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Equine-assisted therapy (EAT) encompasses a range of treatments that involve activities with horses and other equines to promote human physical and mental health. Modern use of horses for mental health treatment dates to the 1990s. Systematic review of studies of EAT as applied to physical health date only to about 2007, and a lack of common terminology and standardization has caused problems with meta-analysis. Due to a lack of high-quality studies assessing the efficacy of equine-assisted therapies for mental health treatment, concerns have been raised that these therapies should not replace or divert resources from other evidence-based mental health therapies. The existing body of evidence does not justify the promotion and use of equine-related treatments for mental disorders. == Terminology == An overall term that encompasses all forms of equine therapy is equine-assisted activities and therapy (EAAT). Various therapies that involve interactions with horses and other equines are used for individuals with and without disabilities including those with physical, cognitive and emotional issues. Terminology within the field is not standardized, and the lack of clear definitions and common terminology presents problems in reviewing medical literature. Within that framework, the more common therapies and terminology used to describe them are: Therapeutic horseback riding uses a therapeutic team, usually including a certified therapeutic riding instructor, two or more volunteers, and a horse, to help an individual ride a horse and work with it on the ground. Hippotherapy involves an occupational therapist, a physiotherapist, or a speech and language therapist working with a client and a horse. Different movements of the horse present challenges to the client to promote different postural responses of the client by the horse influencing the client rather than the client controlling the horse. The word hippotherapy is also used in some contexts to refer to a broader realm of equine therapies. Equine-assisted learning (EAL) is described as an "experiential learning approach that promotes the development of life skills ... through equine-assisted activities." Equine-assisted psychotherapy (EAP) does not necessarily involve riding, but may include grooming, feeding and ground exercises. Mental health professionals work with one or more clients and one or more horses in an experiential manner to help the clients learn about themselves and others, while processing or discussing the client's feelings, behaviours, and patterns. The goal is to help the client in social, emotional, cognitive, or behavioral ways. Other terms for equine psychotherapy include equine-facilitated psychotherapy (EFP), equine-assisted therapy (EAT), equine-facilitated wellness (EFW), equine-facilitated counselling (EFC) and equine facilitated mental health (EFMH). Interactive vaulting involves vaulting activities in a therapeutic milieu. Therapeutic driving involves controlling a horse while driving from a carriage seat or from a wheelchair in a carriage modified to accommodate the wheelchair. Equine-assisted activities (EAA) incorporates all of the above activities plus horse grooming, and stable management, shows, parades, demonstrations, and the like. == Types == Most research has focused on physical benefit of therapeutic work with horses, though the most rigorous studies have only been subject to systematic review since about 2007. EAAT have been used to treat individuals with neurological diseases or disorders such as cerebral palsy, movement disorders, or balance problems. It is believed the rhythmical gait of a horse acts to move the rider's pelvis in the same rotation and side-to-side movement that occurs when walking; the horse's adjustable gait promotes riders to constantly adjust to encourage pelvic motion while promoting strength, balance, coordination, flexibility, posture, and mobility. EAAT have also been used to treat other disabilities, such as autism, behavioral disorders and psychiatric disorders. Due to a lack of rigorous scientific evidence, there is insufficient evidence to demonstrate if equine therapy for mental health treatment provides any benefit. === Therapeutic horseback riding === Therapeutic riding is used by disabled individuals who ride horses to relax, and to develop muscle tone, coordination, confidence, and well-being. Therapeutic horseback riding is considered recreational therapy where an individual is taught by a non-therapist riding instructor how to actively control a horse while riding. It is used as exercise to improve sensory and motor skills for coordination, balance, and posture. Most research has focused on the physical benefit of therapeutic work with horses, with the most rigorous studies being subject to systematic review since about 2007. Claims made as to the efficacy of equine therapies for mental health purposes have been criticized as lacking proper medical evidence due in large part to poor study design and lack of quantitative data. Ethical questions relating to its expense and its continued promotion have been raised in light of this lack of evidence. While such therapies do not appear to cause harm, it has been recommended they not be used as a mental treatment at this time unless future evidence shows a benefit for treating specific disorders. === Hippotherapy === Hippotherapy is an intervention used by a physical therapist, recreational therapist, occupational therapist, or speech and language pathologist. The movement of the horse affects a rider's posture, balance, coordination, strength and sensorimotor systems. It is thought that the warmth and shape of the horse and its rhythmic, three-dimensional movement along with the rider's interactions with the horse and responses to the movement of the horse can improve the flexibility, posture, balance and mobility of the rider. Learning to use verbal cues for the horse, and to speak with the therapist is key to practicing use of speech. It differs from therapeutic horseback riding because it is one treatment strategy used by a licensed physical therapist, occupational therapist, or speech and language pathologists. They guide the rider's posture and actions while the horse is controlled by a horse handler at the direction of the therapist. The therapist guides both the rider and horse to encourage specific motor and sensory inputs. Therapists develop plans to address specific limitations and disabilities such as neuromuscular disorders, walking ability, or general motor function. === Equine-assisted psychotherapy === Equine-assisted psychotherapy (EAP) or equine-facilitated psychotherapy (EFP) is the use of equines to treat human psychological problems in and around an equestrian facility. It is not the same as therapeutic riding or hippotherapy.: 221 Though different organizations may prefer one term over the other for various reasons, in practice, the two terms are used interchangeably.: 287 Other terms commonly used, especially in Canada, include equine-facilitated wellness (EFW), equine-facilitated counselling (EFC) and equine-facilitated mental health (EFMH). While some mental health therapies may incorporate vaulting and riding, some utilize groundwork with horses. Some programs only use ground-based work. There are also differences between programs over whether the horse is viewed as a co-facilitator, or simply as a tool.: 287 The field of equine-assisted psychotherapy did not publicly become a part of the equine-assisted therapy world until the 1990s, although individuals had been experimenting with the concept prior to that time. The first national group in the United States, the Equine-Facilitated Mental Health Association (EFMHA), now a part of PATH International, formed in 1996. The mental health area of equine-assisted therapy became subject to a major rift when a second group, the Equine Growth and Learning Association (EAGALA) formed in 1999, splitting from EFMHA (now PATH) over differences of opinion about safety protocols.: 285–286 Since that time, additional differences have arisen between the two groups over safety orientation, the therapeutic models used, training programs for practitioners, and the role of riding.: 51 EAGALA itself had a further split between its founders in 2006 due to legal issues, with yet another new organization formed.: 52 As a result, although PATH and EAGALA remain the two main certification organizations in the United States, there has been a significant amount of misunderstanding amongst practitioners, client, and within the scientific literature. To resolve these differences, an independent organization, the Certification Board for Equine Interaction Professionals (CBEIP) formed, beginning in 2007, to promote professional credibility in the field.: 286 However, the world of equine-assisted psychotherapy remains disorganized and has not standardized its requirements for education or credentialing.: 287 == History == Horses have been utilized as a therapeutic aid since the ancient Greeks used them for those people who had incurable illnesses. Its earliest recorded mention is in the writings of Hippocrates who discussed the therapeutic value of riding. The claimed benefits of therapeutic riding have been dated back to 17th century literature where it is documented that it was prescribed for gout, neurological disorder and low morale. In 1946 Equine Therapy was introduced in Scandinavia after an outbreak of poliomyelitis. Hippotherapy, as currently practiced was developed in the 1960s, when it began to be used in Germany, Austria, and Switzerland as an adjunct to traditional physical therapy. The treatment was conducted by a physiotherapist, a specially trained horse, and a horse handler. The physiotherapist gave directives to the horse handler as to the gait, tempo, cadence, and direction for the horse to perform. The first standardized hippotherapy curriculum would be formulated in the late 1980s by a group of Canadian and American therapists who travelled to Germany to learn about hippotherapy and would bring the new discipline back to North America upon their return. The discipline was formalized in the United States in 1992 with the formation of the American Hippotherapy Association (AHA). Since its inception, the AHA has established official standards of practice and formalized therapist educational curriculum processes for occupational, physical and speech therapists in the United States. At about 1952, in Germany, therapeutic riding was used to address orthopaedic dysfunctions such as scoliosis. The first riding centers in North America began in the 1960s and the North American Riding for the Handicapped Association (NARHA) was launched in 1969. Therapeutic riding was introduced to the United States and Canada in 1960 with the formation of the Community Association of Riding of the Disabled (CARD). In the United States riding for disabled people developed as a form of recreation and as a means of motivation for education, as well as its therapeutic benefits. In 1969 the Cheff Therapeutic Riding Center for the Handicapped was established in Michigan, and remains the oldest center specifically for people with disabilities in the United States. The North American Riding for Handicapped Association (NARHA) was founded in 1969 to serve as an advisory body to the various riding for disabled groups across the United States and its neighboring countries. In 2011, NARHA changed its name to the Professional Association of Therapeutic Horsemanship (PATH) International. == Horses used == In most cases, horses are trained and selected specifically for therapy before being integrated into a program. Therapy programs choose horses of any breed that they find to be calm, even-tempered, gentle, serviceably sound, and well-trained both under saddle and on the ground. As most equine-assisted therapy is done at slow speeds, an older horse that is not in its athletic prime is sometimes used. Equine-assisted therapy programs try to identify horses that are calm but not lazy and physically suited with proper balance, structure, muscling and gaits. Muscling is not generally considered to be as important as the balance and structural correctness, but proper conditioning for the work it is to do is required. Suitable horses move freely and have good quality gaits, especially the walk. Unsound horses that show any signs of lameness are generally avoided. The welfare of the horse is taken into consideration. Each individual animal has natural biological traits but also has a unique personality with its own likes, dislikes and habits. Paying attention to what the animal is trying to communicate is helpful both in sessions of EAAT, but also to prevent burnout for the horse. Some programs refer to the therapy horse as an "equine partner". Other programs view the horse as a "metaphor" with no defined role other than to "be themselves." Equine-facilitated wellness programs, particularly those following the EFW-Canada certification route view the horse as 'sentient being': "The equine is a sentient being, partner and co-facilitator in the equine facilitated relationship and process". == Effectiveness == There is currently insufficient medical evidence to support the effectiveness of equine-related treatments for mental health. Multiple reviews have noted problems with the quality of research such as the lack of independent observers, rigorous randomized clinical trials, longitudinal studies, and comparisons to currently accepted and effective treatments. A 2014 review found these treatments did no physical harm, but found that all studies examined had methodological flaws, which led to questioning the clinical significance of those studies; the review also raised ethical concerns both about the marketing and promotion of the practice and the opportunity cost if patients in need of mental health services were diverted from evidence-based care. The review recommended that both individuals and organizations avoid this therapy unless future research establishes verifiable treatment benefits. There is some evidence that hippotherapy can help improve the posture control of children with cerebral palsy, although the use of mechanical hippotherapy simulators produced no clear evidence of benefit. A systematic review of studies on the outcomes of horseback riding therapy on gross motor function in children with cerebral palsy was concluded in 2012 with a recommendation for a "large randomized controlled trial using specified protocols" because the studies were too limited to be considered conclusive. Overall, reviews of equine-assisted therapy scientific literature indicate "there is no unified, widely accepted, or empirically supported, theoretical framework for how and why these interventions may be therapeutic". The journal Neurology published a 2014 study finding inadequate data to know whether hippotherapy or therapeutic horseback riding can help the gait, balance, or mood of people with multiple sclerosis. Newer studies have found hippotherapy paired with traditional treatment can increase balance and quality of life in individuals with multiple sclerosis. There is no evidence that therapeutic horseback riding is effective in treating children with autism. == Accreditation and certification == In Canada, centers and instructors for Therapeutic Riding are regulated by CanTRA, also known as The Canadian Therapeutic Riding Association. The field of equine-facilitated wellness is regulated by Equine Facilitated Wellness – Canada (EFW-Can) which provides a national certification program and certifies trainers and mentors to provide independent training at approved programs across Canada. In the UK there are a growing number of training providers offering externally accredited equine-assisted and facilitated qualifications. There is currently no overarching regulating body in the UK. Some organisations are specifically offering therapeutic or coaching based approaches; others offer skills-based approaches which building on existing professional skills and practices. In the US, the Professional Association of Therapeutic Horsemanship (PATH) accredits centers and instructors that provide equine-assisted therapy. The Equine Assisted Growth and Learning Association (EAGALA) focuses only on mental health aspects of human-equine interaction, and provides certification for mental-health and equine professionals. The American Hippotherapy Association offers certification for working as a hippotherapist. == See also == Occupational therapy Physiotherapy Riding for the Disabled Association (UK) Professional Association of Therapeutic Horsemanship (PATH) (US) Horseback riding simulators Wagon-bed riding === Notable examples === Smoke the Donkey == References ==	Wikipedia/Equine_therapy
Transdermal Continuous Oxygen Therapy (TCOT, also known as Transdermal Continuous Oxygen Wound Therapy) is a wound closure technique for chronic and acute wounds which blankets a wound in oxygen on a 24-hour basis until the wound heals. Unlike hyperbaric oxygen treatment for chronic wounds, oxygen treatment used in this therapy is not systemic in nature and treats only the wound area. This treatment differs from topical oxygen treatments, as topical oxygen typically involves sporadic treatments of 1–3 hours several times per week, while TCOT treatment is 24/7 by nature. == Overview == Though early use focused on burns and surgical wounds, wider use of wounds treated with TCOT have become more common in diabetic foot ulcers, venous stasis and decubitus ulcers (pressure sores). TCOT involves inserting a thin tube which delivers the oxygen above the wound bed of a cleaned wound. An absorbent dressing is then placed above the tube and an occlusive or semi occlusive dressing is placed over the entire wound site. The far end of the tube is connected to an oxygen delivery unit, often portable, which delivers oxygen at a slow rate, typically 3ml per hour. == Indications == Although the FDA has approved treatment for at least one company using TCOT for the following indications, most of the interest in TCOT at present concerns diabetic foot ulcers, venous stasis, and decubitus ulcers. Skin ulcers due to diabetes Skin ulcers due to venous stasis Decubitus ulcers (bed sores, pressure sores) Skin ulcers due to post-surgical infections Lesions due to gangrene Skin grafts Burns Frostbite == Effectiveness == Animal studies conducted in 2004-2005 have demonstrated the effectiveness of TCOT on Rabbit ear wounds. A recently published study documented two prevented amputations which have shown TCOT to be highly effective on diabetic foot ulcers, venous stasis and decubitus ulcers and a study completed in 2010 by Dr. Gary Sibbald documented the effectiveness of TCOT on 9 diabetic foot ulcer patients. Manufacturers of devices used in TCOT have published several additional cases whereby treatment using TCOT prevented previously scheduled amputations. == References ==	Wikipedia/Transdermal_continuous_oxygen_therapy
