures and improved case management in 10 of China's 33 provinces. The drugs used in the administrations, mostly chloroquine and piperaquine, were provided free of charge by the central government. The economic reforms instituted by Deng Xiaoping, which ultimately put an end to the provision of free health care through the central government and the emergence of resistance against the most widely used antimalarials modified the use of mass drug administrations after 1980. MDAs are now targeted at high-risk populations, specifically non-immune migratory workers who receive repeated courses during the high transmission season. According to government guidelines, piperaquine, chloroquine, or sulfadoxine combined with primaquine can be used for mass administrations. The artemisinin derivatives are not used in mass drug administrations and are reserved for treatment failures. Malaria burden and control measures are shown in Table 1. Between 1990 and 2000 the malaria prevalence dropped from 10.6 to 1.9 / 100,000, the number of reported malaria cases dropped from 117,359 to 24,088 while the number of reported deaths attributable to malaria remained stable. These data, reported to the national government, depend on reporting from health care providers and like all data depending on passive surveillance tend to underestimate the true disease burden. However, there is no reason to think that the level of underreporting has changed over the last decade. Therefore, the proportional reduction in malaria disease burden is likely to be true. Malaria-control measures, including MDA, as well as major ecologic changes during the second half of the last century are likely to have been responsible for the more than 100-fold reduction in malaria burden in China since the initial surveys in 1955. The widespread use of antimalarials has been followed by the emergence of drug resistance especially in regions with high drug use. By 1995 more than 95% of P.falciparum strains isolated in the South of Yunnan province were found to be resistant to chloroquine, and piperaquine while in the remainder of Yunnan and Hainan province the resistance rates were 85%and 38% respectively.
=== Indirect MDA ===
A different approach to MDA consists of adding an antimalarial to an essential foodstuff, usually salt. Chloroquinized salt for malaria suppression was introduced by Pinotti in 1952 and gave promising results in a number of field trials and malaria-control programmes in Brazil.
In 1959, the WHO conducted a trial in West New Guinea (later known as Irian Jaya). Salt crystals were mixed with pyrimethamine so as to provide a 0.07% pyrimethamine salt. As there were no shops in the catchment area, each family unit received fortnightly a quantity of salt from the local teacher or another member of the village community. Within three and a half months of the onset of the campaign, clinically significant levels of pyrimethamine resistance were reported. It was then decided to mix the remaining stock of pyrimethaminized salt with chloroquine powder. The chloroquine base content was 0.04% or 140 mg per adult per week based on a 5 g per day salt consumption. The emergence of chloroquine resistance was investigated, but this was not detected. The distribution of medicated salts otherwise had no effect and it was concluded that "Pinotti's method holds no prospect of malaria eradication...". The explanation for this finding given by the author is that "the salt consumption by children was too small to reduce significantly the parasite reservoir of the younger age groups".
Between 1961 and 1965, the use of chloroquinized salt was made compulsory over an area of 109,000 km2 (42,000 sq mi) in Guyana, covering a population of 48,500 individuals. The chloroquinized salt was prepared at a state salt plant so as to provide a 0.43% chloroquine concentration. The salt was sold in two pound plastic bags. The state held the monopoly for the salt. The only alternative source was salt smuggled from Brazil. Although the chloroquinized salt was used, its popularity was limited by the occurrence of a photo-allergic dermatitis popularly called 'salt itch' noted in all treatment areas. Chloroquine resistance was first observed in 1962 in the area with the lowest relative uptake of chloroquinized salt. In the course of the following months, a complete replacement of the susceptible strains with resistant P. falciparum strains was observed. Following the reintroduction of DDT spraying, the prevalence of P. falciparum declined.
In Southeast Asia, the medicated salt project at Pailin, on the Kampuchea–Thai border, demonstrated how drug resistance can develop when a large population of P. falciparum undergoing high transmission rates is exposed to intense drug pressure. The project was launched in 1960 and covered a population of approximately 20,000. Sea salt was mixed with pyrimethamine at a concentration of 0.05%. Between 1960 and 1961, 77 tons of medicated salt were distributed in the area. After widespread pyrimethamine resistance was reported, pyrimethamine was replaced by chloroquine. From 1961 to 1962, 75 tons of chloroquine were distributed. In two indicator districts, the parasite rates decreased from 40% to 7% and from 27% to 14%. Chloroquine resistant P. falciparum isolates were first detected in Pailin in 1962 which appeared to be widespread by 1966. However no survey was undertaken to document the prevalence in the area. The factors leading to the emergence and spread of drug resistance appear to have been the continuous introduction of non-immune migrants, attracted by the promise of quick wealth from mining of precious stones, and prolonged drug pressure resulting from individual drug consumption and mass drug administration. Unrelated to MDAs the emergence of artemisinin resistant P. falciparum strains was reported in Pailin in 2008, this may have been related to overuse of artemisinin derivatives including counterfeit drugs but was not related to programmatic MDAs.
Further malaria-control projects have used MDA, but have never been published, or have been published as technical reports.
== Assessing effectiveness ==
Whether MDAs can be considered successful or not depends on the expectation of what they might achieve; many studies do not define whether their main aim was to interrupt transmission or to control disease. When MDAs were used as part of an attempt to interrupt transmission completely, they almost always failed. Only one project, conducted on Aneityum, a small isolated island in the Pacific, succeeded in permanently interrupting transmission using MDA as one of several malaria-control strategies. However, although unable to interrupt transmission, many MDA projects led to a marked reduction in parasite prevalence and probably had a marked also transient effect on malaria-related morbidity and mortality. Most of the early trials used study designs which would now be considered inadequate to provide a definitive answer on study outcome. For example, before-and-after comparisons were used frequently. Such comparisons are especially unreliable for vector-borne diseases which may show marked variations in incidence from season to season as well as from year to year. Furthermore, in several studies only a single intervention and control area or group were compared despite the fact a single control group cannot provide statistically interpretable results (see n = 1 fallacy).
The deficiencies in the study designs mentioned above reflect the evolution of research methodology over the last 50 years. The evaluation of an intervention such as MDA is complicated by the fact that the effect of the intervention on transmission can only be measured at the community and not at the individual level. Trial methods which use a community, a village, or a cluster as unit of inference have taken longer to evolve than those used for individually randomized trials. There are, with some notable exceptions, few properly designed and analysed cluster randomized trials conducted by health care researchers prior to 1978. One major handicap for researchers who need to use the cluster approach, besides the need for a large sample size, is the need to use statistical methods that differ from the familiar methods used in individually randomized trials. Significant progress has been made in the development of statistical methods for the analysis of correlated data.
== MDA and drug resistance ==
The present unpopularity of MDA is not only due to doubts regarding the health benefit of this intervention but to the fear that MDAs will facilitate the spread of drug resistance. Concern that MDA would cause pyrimethamine and later chloroquine resistance was first raised in the early 1960s. Circumstantial evidence linked the use of medicated salts to the emergence of chloroquine resistance in the 1980s: Chloroquine resistance emerged first in three foci, namely South America (Colombia, Venezuela, Brazil), Southeast Asia (Thailand/Kampuchea), and Africa (Tanzania/Kenya). Payne has argued that the one common factor between these three epidemiologically diverse areas was widespread distribution of medicated salts prior to the emergence of chloroquine resistance.
In contrast to indirect MDA, emergence of drug resistance has not been linked to the administration of therapeutic doses of antimalarials through direct MDA programmes. The likely explanation lies in the different pharmacokinetic profiles that result from these two methods of drug administration. The administration of therapeutically dosed antimalarial drugs results in a single peak drug level which kills all susceptible strains. Only during the terminal half life of the drug when the concentration drops below the Cmin, the inhibitory concentration which kills the large majority of a parasite population, will new infections with more resistant strains have a survival advantage. Thus drugs with a very short terminal half-life, including artemisinin derivatives, carry a lower risk of selecting resistant parasites than longer acting drugs. In contrast, the administration of medicated salts is likely to result in drug levels undulating in the sub-lethal range, which reach a steady state after several doses have been administered. The situation is worse if drugs such as chloroquine are used which accumulate progressively. This situation, a steady increase in drug concentration, is identical to the experimental design used for the in vitro induction of drug resistance. Medicated salt projects can be considered as large scale in vivo experiments designed to select resistant parasites.
== MDA and drug toxicity ==
The administration of antimalarials to large numbers of individuals with little or no preliminary screening could result in significant toxicity as nearly all antimalarials in common use can occasionally cause serious adverse events. For example, the widespread use of 8-aminoquinolines in areas where glucose-6-phosphate dehydrogenase deficiency is common carries the risk of precipitating episodes of haemolysis. Few MDA projects have reported specifically on adverse events. No life-threatening outcomes have been reported as a result of an MDA but a rare serious adverse event such as a blood dyscrasia would probably not have been detected without active surveillance for adverse events which was not reported in any of the studies. There is a theoretical risk that administration of antimalarial drugs during the course of MDAs to women in the first trimester of pregnancy, some of whom may not know that they are pregnant, could lead to foetal abnormalities. The benefit of malaria control has to be weighed against potential problems. Hence MDA is likely to be only used in areas with very high malaria endemicity.