Wake therapy (sometimes sleep deprivation therapy) is a specific application of intentional sleep deprivation. It encompasses many sleep-restricting paradigms that aim to address mood disorders with a form of non-pharmacological therapy. == Description == Wake therapy was first popularized in 1966 and 1971 following articles by Schulte and by Pflug and Tölle describing striking symptom relief in depressed individuals after 1 night of total sleep deprivation. Wake therapy can involve partial sleep deprivation, which usually consists of restricting sleep to 4–6 hours, or total sleep deprivation, in which an individual stays up for more than 24 consecutive hours. During total sleep deprivation, an individual typically stays up about 36 hours, spanning a normal awakening time until the evening after the deprivation. It can also involve shifting the sleep schedule to be later or earlier than a typical schedule (eg. going to bed at 5 am), which is called Sleep Phase Advancement. Older studies involved the repetition of sleep deprivation in the treatment of depression, either until the person showed a response to the treatment or until the person had reached a threshold for the possible number of sleep deprivation treatments. Chronic sleep deprivation is dangerous and in modern research studies it is no longer common to repeat sleep deprivation treatments close together in time. Recent closed-loop paradigms have been developed to selectively deprive individuals of some stages—but not others—of sleep. During slow-wave sleep deprivation, researchers monitor the electrical activity on an individual's scalp with electroencephalography (EEG) in real-time. Then, sensory stimulation, like a burst of pink noise, is used to disrupt certain stages of sleep (i.e. by interfering with slow waves during non-rapid eye movement sleep). The goal of these paradigms is to investigate how the deprivation of one type of sleep stage, or sleep microarchitecture, affects outcome measures, as opposed to the deprivation of all sleep stages. One drawback of closed loop sleep deprivation paradigms is that they must be carefully calibrated for each individual. If researchers use auditory stimuli to inhibit slow waves, they must calibrate the volume of the stimulus so that it is loud enough to evoke a sensory response, but quiet enough that it does not wake the patient from sleep. There is some evidence that depriving individuals of slow wave sleep can induce a rapid antidepressant effect in a dose-dependent manner, meaning a greater reduction in slow wave activity relative to baseline is expected to induce greater symptom relief. == Response rate == The response rate to sleep deprivation is generally agreed to be approximately 40-60%. A 2017 meta-analysis of 66 sleep studies with partial or total sleep deprivation in the treatment of depression found that the overall response rate (immediate relief of symptoms) to total sleep deprivation was 50.4% of individuals, and the response rate to partial sleep deprivation was 53.1% In 2009, a separate review on sleep deprivation found that 1700 patients with depression across 75 separate studies showed a response rate that ranged from 40 - 60%. For reference, the non-response rate for conventional antidepressant pharmacotherapy is estimated to be ~30%, but symptom relief may be delayed by several weeks after the onset of treatment (compared to the immediate, transient relief induced by sleep deprivation). Metrics of mood change vary highly across studies, including surveys of daily mood, or clinician administered interviews that assess the severity of depression symptoms. One benefit to sleep deprivation is that it can provide relief from symptoms within 6–12 hours after sleep deprivation, a rapid effect compared to the 4–6 weeks that it may take conventional treatments to have an effect. One downside of sleep deprivation therapy is that the beneficial effects are transient, and disappear after even short periods of sleep. Even ultra-short periods of sleep lasting seconds, termed microsleeps, have been shown to cause a relapse in symptoms. === Relapse after recovery sleep === One meta-analysis of over 1700 unmedicated depressed patients who had undergone sleep deprivation found that 83% relapsed in their symptoms after one night of recovery sleep. Only 5-10 % of patients who initially respond to sleep deprivation show sustained remission. However, when sleep deprivation is combined with pharmacological treatments, the number of patients who show sustained remission is much higher, with rates as high as half of patients experiencing sustained remission. Compared to a relapse rate of 83% for unmedicated patients, patients who simultaneously took antidepressants only experienced a relapse rate of 59% after a night of recovery sleep. === Effect of sleep deprivation depends on psychiatric status === The effect of sleep deprivation on mood is dependent on an individual's psychiatric status. Healthy individuals with no history of mood disorders who undergo sleep deprivation often show no change or a worsening of mood after the sleep deprivation. In addition to constant or worsening mood, they also show an increase in tiredness, agitation, and restlessness. Similarly, individuals with psychiatric disorders such as obsessive compulsive disorder or those who suffer from panic attacks do not show reliable improvements in mood disorder. == Side effects == The only known contraindication to sleep deprivation therapy for individuals with unipolar depression is a risk of seizures. Some studies have shown that the stress associated with a night of sleep deprivation can precipitate unexpected medical conditions, such as a heart attack. Other known side effects of sleep deprivation include general fatigue, and headaches. For individuals with bipolar depression, sleep deprivation can sometimes cause a switch into a manic state. === Associated neurological injuries === Studies show that increase in BDNF is adaptative to neuronal injury and that after 3 hours of sleep loss per night it becomes maladaptative and apoptosis occurs. Studies in mices shows neuronal deaths occurring only after 2 days of REM sleep deprivation. However, mice does not models well effects in humans because they sleep a third of the amount of REM sleep as humans do and caspase-3, which can be used as a proxy for neuron apoptosis, kills 3 times the amount in humans than in mice. Something also not accounted in nearly all of the studies is that acute REM sleep deprivation induces lasting (> 20 days) neuronal apoptosis in mice. Such histological studies cannot be performed on humans for ethical reasons, but long term studies study shows that sleep quality is more associated to grey matter volume reduction than age. Alternatives must be preferably considered because unlike many psychiatric conditions, neuronal losses and its effects are life-long lasting and cannot be treated currently. == Combination of antidepressant pharmacological intervention and total sleep deprivation == === Unipolar depression === Although individual studies have shown a positive effect of combined antidepressant-sleep deprivation therapy, there is currently no widely-accepted consensus about whether combined treatment is superior to pharmacological intervention alone for individuals with unipolar depression. A meta analysis (2020) of more than 368 patients found that sleep deprivation combined with standard treatment did not reduce depressive symptoms compared to standard treatment alone. === Bipolar depression === In contrast with unipolar depression, there is a wide body of evidence that sleep deprivation may be useful in the treatment of bipolar depression. A meta analysis of 90 articles found that combining total sleep deprivation and pharmacological intervention significantly increased the antidepressant effects in patient with bipolar depression when compared to pharmacological intervention alone. The metric that the studies used to assess success of the interventions was a depression symptom scale called the Montgomery-Asberg Depression Scale or the Hamilton Depression Rating Scale, which both are used to measure someone's mood. Multiple studies have shown that adding a mood stabilizing medication (lithium, amineptine, or pindolol) to total sleep deprivation can induce a significant decrease in depression symptoms that is sustained at least 10 days after the treatment. When considering the long-term effects of the combined total sleep deprivation-pharmacological intervention, it appears that combination therapy can also improve the maintenance of the antidepressant effect for individuals with bipolar mood disorders. These results suggest that adding total sleep deprivation to bipolar depression pharmacological treatment may result in an augmented treatment response. Total sleep deprivation may not be necessary to achieve the beneficial effect of combined sleep deprivation-antidepressant therapy- partial sleep deprivation may be sufficient. Compliance in these studies is typically measured with actigraphy in order to track movements and time in bed. === Mechanism === The mechanism by which sleep deprivation enhances the effect of antidepressant pharmacological intervention is still under investigation. One hypothesis is that sleep deprivation could enhance the effects of the antidepressant drugs, or it could shorten the delay of the drugs effects, which can take up to several months depending on the drug. === BDNF hypothesis === One hypothesis for the mechanism of sleep deprivation is that it induces a rapid increase in the level of a neutrophic protein called brain-derived neurotrophic factor (BDNF), which mimics the long term effects of some antidepressant drugs. Drug-naive patients with depression typically show lower levels of BDNF than age and sex-matched controls. An increase in BDNF in patients with depression who take a class of drugs called selective serotonin reuptake inhibitors has been reported in several studies to increase after 8 weeks. Similarly, an increase in serum BDNF level is also observed in patients who undergo a single night of total or REM sleep deprivation, however the effect is observed immediately rather than after a long period of time. This increase is hypothesized to be the result of a compensatory mechanism in the brain that produces BDNF to preserve cognitive functions like working memory and attention. === Serotonin hypothesis === Another hypothesis for the mechanism of sleep deprivation is that it may affect the serotonergic system, including a receptor called the 5-HT1A receptor. Animals models of sleep deprivation suggest that sleep deprivation increases serotonin neurotransmission in several ways, including 1) increasing extracellular serotonin, 2) increasing serotonin turnover, 3) reducing the sensitivity of serotonin inhibitory autoreceptors and 4) increasing behavioral responsiveness to serotonin precursors. Studies in humans that measure pre-sleep deprivation levels of serotonin with single photon emission computer tomography have provided evidence that responders to sleep deprivation may have a specific deficit in serotoninergic systems. == Barriers to sleep deprivation-antidepressant combination therapy research == One barrier to understanding the effects of sleep deprivation is the lack of a consistent metric of "response". Although there are standard mood surveys and clinician-rated scales, different investigators use different criterion as evidence of response to the treatment. For example, some investigators have required a 30% decrease in the Hamilton Rating Scale, while others required a 50% decrease. Other barriers include the fact that researchers are not blind to patient condition when they rate the patient's mood, and that many previous studies have not included control groups, but rather only published findings on patient groups without any control reference. Skeptics of sleep deprivation therapy argue that it is not the sleep deprivation itself, but rather the prolonged contact with other humans and unusual circumstances of the sleep deprivation that lead to improvements in mood symptoms. Another major barrier is that depression is a highly heterogenous disorder, spanning both unipolar and bipolar types. == Predictors of antidepressant response to sleep deprivation therapy == === Diurnal mood === Mood fluctuations are currently thought to be dependent on circadian processes. A typical healthy individual without a mood disorder shows circadian-locked fluctuations in mood, with positive mood beginning right after the morning awakening, and decaying as the day goes on during prolonged wakefulness. A typical individual with depression will show the opposite mood fluctuation cycle, with a low mood right after morning awakening, which gradually becomes more positive with prolonged wakefulness. These circadian-locked changes across the day are referred to as "diurnal" variations in mood. Evidence across many sleep deprivation studies suggests that an individual's diurnal mood fluctuations can be used to predict whether they will respond to sleep deprivation therapy. Individuals with depression who show the typical low morning mood that increases throughout the day are more likely to respond positively to sleep deprivation than individuals who show mood fluctuations that deviate from the typical pattern. One caveat to these findings is that a single individual may show diurnal fluctuations that vary day-to-day, showing typical diurnal changes on one day while not showing any changes (constant mood) on the next. This complexity was addressed in studies that followed single individuals and administered repeated sleep deprivation on days when the individual showed different mood fluctuations. The studies showed that an individual's ability to show the typical mood fluctuations was a better predictor of whether they would respond to sleep deprivation treatment than the individual's mood state on the particular day that they underwent sleep deprivation. === Short REM latency === Responsiveness to sleep deprivation is also currently believed to be dependent on observable pattern in a person's regular sleep cycle, such as how quickly a person enters into a sleep cycle called rapid eye movement (REM) sleep. Individuals with depression typically show abnormally short REM sleep onsets, meaning they enter into the REM sleep stage earlier in the course of the night than matched healthy controls. Individuals with depression who have short-latency REM sleep typically respond to sleep deprivation therapy more often than individuals with depression who do not show the typical short latency REM sleep pattern. == See also == Cognitive behavioral therapy for insomnia == References == == Sources == Kragh, M.; Martiny, K.; Videbech, P.; Møller, D. N.; Wihlborg, C. S.; Lindhardt, T.; Larsen, E. R. (December 2017). "Wake and light therapy for moderate-to-severe depression - a randomized controlled trial". Acta Psychiatrica Scandinavica. 136 (6): 559–570. doi:10.1111/acps.12741. PMID 28422269. S2CID 46869059. Boland et al 2019, "Meta-Analysis of the Antidepressant Effects of Acute Sleep Deprivation"	Wikipedia/Wake_therapy
Antihormone therapy is a type of hormone therapy that suppresses selected hormones or their effects, in contrast with hormone replacement therapy, which encourages hormone activity. The suppression of certain hormones can benefit patients with certain cancers because certain hormones prompt or help the growth of a tumor. This is especially true in cancers relating to the sex organs. Hormones are made by glands and circulated through the bloodstream. Hormones may act as a signal to cells to grow by attaching to them. Antihormone therapy blocks hormones from sending these messages to cells. If a diagnostic test shows cancer in places with hormones attached, drugs may be prescribed to the patient to block the receptors and inhibit the growth of cancer cells. Most antihormone therapies are administered by pill for 5 to 10 years after surgery. == Origin == Hormone replacement therapy began in the 1960s but gained traction in the late 1990s. Therapy methods have been developed rapidly since the 1970s, and survivorship of individuals with hormone receptor-positive cancer has skyrocketed. In more recent years, since the 1990s, new classes of drugs have been released and greatly changed the way hormonal cancers, like prostate and breast cancer, are treated. Research to understand how hormones influence the growth of cancer cells has prompted researchers to find new ways to use drugs to prevent and treat hormone receptor-positive cancer cells by limiting the production of sex hormones. These methods of hormone suppression have opened the door for pioneering new cancer chemoprevention drugs. == Types of Antihormone Therapy == === SERMs (selective estrogen receptor modulator) and SERDs (selective estrogen receptor degrader) === ==== Tamoxifen and Toremifene ==== Tamoxifen is a SERM and is one of the most common and oldest forms of hormone therapy. When breast cancer is found at an early stage or found to be Metastatic breast cancer, tamoxifen can be prescribed to selectively block estrogen's effect on certain cells. SERMs like tamoxifen attach to receptors on the cancer cells which blocks estrogen from attaching to the receptors. Tamoxifen is successful in lowering breast cancer reoccurrence rates, breast cancer occurrence in the opposite breast, and death from breast cancer in cases of hormone receptor-positive and hormone-sensitive cancer. Tamoxifen is also thought to lower the risk of breast cancer in those who have a predisposition or at risk. Tamoxifen may be used in pre and postmenopausal women. Toremifene is a similar SERM drug to tamoxifen, but is less common and only approved for treatment of metastatic cancer. Toremifene is generally prescribed once tamoxifen is no longer effective. ==== Fulvestrant (Faslodex) ==== Fulvestrant is a SERD drug that acts by damaging and blocking estrogen receptors. Fulvestrant is currently only approved by the FDA to treat cancer in postmenopausal women, but it is often prescribed off-label in combination with and LHRH agonist in premenopausal women to halt the functionality of the ovaries. Fulvestrant is administered via injection in the buttocks. === Aromatase inhibitors === A group of drugs called aromatase inhibitors are commonly prescribed to postmenopausal women who test positive for hormone receptor-positive cancer. Aromatase in fat and muscle can circulate estrogen in postmenopausal women. Aromatase in highly estrogen-sensitive tissues, such as the breast, uterus, vagina, bone, and blood vessels, provides estrogen locally, so aromatase inhibitors work by reducing this estrogen production. === Ovarian Suppression === Ovarian suppression is known to slow the growth of hormone receptor-positive breast cancer in premenopausal women and can also help preserve fertility during chemotherapy. Ovarian suppression through drugs temporarily shuts down the ovaries preventing the production of oestrogen, thus slowing the rate of growth of hormone receptor-positive tumors. Ovary suppression may also be achieved through surgical intervention known as an oophorectomy, which removes one or both ovaries sometimes in combination with the fallopian tubes. === LHRH Agonist === LHRH (luteinising hormone-releasing hormone) agonists block the production of sex hormones in both men and women. In men, LHRH agonists seize testosterone production in the testicles, and in women it blocks the ovaries from producing estrogen and progesterone. These drugs are most commonly used in treatments for prostate cancer. == Side Effects == Side effects of antihormone therapy are generally minimal, but can produce similar feelings to menopause in women. Common symptoms of all antihormone therapies include irregular menstrual cycles, hot flashes, weight gain, vaginal dryness, headaches, mood swings and hair thinning. Less common but more serious drug-specific side effects include: === SERMs === Blood clots Stroke Cataracts Uterine cancer Decreased libido Mood swings and depression === Ovarian suppression === Osteoporosis Decreased libido Mood swings and depression === Aromatase Inhibitors === Heart attack, angina, heart failure Osteoporosis Mood swings and depression === Fulvestrant === Gastrointestinal complications (nausea, vomiting, constipation) Bone and musculoskeletal pain Headache == References ==	Wikipedia/Antihormone_therapy