== See also ==
Mass deworming
Premunity
== References == | Wikipedia/Mass_drug_administration |
Fecal microbiota transplant (FMT), also known as a stool transplant, is the process of transferring fecal bacteria and other microbes from a healthy individual into another individual. FMT is an effective treatment for Clostridioides difficile infection (CDI). For recurrent CDI, FMT is more effective than vancomycin alone, and may improve the outcome after the first index infection.
Side effects include a risk of infections, therefore the donor should be screened for pathogens.
With CDI becoming more common, FMT is gaining prominence. Some experts call for it to become the first-line therapy for CDI. FMT has been used experimentally to treat other gastrointestinal diseases, including colitis, constipation, irritable bowel syndrome, and neurological conditions, such as multiple sclerosis and Parkinson's. In the United States, human feces have been regulated as an experimental drug since 2013. In the United Kingdom, FMT regulation is under the remit of the Medicines and Healthcare products Regulatory Agency.
== Medical uses ==
=== Clostridioides difficile infection ===
Fecal microbiota transplant is approximately 85–90% effective in people with CDI for whom antibiotics have not worked or in whom the disease recurs following antibiotics. Most patients recover with a single FMT treatment.
A 2009 study found that FMT was an effective and simple procedure that was more cost-effective than continued antibiotic administration and reduced the incidence of antibiotic resistance.
Once considered to be a "last resort therapy" by some medical professionals, due to its unusual nature and invasiveness compared with antibiotics, perceived potential risk of infection transmission, and lack of Medicare coverage for donor stool, position statements by specialists in infectious diseases and other societies have moved toward acceptance as a standard therapy for relapsing CDI and toward US Medicare.
It has been recommended that endoscopic FMT be elevated to first-line treatment for people with deterioration and severe relapsing C. difficile infection.
In November 2022, FMT (Biomictra) was approved for medical use in Australia, and fecal microbiota, live (Rebyota) was approved for medical use in the United States.
Fecal microbiota spores, live (Vowst) was approved for medical use in the United States in April 2023. It is the first fecal microbiota product that is taken by mouth.
=== Other conditions ===
==== Ulcerative colitis ====
In May 1988, Australian professor Thomas Borody treated the first ulcerative colitis patient using FMT, which led to longstanding symptom resolution. Following on from that, Justin D. Bennet published the first case report documenting reversal of Bennet's own colitis using FMT. While C. difficile is easily eradicated with a single FMT infusion, this generally appears to not be the case with ulcerative colitis. Published experience of ulcerative colitis treatment with FMT largely shows that multiple and recurrent infusions are required to achieve prolonged remission or cure.
==== Cancer ====
Clinical trials are underway to evaluate if FMT from anti-PD-1 immunotherapy donors can promote a therapeutic response in immunotherapy-refractory patients.
==== Autism ====
Once linked with naturopathy, there have been serious studies into treating Autism Spectrum Disorder with fecal microbiota transplants. One such study was conducted in Shanghai, China, and an earlier study led by Arizona State University. The Arizona treatment has received a United States Patent (#11,202,808) though the researchers stress the need for further research due to the small sample size and open-label nature of their research.
==== Fibromyalgia and IBS ====
A 2024 review found that fecal microbiota transplantation may reduce pain intensity and improve fatigue and quality of life in patients with fibromyalgia and irritable bowel syndrome.
== Adverse effects ==
Adverse effects were poorly understood as of 2016. They have included bacterial blood infections, fever, SIRS-like syndrome, exacerbation of inflammatory bowel disease in people who also had that condition, and mild GI distress which generally resolve themselves soon after the procedure, including flatulence, diarrhea, irregular bowel movements, abdominal distension/bloating, abdominal pain/tenderness, constipation, cramping, and nausea. There are also concerns that it may spread COVID-19.
A person died in the United States in 2019, after receiving an FMT that contained drug-resistant bacteria, and another person who received the same transplant was also infected. The US Food and Drug Administration (FDA) issued a warning against potentially life-threatening consequences of transplanting material from improperly screened donors.
== Technique ==
There are evidence-based consensus guidelines for the optimal administration of FMT. Such documents outline the FMT procedure, including preparation of material, donor selection and screening, and FMT administration.
The gut microbiota comprises all microorganisms that reside along the gastrointestinal tract, including commensal, symbiotic and pathogenic organisms. FMT is the transfer of fecal material containing bacteria and natural antibacterials from a healthy individual into a diseased recipient.
=== Donor selection ===
Preparing for the procedure requires careful selection and screening of the potential donor. Close relatives are often chosen on account of ease of screening; however, in the case of treatment of active C. diff., family members and intimate contacts may be more prone to be carriers themselves. This screening involves medical history questionnaires, screening for various chronic medical diseases (e.g. irritable bowel diseases, Crohn's disease, gastrointestinal cancer, etc.), and laboratory testing for pathogenic gastrointestinal infections (e.g. CMV, C. diff., salmonella, Giardia, GI parasites, etc.).
=== Specimen preparation ===
No laboratory standards have been agreed upon, so recommendations vary for size of sample to be prepared, ranging from 30 to 100 grams (1.1 to 3.5 ounces) of fecal material for effective treatment. Fresh stool is used to increase viability of bacteria within the stool and samples are prepared within 6–8 hours. The sample is then diluted with 2.5–5 times the volume of the sample with either normal saline, sterile water, or 4% milk. Some locations mix the sample and the solvent with a mortar and pestle, and others use a blender. There is concern with blender use on account of the introduction of air which may decrease efficacy as well as aerosolization of the feces contaminating the preparation area. The suspension is then strained through a filter and transferred to an administration container. If the suspension is to be used later, it can be frozen after being diluted with 10% glycerol, and used without loss of efficacy compared to the fresh sample. The fecal transplant material is then prepared and administered in a clinical environment to ensure that precautions are taken.
=== Administration ===
After being made into suspensions, the fecal material can be given through nasogastric and nasoduodenal tubes, or through a colonoscope or as a retention enema.
== Mechanism of action ==
One hypothesis behind fecal microbiota transplant rests on the concept of bacterial interference, i.e., using harmless bacteria to displace pathogenic organisms, such as by competitive niche exclusion. In the case of CDI, the C. difficile pathogen is identifiable. Recently, in a pilot study of five patients, sterile fecal filtrate was demonstrated to be of comparable efficacy to conventional FMT in the treatment of recurrent CDI. The conclusion from this study was that soluble filtrate components (such as bacteriophages, metabolites, and/or bacterial components, such as enzymes) may be the key mediators of FMT's efficacy, rather than intact bacteria. It has now been demonstrated that the short-chain fatty acid valerate is restored in human fecal samples from CDI patients and a bioreactor model of recurrent CDI by FMT, but not by antibiotic cessation alone; as such, this may be a key mediator of FMT's efficacy. Other studies have identified rapid-onset but well-maintained changes in the gut bacteriophage profile after successful FMT (with colonisation of the recipient with donor bacteriophages), and this is therefore another key area of interest.
In contrast, in the case of other conditions such as ulcerative colitis, no single culprit has yet been identified. However, analysis of gut microbiome and metabolome changes after FMT as treatment for ulcerative colitis has identified some possible candidates of interest.
== History ==
The first use of donor feces as a therapeutic agent for food poisoning and diarrhea was recorded in the Handbook of Emergency Medicine by a Chinese man, Hong Ge, in the 4th century. Twelve hundred years later Ming dynasty physician Li Shizhen used "yellow soup" (aka "golden syrup") which contained fresh, dry or fermented stool to treat abdominal diseases. "Yellow soup" was made of fecal matter and water, which was drunk by the person.
The consumption of "fresh, warm camel feces" has also been recommended by Bedouins as a remedy for bacterial dysentery; its efficacy, probably attributable to the antimicrobial subtilisin produced by Bacillus subtilis, was anecdotally confirmed by German soldiers of the Afrika Korps during World War II. However, this story is likely a myth; independent research was not able to verify any of these claims.
The first use of FMT in western medicine was published in 1958 by Ben Eiseman and colleagues, a team of surgeons from Colorado, who treated four critically ill people with fulminant pseudomembranous colitis (before C. difficile was the known cause) using fecal enemas, which resulted in a rapid return to health. For over two decades, FMT has been provided as a treatment option at the Centre for Digestive Diseases in Five Dock, by Thomas Borody, the modern-day proponent of FMT. In May 1988 their group treated the first ulcerative colitis patient using FMT, which resulted in complete resolution of all signs and symptoms long term. In 1989 they treated a total of 55 patients with constipation, diarrhea, abdominal pain, ulcerative colitis, and Crohn's disease with FMT. After FMT, 20 patients were considered "cured" and a further 9 patients had a reduction in symptoms. Stool transplants are considered about 90 percent effective in those with severe cases of C. difficile colonization, in whom antibiotics have not worked.
The first randomized controlled trial in C. difficile infection was published in January 2013. The study was stopped early due to the effectiveness of FMT, with 81% of patients achieving cure after a single infusion and over 90% achieving a cure after a second infusion.
Since that time various institutions have offered FMT as a therapeutic option for a variety of conditions.
== Society and culture ==
=== Regulation ===
Interest in FMT grew in 2012 and 2013, as measured by the number of clinical trials and scientific publications.