Maggot debridement therapy (also known as MDT, larval therapy, or simply maggot therapy) is a type of biotherapy involving the introduction of live, disinfected maggots (fly larvae) into non-healing skin and soft-tissue wounds of a human or other animal for the purpose of cleaning out the necrotic (dead) tissue within a wound (debridement), and disinfection. There is evidence that maggot therapy may help with wound healing. == Medical uses == Maggot therapy improves healing in chronic ulcers. In diabetic foot ulcers there is tentative evidence of benefit. A Cochrane review of methods for the debridement of venous leg ulcers found maggot therapy to be broadly as effective as most other methods, but the study also noted that the quality of data was poor. In 2003, the United States Food and Drug Administration (FDA) cleared maggots from common green bottle fly for use as a "medical device" in the US for the purpose of treatment of: Non-healing necrotic skin and soft tissue wounds Pressure ulcers Venous stasis ulcers Neuropathic foot ulcers Non-healing traumatic or post-surgical wounds === Limitations === The wound must be of a type that can benefit from the application of maggot therapy. A moist, exudating wound with sufficient oxygen supply is a prerequisite. Not all wound-types are suitable: wounds which are dry, or open wounds of body cavities do not provide a good environment for maggots to feed. In some cases it may be possible to make a dry wound suitable for larval therapy by moistening it with saline soaks. Patients and doctors may find maggots distasteful, although studies have shown that this does not cause patients to refuse the offer of maggot therapy. Maggots can be enclosed in opaque polymer bags to hide them from sight. Dressings must be designed to prevent any maggots from escaping, while allowing air to get to the maggots. Dressings are also designed to minimize the uncomfortable tickling sensation that the maggots often cause. == Mechanisms of action == The maggots have four principal actions: Debridement Disinfection of the wound Stimulation of healing Biofilm inhibition and eradication === Debridement === In maggot therapy, large numbers of small maggots consume necrotic tissue far more precisely than is possible in a normal surgical operation, and can debride a wound in a day or two. The area of a wound's surface is typically increased with the use of maggots due to the undebrided surface not revealing the actual underlying size of the wound. They derive nutrients through a process known as "extracorporeal digestion" by secreting a broad spectrum of proteolytic enzymes that liquefy necrotic tissue, and absorb the semi-liquid result within a few days. In an optimum wound environment maggots molt twice, increasing in length from about 2 mm to about 10 mm, and in girth, within a period of 48–72 hours by ingesting necrotic tissue, leaving a clean wound free of necrotic tissue when they are removed. === Disinfection === Secretions from maggots believed to have broad-spectrum antimicrobial activity include allantoin, urea, phenylacetic acid, phenylacetaldehyde, calcium carbonate, proteolytic enzymes, and many others. In vitro studies have shown that maggots inhibit and destroy a wide range of pathogenic bacteria including methicillin-resistant Staphylococcus aureus (MRSA), group A and B streptococci, and Gram-positive aerobic and anaerobic strains. Other bacteria like Pseudomonas aeruginosa, E. coli or Proteus spp. are not attacked by maggots, and in case of Pseudomonas even the maggots are in danger. === Biology of maggots === Those flies whose larvae feed on dead animals will sometimes lay their eggs on the dead parts (necrotic or gangrenous tissue) of living animals. The infestation by maggots of live animals is called myiasis. Some maggots will feed only on dead tissue, some only on live tissue, and some on live or dead tissue. The flies used most often for the purpose of maggot therapy are blow flies of the Calliphoridae: the blow fly species used most commonly is Lucilia sericata, the common green bottle fly. Another important species, Protophormia terraenovae, is also notable for its feeding secretions, which combat infection by Streptococcus pyogenes and S. pneumoniae. == History == Written records have documented that maggots have been used since antiquity as a wound treatment. There are reports of the use of maggots for wound healing by Maya, Native Americans, and Aboriginal tribes in Australia. Maggot treatment was reported in Renaissance times. Military physicians observed that soldiers whose wounds had become colonized with maggots experienced significantly less morbidity and mortality than soldiers whose wounds had not become colonized. These physicians included Napoleon's surgeon-general, Baron Dominique Larrey. Larrey reported during the French campaign in Egypt and Syria (1798–1801) that certain species of fly consumed only dead tissue and helped wounds to heal. Joseph Jones, a ranking Confederate medical officer during the American Civil War, stated: I have frequently seen neglected wounds ... filled with maggots ... as far as my experience extends, these worms eat only dead tissues, and do not injure specifically the well parts." The first documented therapeutic use of maggots in the United States is credited to a second Confederate medical officer Dr. J.F. Zacharias, who reported during the American Civil War that: "Maggots in a single day would clean a wound much better than any agents we had at our command ... I am sure I saved many lives by their use." He recorded a high survival rate in patients he treated with maggots. During World War I, orthopedic surgeon William S. Baer recorded the case of a soldier left for several days on the battlefield who had sustained compound fractures of the femur and large flesh wounds. The soldier arrived at the hospital with maggots infesting his wounds but had no fever or other signs of infection and survived his injuries, which would normally have been fatal. After the war, Baer began using maggot therapy at Boston Children's Hospital in Massachusetts.: 169–71 There were reports that American prisoners of war of the Japanese in World War II resorted to maggot therapy to treat severe wounds. A survey of US Army doctors published in 2013 found that 10% of them had used maggot therapy. == Regulation == In January 2004, the FDA granted permission to produce and market maggots for use in humans or animals as a prescription-only medical device for the following indications: "For debriding non-healing necrotic skin and soft tissue wounds, including pressure ulcers, venous stasis ulcers, neuropathic foot ulcers, and non-healing traumatic or post-surgical wounds." == Veterinary use == The use of maggots to clean dead tissue from animal wounds is part of folk medicine in many parts of the world. It is particularly helpful with chronic osteomyelitis, chronic ulcers, and other pus-producing infections that are frequently caused by chafing due to work equipment. Maggot therapy for horses in the United States was re-introduced after a study published in 2003 by veterinarian Dr. Scott Morrison. This therapy is used in horses for conditions such as osteomyelitis secondary to laminitis, sub-solar abscesses leading to osteomyelitis, post-surgical treatment of street-nail procedure for puncture wounds infecting the navicular bursa, canker, non-healing ulcers on the frog, and post-surgical site cleaning for keratoma removal. However, there have not been many case studies done with maggot debridement therapy on animals, and as such it can be difficult to accurately assess how successful it is. == References == == Further reading == Sherman, R. A. (2003). "Maggot Therapy for Treating Diabetic Foot Ulcers Unresponsive to Conventional Therapy". Diabetes Care. 26 (2): 446–51. doi:10.2337/diacare.26.2.446. PMID 12547878. Van Der Plas, M. J. A.; Jukema, G. N.; Wai, S.-W.; Dogterom-Ballering, H. C. M.; Lagendijk, E. L.; Van Gulpen, C.; Van Dissel, J. T.; Bloemberg, G. V.; Nibbering, P. H. (2007). "Maggot excretions/secretions are differentially effective against biofilms of Staphylococcus aureus and Pseudomonas aeruginosa". Journal of Antimicrobial Chemotherapy. 61 (1): 117–22. doi:10.1093/jac/dkm407. PMID 17965032. Cazander, G.; Van Veen, K.E.B.; Bernards, A.T.; Jukema, G.N. (2009). "Do maggots have an influence on bacterial growth? A study on the susceptibility of strains of six different bacterial species to maggots of Lucilia sericata and their excretions/secretions". Journal of Tissue Viability. 18 (3): 80–7. doi:10.1016/j.jtv.2009.02.005. PMID 19362001. Cazander, Gwendolyn; Schreurs, Marco W. J.; Renwarin, Lennaert; Dorresteijn, Corry; Hamann, Dörte; Jukema, Gerrolt. N. (2012). "Maggot excretions affect the human complement system". Wound Repair and Regeneration. 20 (6): 879–86. doi:10.1111/j.1524-475X.2012.00850.x. PMID 23110586. S2CID 24568980. Mumcuoglu, Kosta Y.; Ingber, Arieh; Gilead, Leon; Stessman, Jochanan; Friedmann, Reuven; Schulman, Haim; Bichucher, Hellen; Ioffe-Uspensky, I; Miller, J; Galun, R; Raz, I (1999). "Maggot therapy for the treatment of intractable wounds". International Journal of Dermatology. 38 (8): 623–7. doi:10.1046/j.1365-4362.1999.00770.x. PMID 10487456. S2CID 45118935. Bowler, P. G.; Duerden, B. I.; Armstrong, D. G. (2001). "Wound Microbiology and Associated Approaches to Wound Management". Clinical Microbiology Reviews. 14 (2): 244–69. doi:10.1128/CMR.14.2.244-269.2001. PMC 88973. PMID 11292638. Sherman, R. A.; Hall, M. J. R.; Thomas, S. (2000). "Medicinal Maggots: An Ancient Remedy for Some Contemporary Afflictions". Annual Review of Entomology. 45: 55–81. doi:10.1146/annurev.ento.45.1.55. PMID 10761570. Nigam, Yamni; Bexfield, Alyson; Thomas, Stephen; Ratcliffe, Norman Arthur (2006). "Maggot Therapy: The Science and Implication for CAM Part I—History and Bacterial Resistance". Evidence-Based Complementary and Alternative Medicine. 3 (2): 223–7. doi:10.1093/ecam/nel021. PMC 1475942. PMID 16786052. == External links == Maggot Medicine film produced by Robert Cibis National Geographic video segment on Maggot Medicine on youtube.com The NIH Record; Medieval Miracle Workers — Are Maggots Making a Medical Comeback? The National Institutes of Health experience with maggot therapy	Wikipedia/Maggot_therapy
Horticultural therapy (also known as garden therapy or social and therapeutic horticulture) involves using gardening activities to promote human healing and rehabilitation. == History == Alice Burlingame and Donald Watson authored the first book on horticultural therapy, Therapy through Horticulture, published in 1960. The first degree awarded for work in Horticultural Therapy was given in 1972. In 1973 the Council for Therapy and Rehabilitation through Horticulture (NCTRH) was established by a group of horticulture therapy professionals. In 1988, they changed their name to the American Horticulture Therapy Association (AHTA). == Types of treatment == Goals and types of treatment vary depending on the facility using horticultural therapy. Institutions from schools and nursing homes to prisons utilize horticultural therapy to meet therapeutic needs. Each one of these facilities have different types of horticultural therapy, each with their own individual forms of treatment. Fundamentally horticultural therapy can be divided into three types of programming: Vocational, therapeutic, and social. === Vocational Horticultural Therapy === Vocational Horticultural Therapy is intended to teach skill and enhance behaviors that can be used in a job or workplace. People undergoing vocational therapy can learn skills involving greenhouses, vegetable gardening, tree and shrub care, as well as learn about plant production, sales and services. Activities vocational therapy teaches consists of how to repot, water, and move plants within their space. Learning the basic knowledge of their plants root system and the care different plants need is taught at their own pace. Ultimately aimed at employment, vocational horticulture therapy teaches people how to grow and work with plants while also learning the benefits of supporting themselves mentally and financially. === Therapeutic Horticultural Therapy === Therapeutic Horticultural Therapy has its focus on medical and illness recovery. The central belief that therapeutic horticulture therapy revolves around is that being in nature has restorative properties. Therapeutic horticulture might be used to try and improve physical activity, social skills and engagement. Activities encompassed by therapeutic horticulture vary widely, some activities include: digging and watering, making observations about plant growth and change, relating plant life cycle to human life, and starting seeds. A systematic review and meta-analysis of research comparing horticultural therapy with usual care and other non-pharmacological interventions for individuals with dementia found that participating in certain types of horticultural therapy activities appeared to improve cognitive functioning, agitation, positive emotion and engagement scores when compared to usual care and other non-pharmacological interventions. === Social Horticultural Therapy === Social Horticultural Therapy is focused on leisure activity and enhancement of life quality. Unlike therapeutic horticultural therapy, social horticultural therapy is more likely to be activity based. == See also == == References ==	Wikipedia/Horticultural_therapy
Inversion therapy, or simply inversion, is the process of seeking therapeutic benefits from hanging by the legs, ankles, or feet in an inverted angle or entirely upside down. It is a form of spinal traction. Gravity boots are ankle supports designed for inversion therapy. Some people use gravity boots to add an extra challenge to workouts, doing inverted crunches or squats. People who have heart disease, high blood pressure, eye diseases (such as glaucoma), or are pregnant are at higher risk for the dangers related to inversion therapy and should consult their doctors about it first. The first time anyone tries inversion therapy with gravity, they should be sure to have someone standing by, in case assistance is required to get out of the apparatus, or if health problems are experienced. During an episode of acid reflux, small amounts of stomach acid may manage to escape from the stomach and into the oesophagus. Gravity typically minimizes this upward leakage, but an inversion table and acid reflux can be a painful, nauseating, and potentially dangerous combination. The inverted position, leading to an increase in heart rate and output, peripheral resistance, venous return and myocardial oxygen consumption, is not recommended in cardiac individuals. == Additional images == == References ==	Wikipedia/Inversion_therapy
A therapy dog is a dog that is trained to provide affection, comfort and support to people, often in settings such as hospitals, retirement homes, nursing homes, schools, libraries, hospices, or disaster areas. In contrast to assistance dogs, which are trained to assist specific patients with their day-to-day physical needs, therapy dogs are trained to interact with all kinds of people, not just their handlers. == History == Dogs have been utilized as a therapeutic resource by many medical professionals over the last few centuries. In the late 1800s, Florence Nightingale observed that small pets helped reduce anxiety and improve recovery in children and adults living in psychiatric institutions. Sigmund Freud began using his own pet dog to improve communication with his psychiatric patients in the 1930s. More recently, Elaine Smith established the first therapy dog organization in 1976 after observing positive effects of dogs on hospital patients during her work as a registered nurse. Assistance Dogs International followed in 1986, with the merger of several organizations. == Background == Brian Hare, director of Duke University Canine Cognition Center, says the human-canine bond goes back thousands of years. Hare states, "Dogs have been drawn to people since humans began to exist in settlements [...] part of what makes dogs special is that they are one of the only species that does not generally exhibit xenophobia, meaning fear of strangers. We've done research on this, and what we've found is that not only are most dogs totally not xenophobic, they're actually xenophilic - they love strangers!". Although a dog does not think according to language, people often intuit that dogs are compassionate and communicative. This builds a feeling of intimacy, leading the person to feel safe and understood. This can benefit the grieving human, who may be apprehensive about talking with another person for the fear of being hurt or lied to. Pets are an addition to therapy because they allow people to feel safe and accepted. == Certification == In order for a dog to be a good candidate to become a therapy dog and receive certification, they should be calm and social with strangers. They should also be able to adjust to loud noises and fast movements. There are certain steps that are needed for a dog to become certified by a national organization such as The Alliance of Therapy Dogs, e.g., to socialize the dog around other animals and people. They are tested on behaviors such as not jumping on people and being able to walk on a loose leash. Exact testing/certification requirements differ based on the organization's requirements. Some organizations offer classes such as "distraction-proofing", which strengthens the dog's ability to focus and therapy training to help prepare the dog and the dog's owner for therapy visits. Although therapy dogs are not limited to a certain size or breed, common breeds used in therapy dog application and research include the Golden Retriever and the Labrador Retriever. Cavalier King Charles Spaniels are considered natural therapy dogs since they were bred to be companion dogs. Thus they love meeting new people including children, are very gentle, and are eager to sit on someone's lap for long periods of time and are small enough to do so. Therapy dogs offer many benefits to people and patients. For example, therapy dogs help patients participate in physical activities. They also help encourage them to have cognitive, social, and communication goals. == History == Franklin K. Lane, Secretary of the Interior at the time, proposed utilizing dogs with psychiatric patients at St Elizabeth's Hospital in Washington, DC in the year 1919. Florence Nightingale also contributed ideas to the future field of Animal Assisted Therapy (AAT). She discovered that patients of different ages living in a psychiatric institution were relieved from anxiety when they were able to spend time with small animals. Freud believed that dogs could sense certain levels of tension being felt by his patients. Freud also used his dog to improve communication with his patients. He felt as if his patients were more comfortable talking to his dog at first and this opened up doors for them to later feel more comfortable talking to him. Boris Levinson, an American child psychiatrist, was one of the first to write about animal therapy, specifically with dogs as a tool to facilitate work with a child client. Dr. Levinson found the dog’s presence helped his pediatric clients with positive focus, communication, and allowing the initiation of therapy, and shared this information with the medical world in 1961. About 10 years later, psychiatrists Sam and Elizabeth Corson at Ohio State University Psychiatric Hospital used Levinson's findings to expand this form of therapy to adults. The use of therapy can also be attributed to Elaine Smith, a registered nurse. While a chaplain and his dog visited, Smith noticed the comfort that this visit seemed to bring the patients. In 1976, Smith started a program for training dogs to visit institutions, and the demand for therapy dogs continued to grow. == Classification == Therapy dogs are usually not assistance or service dogs, but can be one or both with some organizations. Many organizations provide evaluation and registration for therapy dogs. Typical tests might ensure that a dog can handle sudden loud or strange noises; can walk on assorted unfamiliar surfaces comfortably; are not frightened by people with canes, wheelchairs, or unusual styles of walking or moving; get along well with children and the elderly; and so on. Institutions may invite, limit, or prohibit access by therapy dogs. If allowed, many institutions have requirements for therapy dogs. United States–based Therapy Dogs International (TDI) bans the use of service dogs in their therapy dog program. Service dogs perform tasks for persons with disabilities and have a legal right to accompany their owners in most areas. In Canada, St John Ambulance provides therapy dog certification. In the UK, Pets As Therapy (PAT) provides visiting dogs and cats to establishments where pets are otherwise not available. Also in the UK, Therapy Dogs Nationwide (TDN) and Canine Concern CIO provide visiting dogs to establishments. === Types === Specialist therapy dogs have been described in various ways: Therapeutic visitation dogs. These dogs are usually household pets; the owner of these dogs will take their pets to hospitals, nursing homes or rehabilitation facilities to visit patients. These dogs are used to improve the mental health of patients through socialization and encouragement. Animal-assisted therapy dogs (AAT): dogs that fall under this category have the duty of providing assistance to patients to reach certain goals towards their recovery. They work to help patients gain skills such as motor skills, use of limbs and hand-eye coordination. They do this by walking patients through certain activities and games to help them practice these skills. These dogs are usually based in rehabilitation facilities. Facility therapy dog: these dogs usually work in nursing homes along with their handlers. They live at the facility and help patients with Alzheimer's disease and other cognitive and mental illnesses. Grief therapy dog (also known as an emotional support dog, companion dog, or comfort dog): assist people in overcoming grief, which has led to a recent rise in the use of therapy dogs; although animal-assisted therapy theory has been around since World War II. Grief therapy dogs can be found in locations such as funeral homes, hospitals, nursing homes, schools, and hospices, and may provide support in situations such as funeral services, counseling sessions, and disaster relief. Popular breeds used as therapy dogs include the Portuguese Water Dog, Bernese Mountain Dog, St. Bernard, and Golden Retriever. In contrast to service dogs who assist disabled people with physical tasks, comfort dogs are not trained in skilled tasks, but serve as constant companions with a keen sense for someone feeling down. They can provide a way for people who are distressed to find sanctuary. == Legal status == === United States === In the United States, therapy dogs are defined but not covered or protected under the Federal Housing Act or Americans with Disabilities Act. According to the Americans with Disabilities Act, only dogs that are "individually trained to do work or perform tasks for the benefit of an individual with a disability" have legal protection as a service animal. Therapy dogs do not have public access rights with exception to the specific places they are visiting and working. Typically the dog would be granted rights by individual facilities only. Therapy dogs are subjected to several tests to ensure that they are fit for the job. These tests look at their ability to block out distractions, comfort level around a variety of people with many different disabilities, and if they are comfortably able to walk through many different terrains. While some states define therapy animals and emotional support animals, they are not protected by federal laws, and therefore can be prohibited from businesses, restaurants and many other locations. == Benefits == === Psychological === Animal Assisted Therapy (AAT) has been reported to improve many psychological conditions such as anxiety, depression, social skills, and simply improving the moods of the patient. Additional psychological benefits of therapy dog programs in educational settings include provided comfort, companionship, a diversion to unpleasant thoughts or situations, and decreased resistance to relationship development in the therapy process. A large number of studies show that animals can offer relief and serenity to a wide age range of vulnerable people with various different emotional issues. Ross DeJohn Jr. of DeJohn Funeral Homes in Ohio says Magic, a Portuguese water dog, "Makes people smile even when they don't want to." (qtd. in Sinatra-Ayers). Amy Sather, Rincon Valley assistant principal, brings her 2-year-old Golden Retriever to the school to assist in the therapy of the children. Sather says, "I've got kids whose parents are going through a divorce and they are so depressed by it. I've had children literally hug and cry into his fur." (qtd. in Warren). Principal Brad Cosorelli claims the students will flock to the dog in time of distress instead of the counselor. Children were found during a study to find their pet (in most cases dogs) a bigger comfort in sharing secrets or scary situations than they found the adults in the family to be. In some cases, life experience has led people to believe they will be hurt by the people closest to them; animals can provide non-judgmental and unrestricted emotional support. This is true for both children and adults. In a survey done by the American Animal Hospital Association, many of those who responded specified that they were emotionally dependent on their pet. Therapists believe they can utilize clients' attachment to animals for therapeutic reasons (Urichuk). The presence of a dog in a therapy session has indicated improvements in a patient's outlook, as well as their willingness to share on a deeper level. The petting of an animal can also put a patient at ease, whereas a therapist must maintain a professional state and thus is unable to provide physical support. This creates a unique bridge for patient-therapist communication (Urichuk). ==== Psychological benefits in school setting ==== The University of Connecticut uses therapy dogs in their program Paws to Relax, available during finals week to help students deal with increased anxiety. The school uses them in other stressful situations, including suicides and deadly automobile accidents. Since 2011, Yale Law School has used therapy dogs to aid students experiencing stress. Some colleges and universities in the US bring therapy dogs to campus to help students de-stress. These campus events are often referred to as "Therapy Fluffies", a term coined by Torrey Trust, the original founder of the University of California San Diego therapy dog de-stress event. In 2009, Sharon Franks shared the idea of bringing therapy dogs to campus with the UC San Diego Office of Student Wellness. Since the autumn of 2010, "Therapy Fluffies" has visited the UC Davis, UC Santa Cruz, and UC Riverside campuses during the week before mid-term and final exams. These events give students and staff the opportunity to pet and relax with therapy-certified dogs. The university also works with the Inland Empire Pet Partners, a service of the Humane Society to bring therapy-certified dogs to the campus' Mental Health Day Spa, held quarterly. In 2014, Concordia University, Wisconsin became the first university in the US to adopt a full-time therapy dog to its campus in Mequon, Wisconsin. The golden retriever, Zoey, is a Lutheran church Charities K-9 Comfort Dog, trained to interact with people at churches, schools, nursing homes, hospitals, events, and in disaster response situations. Concordia later purchased a second comfort dog, named Sage. ==== Stressful situations ==== Therapy dogs were used to offer comfort to faculty, staff and students following the 2007 Virginia Tech shooting in Blacksburg, Virginia, when 32 people were killed. On December 14, 2012, therapy dogs were brought to the Sandy Hook Elementary School in Newtown, Connecticut, following the shooting and deaths of 26 people, providing comfort to children and parents. The court system in King County, Washington uses a comfort dog with crime victims, particularly traumatized minors. In Uganda, The Comfort Dog Project pairs dogs with those traumatized by war. Participants learn how to care for and train the animals as the dogs assist with confidence, help with depression and assist with recovery from post traumatic stress disorder. === Cognitive === Programs such as the Reading Education Assistance Dogs (R.E.A.D.) program promote literacy and communication skills. The practice uses therapy dogs to encourage children to read aloud by giving them a nonjudgmental listener. It has been proven that the academic performance and children's enthusiasm for reading has increased by having a therapeutic dog with them, especially in children with special education. Goals of canine-assisted reading programs include increasing reading fluency, increasing motivation to read, providing encouragement for reluctant readers, and making reading fun. These cognitive benefits can be seen in libraries as well as schools. Internationally, there are programs that use therapy dogs in educational settings such as Germany, Argentina, Finland (Lukukoira Sylvi from Kuopio, Finland was the first animal nominated for Citizen of the Year), and Croatia, for example. An article published by the American Journal of Alzheimer's Disease & Other Dementias reported that during visits with dogs, residents with dementia were able to be involved in special activities and were more verbal than usual. Researchers have identified further cognitive benefits of therapy dogs, which include an increase in mental stimulation and assistance in the recall of memories and the sequence of events. === Physical === Interaction with therapy dogs improves cardiovascular health, and as a result patients may need less medication. Personal pet visitation and animal-assisted interventions (AAIs) can benefit patients' pain, blood pressure, stress, depression, and anxiety, as well as increasing mobility and socialization with staff and families. Further, petting animals promotes the release of hormones that can elevate moods, specifically serotonin, prolactin and oxytocin. Patients receiving occupational therapy have improved their fine motor skills by grooming therapy dogs. Studies have found decreased cortisol levels in children with insecure attachment styles, children with autistic spectrum disorder, in hospital patients with heart failure, and in healthcare professionals, after physical contact with a dog. === Social === Therapy dogs promote greater self-esteem in students and encourage positive interactions with peers and teachers. Additionally, children with autism demonstrated increased verbal abilities and social interaction during therapy sessions when animals were present compared to traditional therapy sessions without them. == Concerns == There are some concerns with using therapy dogs with children and adults in various public facilities. Some include hygiene, allergies, cross-cultural expectations, safety of participants, animal welfare, and lack of consistent training or certification process and liability. AAI (animal-assisted interventions) and AAA (animal-assisted activities) are facilitated by human/dog teams with extensive therapy dog training and have obtained behavioral and health evaluations. They follow guidelines for cleanliness (bathing and brushing dogs before sessions, keeping vaccinations up to date, trimming nails, human hand washing before and after visits) to alleviate most hygiene concerns. In all of these locations, patrons, students or patients are often required to take responsibility for their interactions with dogs in the form of a liability release or parental permission form. Advance considerations of the responsibilities of handlers and the institution or organization include insurance and background checks to address liability. Insurance claims against trained dog teams are rare, however, costs can be high if specialist insurance is not in place. Since therapy dog interaction is an optional activity, those with allergies, those who develop anxiety when near dogs, or those with general opposition to the program need not participate. While there is no nationwide standard for certification or registration of ESAs, many online agencies claim to "register" an animal as an ESA for a fee. The qualifications are not strict which may raise concern. There have been countless incidents of people misusing confusing restrictions, given the sometimes overlapping terminology and recent emergence of service dogs and ESAs. To combat the issue of fraud, numerous states are enacting new regulations, the majority of which are centered on service animals. Some states have more specific laws that focus on exact situations, while other's are more general. == See also == Animal-assisted therapy Postponement of affect Service animal Service dog Therapy cat == References == == External links == Assistance Animal State Laws - Michigan State University Disabilities and Medical Conditions - TSA (Transport Security Administration) Development & Validation of a Research Instrument to Assess the Effectiveness of Animal-Assisted Therapy ‘My Dog Kept Me Sane’: How 9/11 Redefined Therapy Dogs	Wikipedia/Therapy_dog
Supportive psychotherapy is a psychotherapeutic approach that integrates various therapeutic schools such as psychodynamic and cognitive-behavioral, as well as interpersonal conceptual models and techniques. The aim of supportive psychotherapy is to reduce or to relieve the intensity of manifested or presenting symptoms, distress or disability. It also reduces the extent of behavioral disruptions caused by the patient's psychic conflicts or disturbances. Unlike in psychoanalysis, in which the analyst works to maintain a neutral demeanor as a "blank canvas" for transference, in supportive therapy the therapist engages in a fully emotional, encouraging, and supportive relationship with the patient as a method of furthering healthy defense mechanisms, especially in the context of interpersonal relationships. Supportive psychotherapy can be used as treatment for a variety of physical, mental, and emotional ailments, and consists of a variety of strategies and techniques in which therapists or other licensed professionals can treat their patients. The objective of the therapist is to reinforce the patient's healthy and adaptive patterns of thought behaviors in order to reduce the intrapsychic conflicts that produce symptoms of mental disorders. == Evolution of Supportive Psychotherapy == In the late 19th century, Sigmund Freud began to develop the techniques of psychoanalysis, which served as a foundation for all the other psychotherapeutic modalities. Freud found that by letting people talk freely about whatever came to mind (free association), they eventually revealed the origins of their psychological conflicts in disguised form. Upon hearing these confessions revealed through free association, the therapist would then interpret the unconscious cause for the patient's symptoms. In the years following Freud's development of psychoanalysis, this approach was seen as the default in treating mental illness in patients. Psychotherapists faced the problem of patients who were unanalyzable: those without the reflective capacity to hear interpretations, or with “pseudoneurotic schizophrenia”. These patients who would react negatively to psychoanalysis would then receive a more bolstering, “supportive” treatment. This therapy, which would later be recognized as the initial stages of supportive psychotherapy, was not the preferred mode of treatment, not for the preferred patients, and hence, was seen as pejorative from the onset. Franz Alexander studied Freud, and although he was trained in classical psychoanalytic technique, he began to evolve his own ideas about what allowed the curative process to occur in therapy. Alexander noted that in classical psychoanalysis, the essential requirement for change was the insight the patient gained from interpretation of the transference neurosis. Alexander agreed with Freud that during psychoanalysis the patient underwent transference based on earlier life experience and emotional traumas. While Freud believed that the insight the patient gained from this was essential for healing to occur, Alexander felt the process of the patient feeling nurtured or comforted while reliving emotional traumas was also a curative force. He began to look at other factors that might be contributing to improvement, factors not related to insight but rather to the relationship of the patient with the psychoanalyst. The objective of supportive psychotherapy was not to change the patient's personality but to help the patient cope with symptoms, prevent relapse of serious mental illness, or help a relatively healthy person deal with a crisis or transient problem. As defined in earlier years, supportive psychotherapy is a body of techniques, such as praise, advice, exhortation, and encouragement, embedded in psychodynamic understanding and used to treat severely impaired patients. Over the next few decades and with ample studies to demonstrate efficacy, supportive psychotherapy gained momentum among professionals as a practical and efficacious method of therapy and supportive psychotherapy became recognized as the default treatment for patients with more severe psychological symptoms or those who couldn't withstand the rigors of psychoanalysis. == Context and History == === Context === Supportive psychotherapy is often practiced for patients who are considered lower functioning, too fragile, or too unmotivated to participate in more demanding expressive therapy, which might have more chance of leading to personality change. As a dyadic treatment that is characterized by use of direct measures to ameliorate symptoms and to maintain, restore, or improve self-esteem, adaptive skills, and psychological (ego) function, the treatment itself works to observe relationships (real or transferential) and both current and past patterns of emotional or behavioral response. As supportive psychotherapy is introduced in environments less formal than a primary care office, supportive psychotherapy can appear as an expression of interest, attention to concrete services, encouragement and optimism. The relationship between the patient and the professional during supportive treatment exists solely to meet the needs of the patient, and it should not develop as a platonic relationship outside of professionalism. === History === Supportive psychotherapy functions with the objective of reducing anxiety and maintaining a positive patient-therapist relationship with minimal focus on transference. While this practice of therapy is seldom studied, it has since been identified and functions as an alternative to expressive therapy. Supportive psychotherapy and supportive treatment works well for patients who are anticipated to fail at expressive therapy, or who are generally difficult to treat with expressive therapy. An early documentation of supportive psychotherapy can be found in The Journal of Psychotherapy Practice and Research with contributions from David J. Hellerstein, M.D., Henry Pinsker, M.D., Richard N. Rosenthal, M.D., and Steven Klee, Ph.D. In their contributions to the study and exploration of supportive psychotherapy, These researchers note that with supportive and expressive falling on a continuum, the model for individual dynamic psychotherapy should be based on concepts from the supportive end of the continuum, rather than the expressive end. A summary of Otto F. Kernberg's definition of supportive psychotherapy is featured in The Journal of Psychotherapy Practice and Research and defines what supportive therapy does rather than what it is. Kernberg's definition includes actions like: reducing behavioral dysfunctions reducing subjective mental distress supporting and enhancing the patient's strengths, coping skills, and capacity to use environmental supports maximizing treatment autonomy facilitating maximum possible independence from psychiatric illness. == Uses == Supportive psychotherapy has been shown to be effective in a variety of psychiatric conditions including schizophrenia, bipolar disorder, depression, anxiety disorders, personality disorders, substance use disorders, eating disorders, and postpartum depression. Supportive psychotherapy has also shown to be effective in a variety of medical conditions including breast cancer, ovarian cancer, diabetes, leukemia, heart disease, chronic bronchitis, emphysema, inflammatory bowel disease, back pain, and for hemodialysis patients. Additionally, supportive therapy is recognized as the treatment of choice for patients seen by psychiatrists and residents who are suffering from extra-psychic problems, such as poverty, social and political oppression, and abuses of power in relationships that threaten to overwhelm their coping capacities. == Strategies and