In the United States, the FDA announced in February 2013 that it would hold a public meeting entitled "Fecal Microbiota for Transplantation" which was held on May 2–3, 2013. In May 2013 the FDA also announced that it had been regulating human fecal material as a drug. The American Gastroenterological Association (AGA), the American College of Gastroenterology (ACG), the American Society for Gastrointestinal Endoscopy (ASGE), and the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN) sought clarification, and the FDA Center for Biologics Evaluation and Research (CBER) stated that FMT falls within the definition of a biological product as defined in the Public Health Service Act and the definition of a drug within the meaning of the Federal Food, Drug, and Cosmetic Act. It argued since FMT is used to prevent, treat, or cure a disease or condition, and intended to affect the structure or any function of the body, "a product for such use" would require an Investigational New Drug (IND) application.
In July 2013, the FDA issued an enforcement policy ("guidance") regarding the IND requirement for using FMT to treat C. difficile infection unresponsive to standard therapies (78 FR 42965, July 18, 2013).
In March 2014, the FDA issued a proposed update (called "draft guidance") that, when finalized, is intended to supersede the July 2013 enforcement policy for FMT to treat C. difficile infections unresponsive to standard therapies. It proposed an interim discretionary enforcement period, if 1) informed consent is used, mentioning investigational aspect and risks, 2) stool donor is known to either the person with the condition or physician, and 3) stool donor and stool are screened and tested under the direction of the physician (79 FR 10814, February 26, 2014). Some doctors and people who want to use FMT have been worried that the proposal, if finalized, would shutter the handful of stool banks which have sprung up, using anonymous donors and ship to providers hundreds of miles away.
As of 2015, FMT for recurrent C. difficile infections can be done without mandatory donor and stool screening, whereas FMT for other indications cannot be performed without an IND.
The FDA has issued three safety alerts regarding the transmission of pathogens. The first safety alert, issued in June 2019, described the transmission of a multidrug resistant organism from a donor stool that resulted in the death of one person. The second safety alert, issued in March 2020, was regarding FMT produced from improperly tested donor stools from a stool bank which resulted in several hospitalizations and two deaths. A safety alert in late March 2020, was due to concerns of transmission of COVID-19 in donor stool.
In November 2022, the Australian Therapeutic Goods Administration approved faecal microbiota under the brand name Biomictra, and the US FDA approved a specific C. difficile fecal microbiota treatment under the brand name Rebyota, administered rectally. In April 2023, the FDA approved a live spore capsule that can be taken by mouth, under the brand name Vowst.
=== Stool banks ===
In 2012, a team of researchers from the Massachusetts Institute of Technology founded OpenBiome, the first public stool bank in the United States.
Across Europe, numerous stool banks have emerged to serve the increasing demand. While consensus exists, standard operation procedures still differ. Institutions in the Netherlands have published their protocols for managing FMT, and in Denmark institutions manages FMT according to the European Tissue and Cell directive.
=== Names ===
Previous terms for the procedure include fecal bacteriotherapy, fecal transfusion, fecal transplant, stool transplant, fecal enema, and human probiotic infusion (HPI). Because the procedure involves the complete restoration of the entire fecal microbiota, not just a single agent or combination of agents, these terms have been replaced by the term fecal microbiota transplantation.
== Research ==
Cultured intestinal bacteria are being studied as an alternative to fecal microbiota transplant. One example is the rectal bacteriotherapy (RBT), developed by Tvede and Helms, containing 12 individually cultured strains of anaerobic and aerobic bacteria originating from healthy human faeces. Research has also been done to identify the most relevant microbes within fecal transplants, which could then be isolated and manufactured via industrial fermentation; such standardized products would be more scalable, would reduce the risk of infections from unwanted microbes, and would improve the scientific study of the approach, since the same substance would be administered each time.
== Veterinary use ==
Elephants, hippos, koalas, and pandas are born with sterile intestines, and to digest vegetation need bacteria which they obtain by eating their mothers' feces, a practice termed coprophagia. Other animals eat dung.
In veterinary medicine fecal microbiota transplant has been known as "transfaunation" and is used to treat ruminating animals, like cows and sheep, by feeding rumen contents of a healthy animal to another individual of the same species in order to colonize its gastrointestinal tract with normal bacteria.
== References ==
== Further reading ==
Bibbò S, Ianiro G, Gasbarrini A, Cammarota G (December 2017). "Fecal microbiota transplantation: past, present and future perspectives". Minerva Gastroenterologica e Dietologica. 63 (4): 420–430. doi:10.23736/S1121-421X.17.02374-1. PMID 28927251.
El-Salhy M, Patcharatrakul T, Gonlachanvit S (June 2021). "Fecal microbiota transplantation for irritable bowel syndrome: An intervention for the 21st century". World Journal of Gastroenterology. 27 (22): 2921–2943. doi:10.3748/wjg.v27.i22.2921. PMC 8192290. PMID 34168399. | Wikipedia/Fecal_bacteriotherapy |
Penicillin-binding proteins (PBPs) are a group of proteins that are characterized by their affinity for and binding of penicillin. They are a normal constituent of many bacteria; the name just reflects the way by which the protein was discovered. All β-lactam antibiotics (except for tabtoxinine-β-lactam, which inhibits glutamine synthetase) bind to PBPs, which are essential for bacterial cell wall synthesis. PBPs are members of a subgroup of transpeptidase enzymes called DD-transpeptidases.
== Diversity ==
There are a large number of PBPs, usually several in each organism, and they are found as both membrane-bound and cytoplasmic proteins. For example, Spratt (1977) reports that six different PBPs are routinely detected in all strains of E. coli ranging in molecular weight from 40,000 to 91,000. The different PBPs occur in different numbers per cell and have varied affinities for penicillin. The PBPs are usually broadly classified into high-molecular-weight (HMW) and low-molecular-weight (LMW) categories. High Molecular Mass (HMM) PBP’s are essential for cell viability and they are divided between two classes. Class A enzymes catalyze both the polymerization of a peptidoglycan from disaccharide peptides (glycosyltransferase) and the cross-linking of muramyl peptides (transpeptidase). On the other hand, class B enzymes possess transpeptidase activity (only cross linking). Low Molecular-Mass (LMM) PBP’s are dispensable for normal cell growth and control how tightly the peptidoglycan chains are linked together. Proteins that have evolved from PBPs occur in many higher organisms and include the mammalian LACTB protein.
== Function ==
PBPs are all involved in the final stages of the synthesis of peptidoglycan, which is the major component of bacterial cell walls. Bacterial cell wall synthesis is essential to growth, cell division (thus reproduction) and maintaining the cellular structure in bacteria. Inhibition of PBPs leads to defects in cell wall structure and irregularities in cell shape, for example filamentation, pseudomulticellular forms, lesions leading to spheroplast formation, and eventual cell death and lysis.
PBPs have been shown to catalyze a number of reactions involved in the process of synthesizing cross-linked peptidoglycan from lipid intermediates and mediating the removal of D-alanine from the precursor of peptidoglycan. Purified enzymes have been shown to catalyze the following reactions: D-alanine carboxypeptidase, peptidoglycan transpeptidase, and peptidoglycan endopeptidase. In all bacteria that have been studied, enzymes have been shown to catalyze more than one of the above reactions. The enzyme has a penicillin-insensitive transglycosylase N-terminal domain (involved in formation of linear glycan strands) and a penicillin-sensitive transpeptidase C-terminal domain (involved in cross-linking of the peptide subunits) and the serine at the active site is conserved in all members of the PBP family.
Some low-molecular-weight PBPs associate with the MreB cytoskeleton and follow its rotation around the cell, inserting petipdoglycan in an oriented manner during cell growth. In contrast, high-molecular-weight PBPs are independent from MreB and maintain cell wall integrity by detecting and repairing defects in the peptidoglycan.
== Antibiotics ==
PBPs bind to β-lactam antibiotics because they are similar in chemical structure to the modular pieces that form the peptidoglycan. When they bind to penicillin, the β-lactam amide bond is ruptured to form a covalent bond with the catalytic serine residue at the PBPs active site. This is an irreversible reaction and inactivates the enzyme.
There has been a great deal of research into PBPs because of their role in antibiotics and resistance. Bacterial cell wall synthesis and the role of PBPs in its synthesis is a very good target for drugs of selective toxicity because the metabolic pathways and enzymes are unique to bacteria. Resistance to antibiotics has come about through overproduction of PBPs and formation of PBPs that have low affinity for penicillins (among other mechanisms such as lactamase production). These experiments change the structure of PBP by adding different amino acids into the protein, allowing for new discovery of how the drug interacts with the protein. Research on PBPs has led to the discovery of new semi-synthetic β-lactams, wherein altering the side-chains on the original penicillin molecule has increased the affinity of PBPs for penicillin, and, thus, increased effectiveness in bacteria with developing resistance.
Presence of the protein penicillin binding protein 2A (PBP2A) is responsible for the antibiotic resistance seen in methicillin-resistant Staphylococcus aureus (MRSA).
The β-lactam ring is a structure common to all β-lactam antibiotics.
== Structure of Penicillin Binding Protein 3 ==
Penicillin binding protein 3 is important for bacteria wall synthesis and is a main target in β-lactam antibiotics. It is a two-domain protein containing a C-terminal transpeptidase linked to an extended N-terminal domain. This protein is similar to other class B PBP’s since it contains an α-helical subdomain or “head” domain towards the N-terminus. The N-terminal domain’s function is still not known but it is thought it serves to position the transpeptidase domain away from the inner membrane as part of a multienzyme complex involved in cell wall biosynthesis.