Techniques == Strategies and techniques associated with supportive psychotherapy include the following: === Listening === Argued by author John Battaglia as “the most powerful skill of supportive psychotherapy”, the element of listening in regards to supportive psychotherapy helps patients feel “heard” by their therapists or health professionals. Effective listening “includes careful attentiveness to the body language, emotional tone, and overall bearing of patients in the sessions.” === Plussing === Plussing is defined as “promoting a positive atmosphere in the therapy by finding the good in the patient and accentuating the positive in the patient’s situation.” Battaglia compares this supportive psychotherapy strategy to “putting on rose-colored glasses and seeing what the patient presents as half full,” and assisting patients with finding a positive outlook even if it appears difficult to find. === Explaining Behavior or Advice === Using the explaining behavior strategy within supportive psychotherapy allows for therapists and health professionals to lead patients to areas of comfort or security as they navigate complex and overwhelming emotions or compulsions. With this technique, the behavioral explanations brought forth by the professional should aim to make sense to the patient and help them feel supported. Advice is another supportive psychotherapy strategy that branches from the explaining behavior technique. Advice is effective usually when the patient is able to connect it to their goals. === Confrontation and Reframing === Confrontation is essentially allowing the patient to reflect and comprehend how their patterns of behavior are contributing to their suffering. Therapists and professionals help guide patients to understanding how repeated behaviors or emotions contribute to their mental health and symptoms. Reframing is related to the technique of confrontation as reframing involves looking at something in a different light or different angle and can provide patients with a new perspective as they undergo supportive psychotherapy. === Encouragement or Praise === Encouragement or Praise is often used in doses that are based on preexisting elements of the patient, such as their history, strengths, and weaknesses. Encouragement should be used sparingly in order to avoid the patient experiencing emotions of falling short to what their therapist expected of them. Using encouragement in this environment combines opportunities for education and movement in order to bring patients upward in their treatment or outside of their comfort zone. Additionally, this technique can be used to reinforce accomplishments or positive changes in behavior, and can be positioned as the reinforcement of the patient's steps towards achieving their stated goals. === Hope === Very similarly to encouragement, hope is to be used sparingly and appropriately by therapists and health professionals in order to “provide enough hope for the patient to see change as a realistic opportunity.” === Metaphor === The use of metaphors is a stimulating element of supportive psychotherapy that “[utilizes] different parts of the patient’s brain than those stimulated by many of the other more language based techniques.” A metaphor is said to “stick” in a patient's head in a “very durable way.” === Coping Skills === Therapists and health professionals assisting patients with developing cognitive and behavioral coping skills is another technique used for supportive psychotherapy. These techniques range in complexity, and can consist of mantras or coping plans for the patient. === Self-soothing === Giving patients the tools necessary to develop self-soothing habits in opposition to unhealthy acting-out behavior, such as extreme mood swings, substance abuse, or acting out. === Creative Opportunities === Creative opportunities allow for therapists and health professionals to introduce their patients to creative outlets in order to express their emotions. Some of these techniques within this strategy include storytelling, journaling, and writing letters they won't send. Some techniques identified, but generally avoided and used with caution are humor and comparing pain. == Studies on Supportive Psychotherapy == In an extensive longitudinal study developed in the 1950s, the "Menninger Psychotherapy Research Project" compared patients receiving psychoanalysis, psychoanalytic psychotherapy, and supportive psychotherapy over a 23-year span. The main objective of the study was to critically examine the difference between psychoanalysis and psychoanalytic psychotherapy. The supportive psychotherapy arm of the study was placed more as a control condition than as a rigorous technique for comparison. The study results concluded there were no significant differences among the three different types of psychotherapy. In one 1978 study looking at treatment of agoraphobia, mixed phobias, or simple phobias, patients were randomly assigned to one of three treatment conditions: behavior therapy alone, behavior therapy plus imipramine (medication) treatment, or supportive therapy plus imipramine (medication) treatment. Therapists in the behavior therapy groups used a manualized, highly structured treatment protocol that included relaxation training and systematic desensitization in imagination, specific in vivo desensitization homework assignments, and assertiveness training (including modeling, role playing, behavior rehearsal, and in vivo homework assignments). The supportive therapy was nondirective; patients took the initiative in all discussions. The therapists doing supportive therapy were instructed to be empathic and non-judgmental and to encourage patients to ventilate feelings and discuss problems, anxieties, and interpersonal relationships. The researchers found that there were no significant differences between the therapy conditions and that patients did well in both. In a 2005 randomized controlled study looking at cognitive-behavioral therapy versus interpersonal therapy for anorexia nervosa, once again supportive psychotherapy was used as a control condition. In the cognitive-behavioral therapy arm of the study, the patients underwent several phases of treatment, including psychoeducation, motivational assessment, cognitive-behavioral skills (including thought restructuring and homework assignments), relapse prevention, and recovery strategies. == Teaching Supportive Psychotherapy == Researchers Arnold Winston, M.D., Richard N. Rosenthal, M.D., and Laura Weiss Roberts, M.D., M.A. express the elusiveness of the field of supportive psychotherapy: it is not based on “rigorous and internally consistent or appealing theory, it does not offer solutions to intractable clinical problems, and the field itself has no conferences, stars, and relatively few books.” In Winston's Rosenthal's and Robert's text, “Learning Supportive Psychotherapy, Second Edition: An Illustrated Guide,” these authors note that “The psychotherapist’s central task is learning to understand...the emotional experience of the patient” (Balsam and Balsam), which was presented universally in regards to teaching supportive psychotherapy. This universal treatment provided little guidance in how to handle patients who were inarticulate or poorly educated, who have intractable social problems, severe behavioral problems, or those who only visited for a couple months at a time or visited biweekly. In 2012, Adam M. Brenner, M.D. advocated for a “much more sophisticated approach” to teaching health professionals and therapists about supportive psychotherapy, which focused on three important factors of supportive psychotherapy: Its relevance for common factors underlying all forms of psychotherapy Its role on a spectrum of psychodynamically informed psychotherapies Its value as a modality that includes specifically definable techniques and aims Brenner also advocated for “teaching supportive psychotherapy in diverse clinical rotations, including inpatient and consultation-liaison services as well as ambulatory settings.” == Criticism about supportive psychotherapy == As the method of supportive psychotherapy grew in popularity among psychologists and healthcare professionals, backlash concerning the effectiveness or validity of nonpsychoanalytic techniques arose. With psychoanalysis, the theory was that once a person improved through gaining insight, he or she underwent a permanent and curative change of personality. By contrast, changes brought about through more supportive types of psychotherapy were seen by critics as behavioral, meaning more transient and specific to the symptoms and not indicative of permanent personality change, which resulted in psychoanalysts believing that supportive-type therapy was not psychotherapy at all. An additional criticism regarding supportive psychotherapy is that it addresses only problems and conflicts that the patient is aware of. Other types of psychotherapy rely on less direct measures, such as identifying unconscious conflicts. Supportive psychotherapy looks at abstract entities such as defense mechanisms only when they seem maladaptive. == See also == Phenomenology Psychotherapy Expressive therapies Supportive communication == References ==	Wikipedia/Supportive_psychotherapy
Drama therapy is the use of theatre techniques to facilitate personal growth and promote mental health. Drama therapy is used in a wide variety of settings, including hospitals, schools, mental health centers, prisons, and businesses. Drama therapy, as a modality of the creative arts therapies, exists in many forms and can apply to individuals, couples, families, and various groups. == History == The historical roots of drama therapy have been discussed by Jones (2007). At different times in history, drama has been used for psychological, political and religious change, such as Aristotle’s idea to use tragedy for ‘catharsis’. Several drama therapists have analyzed the historical roots of drama therapy in the context of ancient traditions and rituals (Jones, 2007). However, according to Jones (2007), the specific connection between drama and therapy did not emerge until the nineteenth century and developed further throughout the twentieth century. The development of drama therapy did not occur through one given pioneer, or even in one field, country or moment. Ideas about drama and healing were formed through several individual journeys and more or less accidental elements. David Johnstone and Renée Emunah stated that in the early stages of drama therapy, most drama therapists started as doers, actors or clinicians, "who discovered for themselves the exciting possibility of linking drama with healing"(Johnstone and Emunah, 2009, p. 16). Robert Landy noted that "(t)he field of drama therapy is an expansive one, developing in a number of countries simultaneously, most notably England, the United States and the Netherlands"(Landy, 1994, p. 32). The Netherlands. In the Netherlands, the emergence of drama therapy has been closely tied to the jobs of activity leader, youth worker and social welfare worker (Jones, 2007). Learning about therapy and arts in these professions increased during the 1950s. Drama in the context of learning about the arts was strongly influenced by ‘play therapy’. Two main influencers in the early stages were Lex Wils and Jan Boomsluiter, who wrote about drama as therapy in the 1950s. Dutch drama therapist Gé Cimmermans argued that the arts therapies, including drama therapy, were initially mainly practiced by artists from Art Academies (Cimmermans, 2014, interviewed by Jorine Beck). Cimmermans (2014) also pointed to the influence of the School of Middeloo. This school was initially set up to train caregivers who had to work with children affected by the Second World War (van der Linde, 2010). Students were trained in using play and creative activities as the main methodology, and gained knowledge in psychology, pedagogy and other courses related to human development. In the 1960s the school started to offer different art therapy courses, based on the experience in teaching both creativity and human development. England. According to Brenda Meldrum (1994), drama therapy in England evolved from drama in education, theatre in education and remedial drama from the 1960s onwards. Meldrum placed the start of drama therapy in the context of the 1960s, when the establishment, including psychiatry, was being questioned and an optimism about new ideas and approaches to learning and the arts was embraced. These radical approaches can similarly be found in Grotowski’s new way of training actors through laboratory theatre, in which the process was therapy for the actors and spectators and the work of Heathcote, who encouraged children to learn and reflect through drama. Meldrum noted that these radical ideas frightened the establishment, but despite that other practitioners were influenced by these ideas and centres for remedial drama and drama therapy started to be formed. In recent years, the wellbeing of actors in the creative industries has come into sharp focus in the UK. Beyond the therapeutic by-products of a life in the theatre, industrial protocols and educational policies are beginning to emerge that offer formalised support for student actors and actors in the profession. Further development of the field After the initial discoveries of the healing aspect of drama, the emerging field of drama therapy became more organized. Different schools of emerged in both the Netherlands and England. In the Netherlands the first two art therapy organisations were formed in the 1960s and from 1974 onwards official training courses were created (Jones, 2007). Cimmermans (2014) asserted that three main schools of thought emerged in drama therapy in The Netherlands: The Creative Process Theory, the Analogue Process Model and the Cognitive Behavioural Model. According to Cimmermans, the Creative Process Theory was influenced by psychoanalytical and Rogerian theory. Henk Smeijsters (2006) wrote that the Creative Process Theory is based on the idea that through the creative arts process the client explores his or her needs, rediscovers suppressed needs, lets go of rigid patterns and experiments with new behaviour that fulfils the new discovered needs. The important element is the ‘aesthetic illusion’ that creates a safe distance in exploring the suppressed needs, which makes it less threatening for the client (Smeijsters, 2006). The Analogue Process Model is based on how the personal characteristics and the mental health issues of the client resonate with the client’s expression in the artistic process. The therapist tunes in with the client’s creative expression and explores alternative ways of thinking, feeling and acting together with the client through play and creativity (Smeijsters, 2006). Cognitive Behavioural Therapy (CBT) can be implemented in drama therapy, for instance in skills-based trainings (Cleven,2004). The emphasis here is on ‘rationalising objectively what clients hear, where and when, based on the idea that thoughts influence the experience, just such as the feeling about and meaning of the thoughts’ (Cleven, 2004, p. 44, translated from Dutch). The dialectical behavioural therapy and schema therapy as sub-branches of CBT, are part of this school of thought in drama therapy (Cimmermans, 2014). In England by 1977 drama therapy was known as an alternative to psychodrama, and the first drama therapy courses were established (Meldrum, 1994). According to Meldrum, Stanislavski, Artaud and Growtowski are influential on the practice of drama therapy in England. The work of Stanislavski provides ideas about character building, the use of unconscious material, the re-creation of feeling and improvisation (Meldrum, 1994). The work of Artaud was inspired by symbolism and was a response to the dominance of realism which he found to be too word-bound and moralistic (Styan, 2003). Artaud argued that emotion is not verbal in itself and thus words cannot communicate the fullness of the human experience. Growtowski’s Poor Theatre was characterized by the rediscovery of the religious and mythical roots of drama (Meldrum, 1994). The Sesame Institute for drama and movement therapy cannot be excluded when discussing important influences in the field of drama therapy in England. The institute was founded by Marian Lindkvist in the 1960s as a response to the dominant drug oriented treatments of mental illnesses (Sesame Institute, 2014). Therapies are based on the key concepts of drama, movement, ritual, play, psyche and touch. Today, drama therapy is practiced around the world and there are presently academic training programs in Britain, Germany, the Netherlands, Canada, Croatia, Israel and the United States. == Core processes == Phil Jones has written in his book Drama as Therapy, Theatre as Living that there are nine core processes at the heart of drama therapy. These include projective identification and dramatic distancing. Projective identification is the process whereby a person feels the feelings that the other is unable to access themselves. Dramatic distancing refers to the way that emotional and psychological problems can be accessed easier through metaphor. The client has a distanced relationship through metaphor to these problems that make them easier to tolerate. == Becoming a drama therapist == In the US and Canada, the governing body is the North American Drama Therapy Association (NADTA), which establishes guidelines for the RDT (Registered Drama Therapist) credential and which provides accreditation for MA level programs and guidelines for alternative track training. In North America, Registered Drama Therapists hold a master's degree from one of five institutions accredited by the National Association for Drama Therapy: Antioch University at Seattle, Washington; Lesley University at Cambridge, Massachusetts; NYU Steinhardt at New York City, New York; California Institute of Integral Studies (CIIS) at San Francisco, California and Concordia University at Montreal, Quebec, Canada. Persons who hold a master's degree in a related field can be registered as a Drama Therapist by pursuing what is known as Alternate Route Training, which consists of graduate coursework and internships performed under the supervision of a board-certified trainer. In The Netherlands, there are fulltime (voltijd) and parttime (deeltijd) Bachelor Dramatherapy qualifications, which are usually 4 years long. Institutions which offer the programs are University of Applied Sciences Hogeschool Arnhem and Nijmegen (HAN), Hogeschool Zuyd and Stenden Hogeschool. The Dutch professional body is the NvDt, the Nederlandse Vereniging voor Dramatherapie. In the UK, the statutory regulator of drama therapists is the HCPC and the professional body is the British Association of Dramatherapists (BADth). There are currently four post-graduate training courses in Dramatherapy in the UK that lead to a qualification approved by the Health Professions Council, accredited by the British Association of Dramatherapists, and recognized by the Department of Health. These courses are offered at Roehampton University, University of Derby, Central School of Speech and Drama, and Anglia Ruskin University. In China, drama therapy is an emerging field. It was first introduced to China in 2013. There have been a few organizations working on the field recently, such as Apollo, Xinyishe etc. The Hong Kong Association of Drama Therapists was established in 2009. Mr. Eddie Yu (President), Adeline Chan (Vice-president), Dorothy Wong and Kevin Ma are the founding members. Missions are to promote the professional development of drama therapists in Hong Kong. Many of these universities suggest specific subjects to complete at degree level if you wish to pursue on to a masters programme in Drama Therapy. Some of these subjects are the following, Drama, Psychology or another such relevant profession. == In practice == The field of drama therapy can be somewhat varied in terms of techniques and procedures. However, there are some general commonalities. At the center of drama, therapy are the elements of role and story. Participants in drama therapy follow roles to tell a story or perform a part, thus embracing a new perspective of the character and themselves. Another key element is space, or where the acting takes place. Other components of drama therapy include ritual, conflict, resistance, spontaneity, distance and catharsis. Drama therapy works to shed light on feelings and behaviors of a person and helps teach them ways to manage and overcome obstacles they struggle with. Clive Barker has called this a "journey through our own psychic landscape." The hope is that by taking on specific roles a person can gain personal insight and break free from barriers. Though this process can be very beneficial and rewarding, it can be very difficult. Progressions and developments can be slow going, and participants may be resistant to the process. Though drama therapy can be done individually, it is typically done in groups or community settings. Groups can involve hundreds of people at a time, but more commonly range from six to ten people in institutional settings. As a form of counseling drama therapy is usually private and doesn't involve spectators. The exception to this rule is therapeutic theatre, which blends the techniques of applied drama to drama therapy. Therapeutic theatre entails the performance of a group of people to a selected audience, making it somewhat public. == See also == == References == == External links == World Alliance of Dramatherapy North American Drama Therapy Association (USA & Canada) British Association of Dramatherapists (UK) Società Professionale Italiana Drammaterapia (IT) The German Association of Dramatherapy (DE) Dramatherapy in Greece and Cyprus (GR) Archived 2013-09-24 at the Wayback Machine	Wikipedia/Drama_therapy