== Active Site of Penicillin Binding Protein 3 and a β-lactam (carbenicillin) ==
The active site is located in a long cleft running parallel with the 3 strand across the lower part of the transpeptidase domain. When carbenicillin binds to penicillin binding protein 3, it forms an acyl-enzyme complex which means the β-lactam is chemically attached to PBP3. The β-lactams are covalently bound to S294 which inactivates the enzyme. Also, the N-terminal end of PBP3 is more flexible, however, the C-terminal part, which contains the enzyme’s active site, is very stable and does not change much. The binding of carbenicillin to the active site increases the enzymes thermostability with conformational changes. The first carboxylate group in carbenicillin forms hydrogen bonding interactions with S485, T487, and N351. These hydrogen bonding interactions help stabilize the binding between carbenicillin and PBP 3.
== Other images ==
== See also ==
PASTA domain
== References == | Wikipedia/Penicillin-binding_protein |
Sulfonamide is a functional group (a part of a molecule) that is the basis of several groups of drugs, which are called sulphonamides, sulfa drugs or sulpha drugs. The original antibacterial sulfonamides are synthetic antimicrobial agents that contain the sulfonamide group. Some sulfonamides are also devoid of antibacterial activity, e.g., the anticonvulsant sultiame. The sulfonylureas and thiazide diuretics are newer drug groups based upon the antibacterial sulfonamides.
Allergies to sulfonamides are common. The overall incidence of adverse drug reactions to sulfa antibiotics is approximately 3%, close to penicillin; hence medications containing sulfonamides are prescribed carefully.
Sulfonamide drugs were the first broadly effective antibacterials to be used systemically, and paved the way for the antibiotic revolution in medicine.
== Function ==
In bacteria, antibacterial sulfonamides act as competitive inhibitors of the enzyme dihydropteroate synthase (DHPS), an enzyme involved in folate synthesis. Sulfonamides are therefore bacteriostatic and inhibit growth and multiplication of bacteria, but do not kill them. Humans, in contrast to bacteria, acquire folate (vitamin B9) through the diet.
Sulfonamides are used to treat allergies and coughs, as well as having antifungal and antimalarial functions. The moiety is also present in other medications that are not antimicrobials, including thiazide diuretics (including hydrochlorothiazide, metolazone, and indapamide, among others), loop diuretics (including furosemide, bumetanide, and torsemide), acetazolamide, sulfonylureas (including glipizide, glyburide, among others), and some COX-2 inhibitors (e.g., celecoxib).
Sulfasalazine, in addition to its use as an antibiotic, is also used in the treatment of inflammatory bowel disease.
== History ==
Sulfonamide drugs were the first broadly effective antibacterials to be used systemically, and paved the way for the antibiotic revolution in medicine. The first sulfonamide, trade-named Prontosil, was a prodrug. Experiments with Prontosil began in 1932 in the laboratories of Bayer AG, at that time a component of the huge German chemical trust IG Farben. The Bayer team believed that coal-tar dyes which are able to bind preferentially to bacteria and parasites might be used to attack harmful organisms in the body. After years of fruitless trial-and-error work on hundreds of dyes, a team led by physician/researcher Gerhard Domagk (working under the general direction of IG Farben executive Heinrich Hörlein) finally found one that worked: a red dye synthesized by Bayer chemist Josef Klarer that had remarkable effects on stopping some bacterial infections in mice. The first official communication about the breakthrough discovery was not published until 1935, more than two years after the drug was patented by Klarer and his research partner Fritz Mietzsch.
Prontosil, as Bayer named the new drug, was the first medicine ever discovered that could effectively treat a range of bacterial infections inside the body. It had a strong protective action against infections caused by streptococci, including blood infections, childbed fever, and erysipelas, and a lesser effect on infections caused by other cocci. However, it had no effect at all in the test tube, exerting its antibacterial action only in live animals. Later, it was discovered by Daniel Bovet, Federico Nitti, and Jacques and Thérèse Tréfouël, a French research team led by Ernest Fourneau at the Pasteur Institute, that the drug was metabolized into two parts inside the body, releasing from the inactive dye portion a smaller, colorless, active compound called sulfanilamide. The discovery helped establish the concept of "bioactivation" and dashed the German corporation's dreams of enormous profit; the active molecule sulfanilamide (or sulfa) had first been synthesized in 1906 and was widely used in the dye-making industry; its patent had since expired and the drug was available to anyone.
The result was a sulfa craze. For several years in the late 1930s, hundreds of manufacturers produced myriad forms of sulfa. This and the lack of testing requirements led to the elixir sulfanilamide disaster in the fall of 1937, during which at least 100 people were poisoned with diethylene glycol. This led to the passage of the Federal Food, Drug, and Cosmetic Act in 1938 in the United States, giving authority to the U.S. Food and Drug Administration (FDA) to oversee the safety of food, drugs, medical devices, and cosmetics. As the first and only effective broad-spectrum antibiotic available in the years before penicillin, heavy use of sulfa drugs continued into the early years of World War II. They are credited with saving the lives of tens of thousands of patients, including Franklin Delano Roosevelt Jr. (son of US President Franklin Delano Roosevelt) and Winston Churchill. Sulfa had a central role in preventing wound infections during the war. American soldiers were issued a first-aid kit containing sulfa pills and powder and were told to sprinkle it on any open wound.
The sulfanilamide compound is more active in the protonated form. The drug has very low solubility and sometimes can crystallize in the kidneys, due to its first pKa of around 10. This is a very painful experience, so patients are told to take the medication with copious amounts of water. Newer analogous compounds prevent this complication because they have a lower pKa, around 5–6, making them more likely to remain in a soluble form.
Many thousands of molecules containing the sulfanilamide structure have been created since its discovery (by one account, over 5,400 permutations by 1945), yielding improved formulations with greater effectiveness and less toxicity. Sulfa drugs are still widely used for conditions such as acne and urinary tract infections, and are receiving renewed interest for the treatment of infections caused by bacteria resistant to other antibiotics.
== Preparation ==
Sulfonamides are prepared by the reaction of a sulfonyl chloride with ammonia or an amine. Certain sulfonamides (sulfadiazine or sulfamethoxazole) are sometimes mixed with the drug trimethoprim, which acts against dihydrofolate reductase. As of 2013 Ireland is the largest exporter worldwide of sulfonamides, accounting for approximately 32% of total exports.
== Varieties ==
== Side effects ==
Sulfonamides have the potential to cause a variety of adverse effects, including urinary tract disorders, haemopoietic disorders, porphyria and hypersensitivity reactions. When used in large doses, they may cause a strong allergic reaction. The most serious of these are classified as severe cutaneous adverse reactions (i.e. SCARs) and include the Stevens–Johnson syndrome, toxic epidermal necrolysis (also known as Lyell syndrome), the DRESS syndrome, and a not quite as serious SCARs reaction, acute generalized exanthematous pustulosis. Any one of these SCARs may be triggered by certain sulfonamides.
Approximately 3% of the general population have adverse reactions when treated with sulfonamide antimicrobials. Of note is the observation that patients with HIV have a much higher prevalence, at about 60%.
Hypersensitivity reactions are less common in nonantibiotic sulfonamides, and, though controversial, the available evidence suggests those with hypersensitivity to sulfonamide antibiotics do not have an increased risk of hypersensitivity reaction to the nonantibiotic agents. A key component to the allergic response to sulfonamide antibiotics is the arylamine group at N4, found in sulfamethoxazole, sulfasalazine, sulfadiazine, and the anti-retrovirals amprenavir and fosamprenavir. Other sulfonamide drugs do not contain this arylamine group; available evidence suggests that patients who are allergic to arylamine sulfonamides do not cross-react to sulfonamides that lack the arylamine group, and may therefore safely take non-arylamine sulfonamides. It has therefore been argued that the terms "sulfonamide allergy" or "sulfa allergy" are misleading and should be replaced by a reference to a specific drug (e.g., "cotrimoxazole allergy").
Two regions of the sulfonamide antibiotic chemical structure are implicated in the hypersensitivity reactions associated with the class.
The first is the N1 heterocyclic ring, which causes a type I hypersensitivity reaction.
The second is the N4 amino nitrogen that, in a stereospecific process, forms reactive metabolites that cause either direct cytotoxicity or immunologic response.
The nonantibiotic sulfonamides lack both of these structures.
The most common manifestations of a hypersensitivity reaction to sulfa drugs are rash and hives. However, there are several life-threatening manifestations of hypersensitivity to sulfa drugs, including Stevens–Johnson syndrome, toxic epidermal necrolysis, agranulocytosis, hemolytic anemia, thrombocytopenia, fulminant hepatic necrosis, and acute pancreatitis, among others.
== See also ==
Dihydropteroate synthase
Elixir sulfanilamide
Hellmuth Kleinsorge (1920–2001) German medical doctor
PABA
Timeline of antibiotics
== References ==
== External links ==
List of sulfonamides
A History of the Fight Against Tuberculosis in Canada (Chemotherapy)
Presentation speech, Nobel Prize in Physiology and Medicine, 1939
The History of WW II Medicine
"Five Medical Miracles of the Sulfa Drugs". Popular Science, June 1942, pp. 73–78.
A history of antibiotics | Wikipedia/Sulfa_drugs |
Subsets and Splits
No community queries yet
The top public SQL queries from the community will appear here once available.