Stem-cell therapy uses stem cells to treat or prevent a disease or condition. As of 2024, the only FDA-approved therapy using stem cells is hematopoietic stem cell transplantation. This usually takes the form of a bone marrow or peripheral blood stem cell transplantation, but the cells can also be derived from umbilical cord blood. Research is underway to develop various sources for stem cells as well as to apply stem-cell treatments for neurodegenerative diseases and conditions such as diabetes and heart disease. Stem-cell therapy has become controversial following developments such as the ability of scientists to isolate and culture embryonic stem cells, to create stem cells using somatic cell nuclear transfer, and their use of techniques to create induced pluripotent stem cells. This controversy is often related to abortion politics and human cloning. Additionally, efforts to market treatments based on transplant of stored umbilical cord blood have been controversial. == Medical uses == For over 90 years, hematopoietic stem cell transplantation (HSCT) has been used to treat people with conditions such as leukemia and lymphoma; this is the only widely practiced form of stem-cell therapy. During chemotherapy, most growing cells are killed by the cytotoxic agents. These agents, however, cannot discriminate between the leukaemia or neoplastic cells, and the hematopoietic stem cells within the bone marrow. This is the side effect of conventional chemotherapy strategies that the stem-cell transplant attempts to reverse; a donor's healthy bone marrow reintroduces functional stem cells to replace the cells lost in the host's body during treatment. The transplanted cells also generate an immune response that helps to kill off the cancer cells; this process can go too far, however, leading to graft vs host disease, the most serious side effect of this treatment. Another stem-cell therapy, called Prococvhymal, was conditionally approved in Canada in 2012 for the management of acute graft-vs-host disease in children who are unresponsive to steroids. It is an allogenic stem therapy based on mesenchymal stem cells (MSCs) derived from the bone marrow of adult donors. MSCs are purified from the marrow, cultured and packaged, with up to 10,000 doses derived from a single donor. The doses are stored frozen until needed. The FDA has approved five hematopoietic stem-cell products derived from umbilical cord blood, for the treatment of blood and immunological diseases. In 2014, the European Medicines Agency recommended approval of limbal stem cells for people with severe limbal stem cell deficiency due to burns in the eye. == Research only == Stem cells are being studied for several reasons. The molecules and exosomes released from stem cells are also being studied in an effort to make medications. In addition to the functions of the cells themselves, paracrine soluble factors produced by stem cells, known as the stem cell secretome, have been found to be another mechanism by which stem cell-based therapies mediate their effects in degenerative, autoimmune, and inflammatory diseases. === Sources for human stem cells === Most stem cells intended for regenerative therapy are generally isolated either from the patient's bone marrow or from adipose tissue. Mesenchymal stem cells can differentiate into the cells that make up bone, cartilage, tendons, and ligaments, as well as muscle, neural and other progenitor tissues. They have been the main type of stem cells studied in the treatment of diseases affecting these tissues. The number of stem cells transplanted into damaged tissue may alter the efficacy of treatment. Accordingly, stem cells derived from bone marrow aspirates, for instance, are cultured in specialized laboratories for expansion to millions of cells. Although adipose-derived tissue also requires processing prior to use, the culturing methodology for adipose-derived stem cells is not as extensive as that for bone marrow-derived cells. While it is thought that bone-marrow-derived stem cells are preferred for bone, cartilage, ligament, and tendon repair, others believe that the less challenging collection techniques and the multi-cellular microenvironment already present in adipose-derived stem cell fractions make the latter the preferred source for autologous transplantation. New sources of mesenchymal stem cells are being researched, including stem cells present in the skin and dermis which are of interest because of the ease at which they can be harvested with minimal risk to the animal. Hematopoietic stem cells have also been discovered to be travelling in the blood stream and possess equal differentiating ability as other mesenchymal stem cells, again with a very non-invasive harvesting technique. There has been more recent interest in the use of extra embryonic mesenchymal stem cells. Research is underway to examine the differentiating capabilities of stem cells found in the umbilical cord, yolk sac and placenta of different animals. These stem cells are thought to have more differentiating ability than their adult counterparts, including the ability to more readily form tissues of endodermal and ectodermal origin. ==== Embryonic stem cell lines ==== As of 2010, there was widespread controversy over the use of human embryonic stem cells. This controversy primarily targets the techniques used to derive new embryonic stem cell lines, which often requires the destruction of the blastocyst. Opposition to the use of human embryonic stem cells in research is often based on philosophical, moral, or religious objections. There is other stem cell research that does not involve the destruction of a human embryo, and such research involves adult stem cells, amniotic stem cells, and induced pluripotent stem cells. In January 2009, the US Food and Drug Administration gave clearance to Geron Corporation for the first clinical trial of an embryonic stem-cell-based therapy on humans. The trial aimed to evaluate the drug GRNOPC1, embryonic stem cell-derived oligodendrocyte progenitor cells, on people with acute spinal cord injury. The trial was discontinued in November 2011 so that the company could focus on therapies in the "current environment of capital scarcity and uncertain economic conditions". In 2013 biotechnology and regenerative medicine company BioTime (AMEX: BTX) acquired Geron's stem cell assets in a stock transaction, with the aim of restarting the clinical trial. ==== Mesenchymal stromal cells (MSCs) ==== Scientists reported 2012 that MSCs when transfused immediately within few hours post thawing may show reduced function or show decreased efficacy in treating diseases as compared to those MSCs which are in log phase of cell growth (fresh), so cryopreserved MSCs should be brought back into log phase of cell growth in in vitro culture before administration. Re-culturing of MSCs will help in recovering from the shock the cells get during freezing and thawing. Various MSC clinical trials which used cryopreserved product immediately post thaw have failed as compared to those clinical trials which used fresh MSCs. === In drug discovery and biomedical research === The ability to grow up functional adult tissues indefinitely in culture through Directed differentiation creates new opportunities for drug research. Researchers are able to grow up differentiated cell lines and then test new drugs on each cell type to examine possible interactions in vitro before performing in vivo studies. This is critical in the development of drugs for use in veterinary research because of the possibilities of species-specific interactions. The hope is that having these cell lines available for research use will reduce the need for research animals used because effects on human tissue in vitro will provide insight not normally known before the animal testing phase. With the advent of induced pluripotent stem cells (iPSC), treatments being explored and created for the used in endangered low production animals possible. Rather than needing to harvest embryos or eggs, which are limited, the researchers can remove mesenchymal stem cells with greater ease and greatly reducing the danger to the animal due to noninvasive techniques. This allows the limited eggs to be put to use for reproductive purposes only. === Stem cell expansion === To be used for research or treatment applications, large numbers of high-quality stem cells are needed. Thus, it is necessary to develop culture systems which produce pure populations of tissue-specific stem cells in vitro without the loss of stem-cell potential. Two main approaches are taken for this purpose: two-dimensional and three-dimensional cell culture. Cell culture in two dimensions has been routinely performed in thousands of laboratories worldwide for the past four decades. In two-dimensional platforms, cells are typically exposed to a solid, rigid flat surface on the basal side and to liquid at the apical surface. Inhabiting such a two-dimensional rigid substrate requires a dramatic adaption for the surviving cells because they lack the extracellular matrix that is unique to each cell type which may alter cell metabolism and reduce its functionality. Three-dimensional cell culture systems may create a biomimicking microenvironment for stem cells, resembling their native three-dimensional extracellular matrix (ECM). Advanced biomaterials have significantly contributed to three-dimensional cell culture systems in recent decades, and more unique and complex biomaterials have been proposed for improving stem-cell proliferation and controlled differentiation. Among them, nanostructured biomaterials are of particular interest because they have the advantage of a high surface-to-volume ratio, and they mimic the physical and biological features of natural ECM at the nanoscale. === Assumed regenerative models === Stem cells are thought to mediate repair via five primary mechanisms: 1) providing an anti-inflammatory effect, 2) homing to damaged tissues and recruiting other cells, such as endothelial progenitor cells, that are necessary for tissue growth, 3) supporting tissue remodeling over scar formation, 4) inhibiting apoptosis, and 5) differentiating into bone, cartilage, tendon, and ligament tissue. To further enrich blood supply to the damaged areas, and consequently promote tissue regeneration, platelet-rich plasma could be used in conjunction with stem cell transplantation. The efficacy of some stem cell populations may also be affected by the method of delivery; for instance, to regenerate bone, stem cells are often introduced in a scaffold where they produce the minerals necessary for generation of functional bone. Stem cells have been shown to have low immunogenicity due to the relatively low number of MHC molecules found on their surface. In addition, they have been found to secrete chemokines that alter the immune response and promote tolerance of the new tissue. This allows for allogeneic treatments to be performed without a high rejection risk. === Potential applications === ==== Neurodegeneration ==== Research has been conducted on the effects of stem cells on animal models of brain degeneration, such as in Parkinson's disease, Amyotrophic lateral sclerosis, and Alzheimer's disease. Preliminary studies related to multiple sclerosis have been conducted, and a 2020 phase 2 trial found significantly improved outcomes for mesenchymal stem cell treated patients compared to those receiving a sham treatment. In January 2021 the FDA approved the first clinical trial for an investigational stem cell therapy to restore lost brain cells in people with advanced Parkinson's disease. Healthy adult brains contain neural stem cells, which divide to maintain general stem-cell numbers, or become progenitor cells. In healthy adult laboratory animals, progenitor cells migrate within the brain and function primarily to maintain neuron populations for olfaction (the sense of smell). Pharmacological activation of endogenous neural stem cells has been reported to induce neuroprotection and behavioral recovery in adult rat models of neurological disorders. ==== Brain and spinal cord injury ==== Stroke and traumatic brain injury lead to cell death, characterized by a loss of neurons and oligodendrocytes within the brain. Clinical and animal studies have been conducted into the experimental use of stem cells in cases of spinal cord injury. ==== Frailty syndrome ==== In 2017, a small-scale study on individuals 60 years or older with aging frailty showed, after intravenous treatment with Mesenchymal stem cells (MSC) from healthy young donors, significant improvements in physical performance measures. MSC helps with the blockade of inflammation by decreasing it, causing the effects of frailty to reverse. ==== Heart ==== In 2012, stem cells were studied in people with severe heart disease. The work by Bodo-Eckehard Strauer was discredited by identifying hundreds of factual contradictions. Among several clinical trials reporting that adult stem cell therapy is safe and effective, actual evidence of benefit has been reported from only a few studies. Some preliminary clinical trials achieved only modest improvements in heart function following the use of bone marrow stem cell therapy. Stem-cell therapy for the treatment of myocardial infarction usually makes use of autologous bone marrow stem cells, but other types of adult stem cells may be used, such as adipose-derived stem cells. Possible mechanisms of recovery include:Generation of heart muscle cells, Stimulating growth of new blood vessels to repopulate damaged heart tissue and secretion of growth factors. ==== Blood-cell formation ==== The specificity of the human immune-cell repertoire is what allows the human body to defend itself from rapidly adapting antigens. However, the immune system is vulnerable to degradation upon the pathogenesis of disease, and because of the critical role that it plays in overall defense, its degradation is often fatal to the organism as a whole. Diseases of hematopoietic cells are diagnosed and classified via a subspecialty of pathology known as hematopathology. The specificity of the immune cells is what allows recognition of foreign antigens, causing further challenges in the treatment of immune disease. Identical matches between donor and recipient are no longer required for successful transplantation. Rather, haploidentical matches have facilitated numerous transplants, given improvements in post-transplant immunosuppressive regimens. Research using both hematopoietic adult stem cells and embryonic stem cells has provided insight into the possible mechanisms and methods of treatment for many of these ailments. Fully mature human red blood cells may be generated ex vivo by hematopoietic stem cells (HSCs), which are precursors of red blood cells. In this process, HSCs are grown together with stromal cells, creating an environment that mimics the conditions of bone marrow, the natural site of red-blood-cell growth. Erythropoietin, a growth factor, is added, coaxing the stem cells to complete terminal differentiation into red blood cells. Further research into this technique should have potential benefits for gene therapy, blood transfusion, and topical medicine. ==== Regrowing teeth ==== In 2004, scientists at King's College London discovered a way to cultivate a complete tooth in mice and were able to grow bioengineered teeth stand-alone in the laboratory. Researchers are confident that tooth regeneration technology can be used to grow live teeth in people. In theory, stem cells taken from the patient could be coaxed in the lab turning into a tooth bud which, when implanted in the gums, will give rise to a new tooth, and would be expected to be grown in a time over three weeks. It will fuse with the jawbone and release chemicals that encourage nerves and blood vessels to connect with it. The process is similar to what happens when humans grow their original adult teeth. Many challenges remain, however, before stem cells can be a choice for the replacement of missing teeth in the future. ==== Cochlear hair cell regrowth ==== Heller has reported success in re-growing cochlea hair cells with the use of embryonic stem cells. In a 2019 review that looked at hearing regeneration and regenerative medicine, stem cell-derived otic progenitors have the potential to greatly improve hearing. ==== Blindness and vision impairment ==== Since 2003, researchers have successfully transplanted corneal stem cells into damaged eyes to restore vision. "Sheets of retinal cells used by the team are harvested from aborted fetuses, which some people find objectionable." When these sheets are transplanted over the damaged cornea, the stem cells stimulate renewed repair, eventually restoring vision. The latest such development was in June 2005, when researchers at the Queen Victoria Hospital of Sussex, England were able to restore the sight of forty people using the same technique. The group, led by Sheraz Daya, was able to successfully use adult stem cells obtained from the patient, a relative, or even a cadaver. Further rounds of trials are ongoing. ==== Pancreatic beta cells ==== People with Type 1 diabetes lose the function of insulin-producing beta cells within the pancreas. In a 2007 publication of experiments, scientists have been able to coax embryonic stem cells to turn into beta cells in the lab. In theory, if the beta cell is transplanted successfully, they will be able to replace malfunctioning ones in a diabetic patient. There are adverse effects of high glucose concentrations on stem cell therapy, however. A key challenge in cell transplantation therapies for Type 1 diabetes is hypoxia and low oxygen conditions in transplant environments that can impair the function and identity of stem cell-derived beta cells. ==== Orthopedics ==== As of 2017, use of mesenchymal stem cells (MSCs) derived from adult stem cells was under preliminary research for potential orthopedic applications in bone and muscle trauma, cartilage repair, osteoarthritis, intervertebral disc surgery, rotator cuff surgery, and musculoskeletal disorders, among others. Other areas of orthopedic research for uses of MSCs include tissue engineering and regenerative medicine. ==== Wound healing ==== Stem cells can also be used to stimulate the growth of human tissues. In an adult, wounded tissue is most often replaced by scar tissue, which is characterized in the skin by disorganized collagen structure, loss of hair follicles and irregular vascular structure. In the case of wounded fetal tissue, however, wounded tissue is replaced with normal tissue through the activity of stem cells. A possible method for tissue regeneration in adults is to place adult stem cell "seeds" inside a tissue bed "soil" in a wound bed and allow the stem cells to stimulate differentiation in the tissue bed cells. This method elicits a regenerative response more similar to fetal wound-healing than adult scar tissue formation. As of 2018, researchers were still investigating different aspects of the "soil" tissue that are conducive to regeneration. Because of the general healing capabilities of stem cells, they have gained interest for the treatment of cutaneous wounds, such as in skin cancer. ==== HIV/AIDS ==== In 2013, scientists have been investigating an alternative approach to treating HIV-1/AIDS, based on the creation of a disease-resistant immune system through transplantation of autologous, gene-modified (HIV-1-resistant) hematopoietic stem and progenitor cells (GM-HSPC). ==== Stem Cell-Derived Exosomes ==== Recent research suggests that stem cell-derived exosomes could become an alternative to stem cell-based therapy to minimize the limitations associated with traditional stem cell therapy such as immunogenicity and tumorigenic risk. == Criticisms == In 2013, studies of autologous bone marrow stem cells on ventricular function were found to contain "hundreds" of discrepancies. Critics report that of 48 reports, just five underlying trials seemed to be used, and that in many cases whether they were randomized or merely observational accepter-versus-rejecter, was contradictory between reports of the same trial. One pair of reports of identical baseline characteristics and final results, was presented in two publications as, respectively, a 578-patient randomized trial and as a 391-subject observational study. Other reports required (impossible) negative standard deviations in subsets of people or contained fractional subjects, negative NYHA classes. Overall, many more people were reported as having receiving stem cells in trials, than the number of stem cells processed in the hospital's laboratory during that time. A university investigation, closed in 2012 without reporting, was reopened in July 2013. In 2014, a meta-analysis on stem cell therapy using bone-marrow stem cells for heart disease revealed discrepancies in published clinical trial reports, whereby studies with a higher number of discrepancies showed an increase in effect sizes. Another meta-analysis based on the intra-subject data of 12 randomized trials was unable to find any significant benefits of stem cell therapy on primary endpoints, such as major adverse events or increase in heart function measures, concluding there was no benefit. 2018 results of the TIME trial, which used a randomized, double-blind, placebo-controlled trial design, concluded that "bone marrow mononuclear cells administration did not improve recovery of LV function over 2 years" in people who had a myocardial infarction. Accordingly, the BOOST-2 trial conducted in 10 medical centers in Germany and Norway reported that the trial result "does not support the use of nucleated BMCs in patients with STEMI and moderately reduced LVEF". Furthermore, the trial also did not meet any other secondary MRI endpoints, leading to a conclusion that intracoronary bone marrow stem cell therapy does not offer a functional or clinical benefit. In 2021, stem cell injections in the US have caused grave infections in at least 20 patients who received umbilical cord blood-derived products marketed as "stem cell treatment". In 2023, the case of a woman who was infected with Mycobacterium abscessus and sustained meningitis after stem cell treatment for multiple sclerosis at a commercial clinic in Baja California, Mexico was published. == Veterinary medicine == Research conducted on horses, dogs, and cats has led to the development of stem cell treatments in veterinary medicine which can target a wide range of injuries and diseases, such as myocardial infarction, stroke, tendon and ligament damage, osteoarthritis, osteochondrosis and muscular dystrophy, both in large animals as well as in humans. While investigation of cell-based therapeutics generally reflects human medical needs, the high degree of frequency and severity of certain injuries in racehorses has put veterinary medicine at the forefront of this novel regenerative approach. Companion animals can serve as clinically relevant models that closely mimic human disease. === Sources of veterinarian stem cells === Veterinary applications of stem cell therapy as a means of tissue regeneration have been largely shaped by research that began with the use of adult-derived mesenchymal stem cells to treat animals with injuries or defects affecting bone, cartilage, ligaments and/or tendons. There are two main categories of stem cells used for treatments: allogeneic stem cells derived from a genetically different donor within the same species, and autologous mesenchymal stem cells, derived from the patient before use in various treatments. A third category, xenogenic stem cells, or stem cells derived from different species, are used primarily for research purposes, especially for human treatments. === Bone repair === Bone has a unique and well-documented natural healing process that normally is sufficient to repair fractures and other common injuries. Misaligned breaks due to severe trauma, as well as treatments like tumor resections of bone cancer, are prone to improper healing if left to the natural process alone. Scaffolds composed of natural and artificial components are seeded with mesenchymal stem cells and placed in the defect. Within four weeks of placing the scaffold, newly formed bone begins to integrate with the old bone and within 32 weeks, full union is achieved. Further studies are necessary to fully characterize the use of cell-based therapeutics for treatment of bone fractures. Stem cells have been used to treat degenerative bone diseases in dogs. The normally recommended treatment for dogs that have Legg–Calve–Perthes disease is to remove the head of the femur after the degeneration has progressed. Recently, mesenchymal stem cells have been injected directly in to the head of the femur, with success not only in bone regeneration, but also in pain reduction. === Ligament and tendon repair === Autologous stem cell-based treatments for ligament injury, tendon injury, osteoarthritis, osteochondrosis, and sub-chondral bone cysts have been commercially available to practicing veterinarians to treat horses since 2003 in the United States and since 2006 in the United Kingdom. Autologous stem cell based treatments for tendon injury, ligament injury, and osteoarthritis in dogs have been available to veterinarians in the United States since 2005. Over 3000 privately owned horses and dogs have been treated with autologous adipose-derived stem cells. The efficacy of these treatments has been shown in double-blind clinical trials for dogs with osteoarthritis of the hip and elbow and horses with tendon damage. Race horses are especially prone to injuries of the tendon and ligaments. Conventional therapies are very unsuccessful in returning the horse to full functioning potential. Natural healing, guided by the conventional treatments, leads to the formation of fibrous scar tissue that reduces flexibility and full joint movement. Traditional treatments prevented a large number of horses from returning to full activity and also have a high incidence of re-injury due to the stiff nature of the scarred tendon. Introduction of both bone marrow and adipose derived stem cells, along with natural mechanical stimulus promoted the regeneration of tendon tissue. The natural movement promoted the alignment of the new fibers and tendocytes with the natural alignment found in uninjured tendons. Stem cell treatment not only allowed more horses to return to full duty and also greatly reduced the re-injury rate over a three-year period. The use of embryonic stem cells has also been applied to tendon repair. The embryonic stem cells were shown to have a better survival rate in the tendon as well as better migrating capabilities to reach all areas of damaged tendon. The overall repair quality was also higher, with better tendon architecture and collagen formed. There was also no tumor formation seen during the three-month experimental period. Long-term studies need to be carried out to examine the long-term efficacy and risks associated with the use of embryonic stem cells. Similar results have been found in small animals. ==== Joint repair ==== Osteoarthritis is the main cause of joint pain both in animals and humans. Horses and dogs are most frequently affected by arthritis. Natural cartilage regeneration is very limited. Different types of mesenchymal stem cells and other additives are still being researched to find the best type of cell and method for long-term treatment. Adipose-derived mesenchymal cells are currently the most often used for stem cell treatment of osteoarthritis because of the non-invasive harvesting. This is a recently developed, non-invasive technique developed for easier clinical use. Dogs receiving this treatment showed greater flexibility in their joints and less pain. === Muscle repair === Stem cells have successfully been used to ameliorate healing in the heart after myocardial infarction in dogs. Adipose and bone marrow derived stem cells were removed and induced to a cardiac cell fate before being injected into the heart. The heart was found to have improved contractility and a reduction in the damaged area four weeks after the stem cells were applied. In 2007, a trial was underway for a patch made of a porous substance onto which the stem cells are "seeded" in order to induce tissue regeneration in heart defects. Tissue was regenerated and the patch was well incorporated into the heart tissue. This is thought to be due, in part, to improved angiogenesis and reduction of inflammation. Although cardiomyocytes were produced from the mesenchymal stem cells, they did not appear to be contractile. Other treatments that induced a cardiac fate in the cells before transplanting had greater success at creating contractile heart tissue. 2018 research, such as the European nTRACK research project, aims to demonstrate that multimodal nanoparticles can structurally and functionally track stem cell in muscle regeneration therapy. The idea is to label stem cells with gold nano-particles that are fully characterised for uptake, functionality, and safety. The labelled stem cells will be injected into an injured muscle and tracked using imaging systems. However, the system still needs to be demonstrated at lab scale. === Nervous system repair === Spinal cord injuries are one of the most common traumas brought into veterinary hospitals. Spinal injuries occur in two ways after the trauma: the primary mechanical damage, and in secondary processes, like inflammation and scar formation, in the days following the trauma. These cells involved in the secondary damage response secrete factors that promote scar formation and inhibit cellular regeneration. Mesenchymal stem cells that are induced to a neural cell fate are loaded onto a porous scaffold and are then implanted at the site of injury. The cells and scaffold secrete factors that counteract those secreted by scar forming cells and promote neural regeneration. Eight weeks later, dogs treated with stem cells showed immense improvement over those treated with conventional therapies. Dogs treated with stem cells were able to occasionally support their own weight, which has not been seen in dogs undergoing conventional therapies. In a study to evaluate the treatment of experimentally induced MS in dogs using laser activated non-expanded adipose derived stem cells. The results showed amelioration of the clinical signs over time confirmed by the resolution of the previous lesions on MRI. Positive migration of the injected cells to the site of lesion, increased remyelination detected by Myelin Basic Proteins, positive differentiation into Olig2 positive oligodendrocytes, prevented the glial scar formation and restored axonal architecture. Treatments are also in clinical trials to repair and regenerate peripheral nerves. Peripheral nerves are more likely to be damaged, but the effects of the damage are not as widespread as seen in injuries to the spinal cord. Treatments are currently in clinical trials to repair severed nerves, with early success. Stem cells induced to a neural fate injected in to a severed nerve. Within four weeks, regeneration of previously damaged stem cells and completely formed nerve bundles were observed. Stem cells are also in clinical phases for treatment in ophthalmology. Hematopoietic stem cells have been used to treat corneal ulcers of different origin of several horses. These ulcers were resistant to conventional treatments available, but quickly responded positively to the stem cell treatment. Stem cells were also able to restore sight in one eye of a horse with retinal detachment, allowing the horse to return to daily activities. === Conservation === Stem cells are being explored for use in conservation efforts. Spermatogonial stem cells have been harvested from a rat and placed into a mouse host and fully mature sperm were produced with the ability to produce viable offspring. Currently research is underway to find suitable hosts for the introduction of donor spermatogonial stem cells. If this becomes a viable option for conservationists, sperm can be produced from high genetic quality individuals who die before reaching sexual maturity, preserving a line that would otherwise be lost. == Society and culture == === Marketing and costs === In the late 1990s and early 2000s, there was an initial wave of companies and clinics offering stem cell therapy, while not substantiating health claims or having regulatory approval. By 2012, a second wave of companies and clinics had emerged, usually located in developing countries where medicine is less regulated and offering stem cell therapies on a medical tourism model. Like the first wave companies and clinics, they made similar strong, but unsubstantiated, claims, mainly by clinics in the United States, Mexico, Thailand, India, and South Africa. By 2016, research indicated that there were more than 550 stem cell clinics in the US alone selling generally unproven therapies for a wide array of medical conditions in almost every state in the country, altering the dynamic of stem cell tourism. In 2018, the FDA sent a warning letter to StemGenex Biologic Laboratories in San Diego, which marketed a service in which it took body fat from people, processed it into mixtures it said contained various forms of stem cells, and administered it back to the person by inhalation, intravenously, or infusion into their spinal cords; the company said the treatment was useful for many chronic and life-threatening conditions. One common marketing tactic is registering on ClinicalTrials.gov, the US government database for clinical trials. Registration of a study notifies the agency but does not prove that review has taken place. Registration with the FDA similarly does not prove that approval has been granted. Costs of stem cell therapies range widely by clinic, condition, and cell type, but most commonly range between $10,000-$20,000. Insurance does not cover stem cell injections at clinics so patients often use on-line fundraising. In 2018, the US Federal Trade Commission found health centers and an individual physician making unsubstantiated claims for stem cell therapies, and forced refunds of some $500,000. The FDA filed suit against two stem cell clinic firms around the same time, seeking permanent injunctions against their marketing and use of unapproved adipose stem cell products. === COVID-19-related marketing and government agency responses === Although according to the NIH no stem cell treatments have been approved for COVID-19, and the agency recommends against the use of MSCs for the disease, some stem cell clinics began marketing both unproven and non-FDA-approved stem cells and exosomes for COVID-19 in 2020. The FDA took prompt action by sending letters to the firms in question. The FTC also warned a stem cell firm for misleading COVID-19-related marketing. == See also == == References == == External links == Media related to Stem-cell therapy at Wikimedia Commons EuroStemCell: types of stem cells and their uses	Wikipedia/Stem_cell_therapy
Dark therapy is the practice of keeping people in complete darkness for extended periods of time in an attempt to treat psychological conditions. The human body produces the melatonin hormone, which is responsible for supporting the circadian rhythms. Darkness seems to help keep these circadian rhythms stable. Dark therapy was said to be founded by a German anthropologist by the name of Holger Kalweit. A form of dark therapy is to block blue wavelength lights to stop the disintegration of melatonin. This dark therapy concept was originated back in 1998 from a research which suggested that systematic exposure to darkness might alter people's mood. Original studies enforced 14 hours of darkness to bipolar patients for three nights straight. This study showed a decrease of manic episodes in the patients. Participation in this study became unrealistic, as patients did not want to participate in treatment of total darkness from 6 p.m. to 8 a.m. More recently, with the discovery of intrinsically photosensitive retinal ganglion cells, it has been hypothesized that similar results could be achieved by blocking blue light, as a potential treatment for bipolar disorder. Moreover, researchers exploring blue-blocking glasses have so far considered dark therapy only as an add-on treatment to be used together with psychotherapy, rather than a replacement for other therapies. Another study consisting of healthy females and males suggested that a single exposure to blue light after being kept in a dim setting could reduce sleepiness. Contrary to the original claim that decreasing the amount of blue light could help with insomnia, this study suggested improvement with blue light exposure. == See also == Clinical depression Light therapy Seasonal affective disorder Sleep hygiene == References ==	Wikipedia/Dark_therapy
Gold-containing drugs are pharmaceuticals that contain gold. Sometimes these species are referred to as "gold salts". "Chrysotherapy" and "aurotherapy" are the applications of gold compounds to medicine. Research on the medicinal effects of gold began in 1935, primarily to reduce inflammation and to slow disease progression in patients with rheumatoid arthritis. The use of gold compounds has decreased since the 1980s because of numerous side effects and monitoring requirements, limited efficacy, and very slow onset of action. Most chemical compounds of gold, including some of the drugs discussed below, are not salts, but are examples of metal thiolate complexes. In the modern period research has increased on gold nanoparticles which has applications in diagnostics, drug delivery and various therapies. == Use in rheumatoid arthritis == Investigation of medical applications of gold began at the end of the 19th century, when gold cyanide demonstrated efficacy in treating Mycobacterium tuberculosis in vitro. === Indications === The use of injected gold compound is indicated for rheumatoid arthritis. Its uses have diminished with the advent of newer compounds such as methotrexate and because of numerous side effects. The efficacy of orally administered gold is more limited than injecting the gold compounds. === Mechanism in arthritis === The mechanism by which gold drugs affect arthritis is unknown. === Administration === Gold-containing drugs for rheumatoid arthritis are administered by intramuscular injection but can also be administered orally (although the efficacy is low). Regular urine tests to check for protein, indicating kidney damage, and blood tests are required. === Efficacy === A 1997 review (Suarez-Almazor ME, et al) reports that treatment with intramuscular gold (parenteral gold) reduces disease activity and joint inflammation. Gold-containing drugs taken by mouth are less effective than by injection. Three to six months are often required before gold treatment noticeably improves symptoms. == Side effects == === Chrysiasis === A noticeable side-effect of gold-based therapy is skin discoloration, in shades of mauve to a purplish dark grey when exposed to sunlight. Skin discoloration occurs when gold salts are taken on a regular basis over a long period of time. Excessive intake of gold salts while undergoing chrysotherapy results – through complex redox processes – in the saturation by relatively stable gold compounds of skin tissue and organs (as well as teeth and ocular tissue in extreme cases) in a condition known as chrysiasis. This condition is similar to argyria, which is caused by exposure to silver salts and colloidal silver. Chrysiasis can ultimately lead to acute kidney injury (such as tubular necrosis, nephrosis, glomerulitis), severe heart conditions, and hematologic complications (leukopenia, anemia). While some effects can be healed with moderate success, the skin discoloration is considered permanent. === Other side effects === Other side effects of gold-containing drugs include kidney damage, itching rash, and ulcerations of the mouth, tongue, and pharynx. Approximately 35% of patients discontinue the use of gold salts because of these side effects. Kidney function must be monitored continuously while taking gold compounds. == Types == Disodium aurothiomalate Sodium aurothiosulfate (Gold sodium thiosulfate) Sodium aurothiomalate (Gold sodium thiomalate) (UK) Auranofin (UK & US) Aurothioglucose (Gold thioglucose) (US) == References == == External links == "Gold salts for juvenile rheumatoid arthritis". BCHealthGuide.org "Gold salts information". DiseasesDatabase.com "HMS researchers find how gold fights arthritis: Sheds light on how medicinal metal function against rheumatoid arthritis and other autoimmune diseases." Harvard University Gazette (2006) "Aurothioglucose is a gold salt used in treating inflammatory arthritis". MedicineNet.com "About gold treatment: What is it? Gold treatment includes different forms of gold salts used to treat arthritis." Washington.edu University of Washington (December 30, 2004)	Wikipedia/Chrysotherapy
Feminizing hormone therapy, also known as transfeminine hormone therapy, is a form of gender-affirming care and a gender-affirming hormone therapy to change the secondary sex characteristics of transgender people from masculine to feminine. It is a common type of transgender hormone therapy (another being masculinizing hormone therapy) and is used to treat transgender women and non-binary transfeminine individuals. Some, in particular intersex people, but also some non-transgender people, take this form of therapy according to their personal needs and preferences. The purpose of the therapy is to cause the development of the secondary sex characteristics of the desired sex, such as breasts and a feminine pattern of hair, fat, and muscle distribution. It cannot undo many of the changes produced by naturally occurring puberty, which may necessitate surgery and other treatments to reverse (see below). The medications used for feminizing hormone therapy include estrogens, antiandrogens, progestogens, and gonadotropin-releasing hormone modulators (GnRH modulators). Feminizing hormone therapy has been empirically shown to reduce the distress and discomfort associated with gender dysphoria in transfeminine individuals. == Requirements == Many physicians operate by the World Professional Association of Transgender Health (WPATH) Standards of Care (SoC) model and require psychotherapy and a letter of recommendation from a psychotherapist in order for a transgender person to obtain hormone therapy. Other physicians operate by an informed consent model and have no requirements for transgender hormone therapy aside from consent. Medications used in transgender hormone therapy are also sold without a prescription on the Internet by unregulated online pharmacies, and some transgender women purchase these medications and treat themselves using a do-it-yourself (DIY) or self-medication approach. One reason that many transgender people turn to DIY hormone therapy is due to long waiting lists of up to years for standard physician-based hormone therapy in some parts of the world such as the United Kingdom, as well as due to the often high costs of seeing a physician and the restrictive criteria that make some ineligible for treatment. The accessibility of transgender hormone therapy differs throughout the world and throughout individual countries. == Medications == A variety of different sex-hormonal medications are used in feminizing hormone therapy for transgender women. These include estrogens to induce feminization and suppress testosterone levels; antiandrogens such as androgen receptor antagonists, antigonadotropins, GnRH modulators, and 5α-reductase inhibitors to further oppose the effects of androgens like testosterone; and progestogens for various possible though uncertain benefits. An estrogen in combination with an antiandrogen is the mainstay of feminizing hormone therapy for transgender women. === Estrogens === Estrogens are the major sex hormones in women, and are responsible for the development and maintenance of feminine secondary sexual characteristics, such as breasts, wide hips, and a feminine pattern of fat distribution. Estrogens act by binding to and activating the estrogen receptor (ER), their biological target in the body. A variety of different forms of estrogens are available and used medically. The most common estrogens used in transgender women include estradiol, which is the predominant natural estrogen in women, and estradiol esters such as estradiol valerate and estradiol cypionate, which are prodrugs of estradiol. Conjugated estrogens (Premarin), which are used in menopausal hormone therapy, and ethinylestradiol, which is used in birth control pills, have been used in transgender women in the past, but are no longer recommended and are rarely used today due to their higher risks of blood clots and cardiovascular problems. Estrogens may be administered orally, sublingually, transdermally/topically (via patch or gel), rectally, by intramuscular or subcutaneous injection, or by an implant. Parenteral (non-oral) routes are practically preferred, owing to a minimal or negligible risk of blood clots and cardiovascular issues. The pharmacokinetics of estradiol's routes of administration vary greatly. Sublingual and rectal administration result in peak concentrations up to ten times higher than oral administration, and higher trough concentrations. This makes frequent, small sublingual or rectal doses, a very efficient way to create a stable and constant increase in trough levels. A large amount of estradiol consumed sublingually, and especially orally is converted by the GI tract into estrone and other compounds, causing a higher estrone:estradiol (E1:E2) ratio. This means oral doses are more subject to individual variances in enzymes and physiological chemistry. The extent of the estrone ratio's effects are unclear but, as a weaker estrogen agonist than estradiol, a high estrone level can reduce feminization by competitive antagonism. A high estrone ratio is linked to reduced skeletal growth in pubertal boys and insulin resistance in PCOS. The ratio is also known to be higher in early female puberty (~1:3), and lower in the later stages (~1-5). An average dose intramuscular injection can vary from far above to far below the average female range over the course of a week, depending on an individual's body. In addition to producing feminization, estrogens have antigonadotropic effects, suppressing testosterone and other gonadal sex hormones. Levels of estradiol of 200 pg/mL and above suppress testosterone levels by about 90%, while estradiol levels of 500 pg/mL and above suppress testosterone levels by about 95%, or to an equivalent extent as surgical castration and GnRH modulators. Lower levels of estradiol can also considerably but incompletely suppress testosterone production. When testosterone levels are insufficiently suppressed by estradiol alone, antiandrogens can be used to suppress or block the effects of residual testosterone. Oral estradiol often has difficulty adequately suppressing testosterone levels, due to the relatively low estradiol levels achieved with it. Prior to orchiectomy (surgical removal of the gonads) or sex reassignment surgery, the doses of estrogens used in transgender women are often higher than replacement doses used in cisgender women. This is to help suppress testosterone levels. The Endocrine Society (2017) recommends maintaining estradiol levels roughly within the normal average range for premenopausal women of about 100 to 200 pg/mL. However, it notes that these physiological levels of estradiol are usually unable to suppress testosterone levels into the female range. A 2018 Cochrane review proposal questioned the notion of keeping estradiol levels lower in transgender women, which results in incomplete suppression of testosterone levels and necessitates the addition of antiandrogens. The review proposal noted that high-dose parenteral estradiol is known to be safe. The Endocrine Society itself recommends dosages of injected estradiol esters that result in estradiol levels markedly in excess of the normal female range, for instance 10 mg per week estradiol valerate by intramuscular injection. A single such injection results in estradiol levels of about 1,250 pg/mL at peak and levels of around 200 pg/mL after 7 days. Dosages of estrogens can be reduced after an orchiectomy or sex reassignment surgery, when gonadal testosterone suppression is no longer needed. === Antiandrogens === Antiandrogens are medications that prevent the effects of androgens in the body. Androgens, such as testosterone and dihydrotestosterone (DHT), are the major sex hormones in individuals with testes, and are responsible for the development and maintenance of masculine secondary sex characteristics, such as a deep voice, broad shoulders, and a masculine pattern of hair, muscle, and fat distribution. In addition, androgens stimulate sex drive and the frequency of spontaneous erections and are responsible for acne, body odor, and androgen-dependent scalp hair loss. Androgens also have functional antiestrogenic effects in the breasts and oppose estrogen-mediated breast development, even at low levels. Androgens act by binding to and activating the androgen receptor, their biological target in the body. Antiandrogens work by blocking androgens from binding to the androgen receptor and/or by inhibiting or suppressing the production of androgens. Antiandrogens that directly block the androgen receptor are known as androgen receptor antagonists or blockers, while antiandrogens that inhibit the enzymatic biosynthesis of androgens are known as androgen synthesis inhibitors and antiandrogens that suppress androgen production in the gonads are known as antigonadotropins. Estrogens and progestogens are antigonadotropins and hence are functional antiandrogens. The purpose of the use of antiandrogens in transgender women is to block or suppress residual testosterone that is not suppressed by estrogens alone. Additional antiandrogen therapy is not necessarily required if testosterone levels are in the normal female range or if the person has undergone orchiectomy. However, individuals with testosterone levels in the normal female range and with persisting androgen-dependent skin and/or hair symptoms, such as acne, seborrhea, oily skin, or scalp hair loss, can potentially still benefit from the addition of an antiandrogen, as antiandrogens can reduce or eliminate such symptoms. ==== Steroidal antiandrogens ==== Steroidal antiandrogens are antiandrogens that resemble steroid hormones like testosterone and progesterone in chemical structure. They are the most commonly used antiandrogens in transgender women. Spironolactone (Aldactone), which is relatively safe and inexpensive, is the most frequently used antiandrogen in the United States. Cyproterone acetate (Androcur), which is unavailable in the United States, is widely used in Europe, Canada, and the rest of the world. Medroxyprogesterone acetate (Provera, Depo-Provera), a similar medication, is sometimes used in place of cyproterone acetate in the United States. Spironolactone is an antimineralocorticoid (antagonist of the mineralocorticoid receptor) and potassium-sparing diuretic, which is mainly used to treat high blood pressure, edema, high aldosterone levels, and low potassium levels caused by other diuretics, among other uses. Spironolactone is an antiandrogen as a secondary and originally unintended action. It works as an antiandrogen mainly by acting as an androgen receptor antagonist. The medication is also a weak steroidogenesis inhibitor, and inhibits the enzymatic synthesis of androgens. However, this action is of low potency, and spironolactone has mixed and inconsistent effects on hormone levels. In any case, testosterone levels are usually unchanged by spironolactone. Studies in transgender women have found testosterone levels to be unaltered with spironolactone or to be decreased. Spironolactone is described as a relatively weak antiandrogen. It is widely used in the treatment of acne, excessive hair growth, and hyperandrogenism in women, who have much lower testosterone levels than men. Because of its antimineralocorticoid activity, spironolactone has antimineralocorticoid side effects and can cause high potassium levels. Hospitalization and/or death can potentially result from high potassium levels due to spironolactone, but the risk of high potassium levels in people taking spironolactone appears to be minimal in those without risk factors for it. As such, monitoring of potassium levels may not be necessary in most cases. Spironolactone has been found to decrease the bioavailability of high doses of oral estradiol. Although widely employed, the use of spironolactone as an antiandrogen in transgender women has recently been questioned due to the various shortcomings of the medication for such purposes. Cyproterone acetate is an antiandrogen and progestin which is used in the treatment of numerous androgen-dependent conditions and is also used as a progestogen in birth control pills. It works primarily as an antigonadotropin, secondarily to its potent progestogenic activity, and strongly suppresses gonadal androgen production. Cyproterone acetate at a dosage of 5 to 10 mg/day has been found to lower testosterone levels in men by about 50 to 70%, while a dosage of 100 mg/day has been found to lower testosterone levels in men by about 75%. The combination of 25 mg/day cyproterone acetate and a moderate dosage of estradiol has been found to suppress testosterone levels in transgender women by about 95%. In combination with estrogen, 10, 25, and 50 mg/day cyproterone acetate have all shown the same degree of testosterone suppression. In addition to its actions as an antigonadotropin, cyproterone acetate is an androgen receptor antagonist. However, this action is relatively insignificant at low dosages, and is more important at the high doses of cyproterone acetate that are used in the treatment of prostate cancer (100–300 mg/day). Cyproterone acetate can cause elevated liver enzymes and liver damage, including liver failure. However, this occurs mostly in prostate cancer patients who take very high doses of cyproterone acetate; liver toxicity has not been reported in transgender women. Cyproterone acetate also has a variety of other adverse effects, such as fatigue and weight gain, and risks, such as blood clots and benign brain tumors, among others. High dosages of cyproterone-based medication have been linked with meningioma. Periodic monitoring of liver enzymes and prolactin levels may be advisable during cyproterone acetate therapy. Medroxyprogesterone acetate is a progestin that is related to cyproterone acetate and is sometimes used as an alternative to it. It is specifically used as an alternative to cyproterone acetate in the United States, where cyproterone acetate is not approved for medical use and is unavailable. Medroxyprogesterone acetate suppresses testosterone levels in transgender women similarly to cyproterone acetate. Oral medroxyprogesterone acetate has been found to suppress testosterone levels in men by about 30 to 75% across a dosage range of 20 to 100 mg/day. In contrast to cyproterone acetate however, medroxyprogesterone acetate is not also an androgen receptor antagonist. Medroxyprogesterone acetate has similar side effects and risks as cyproterone acetate, but is not associated with liver problems. Numerous other progestogens and by extension antigonadotropins have been used to suppress testosterone levels in men and are likely useful for such purposes in transgender women as well. Progestogens alone are in general able to suppress testosterone levels in men by a maximum of about 70 to 80%, or to just above female/castrate levels when used at sufficiently high doses. The combination of a sufficient dosage of a progestogen with very small doses of an estrogen (e.g., as little as 0.5–1.5 mg/day oral estradiol) is synergistic in terms of antigonadotropic effect and is able to fully suppress gonadal testosterone production, reducing testosterone levels to the female/castrate range. ==== Nonsteroidal antiandrogens ==== Nonsteroidal antiandrogens are antiandrogens which are nonsteroidal and hence unrelated to steroid hormones in terms of chemical structure. These medications are primarily used in the treatment of prostate cancer, but are also used for other purposes such as the treatment of acne, excessive facial/body hair growth, and high androgen levels in women. Unlike steroidal antiandrogens, nonsteroidal antiandrogens are highly selective for the androgen receptor and act as pure androgen receptor antagonists. Similarly to spironolactone however, they do not lower androgen levels, and instead work exclusively by preventing androgens from activating the androgen receptor. Nonsteroidal antiandrogens are more efficacious androgen receptor antagonists than are steroidal antiandrogens, and for this reason, in conjunction with GnRH modulators, have largely replaced steroidal antiandrogens in the treatment of prostate cancer. The nonsteroidal antiandrogens that have been used in transgender women include the first-generation medications flutamide (Eulexin), nilutamide (Anandron, Nilandron), and bicalutamide (Casodex). Newer and even more efficacious second-generation nonsteroidal antiandrogens like enzalutamide (Xtandi), apalutamide (Erleada), and darolutamide (Nubeqa) also exist, but are very expensive due to generics being unavailable and have not been used in transgender women. Flutamide and nilutamide have relatively high toxicity, including considerable risks of liver damage and lung disease. Due to its risks, the use of flutamide in cisgender and transgender women is now limited and discouraged. Flutamide and nilutamide have largely been superseded by bicalutamide in clinical practice, with bicalutamide accounting for almost 90% of nonsteroidal antiandrogen prescriptions in the United States by the mid-2000s. Bicalutamide is said to have excellent tolerability and safety relative to flutamide and nilutamide, as well as in comparison to cyproterone acetate. It has few to no side effects in women. Despite its greatly improved tolerability and safety profile however, bicalutamide does still have a small risk of elevated liver enzymes and association with rare cases of serious liver damage and lung disease. Nonsteroidal antiandrogens like bicalutamide may be a particularly favorable option for transgender women who wish to preserve sex drive, sexual function, and/or fertility, relative to antiandrogens that suppress testosterone levels and can greatly disrupt these functions such as cyproterone acetate and GnRH modulators. However, estrogens suppress testosterone levels and at high doses can markedly disrupt sex drive and function and fertility on their own. Moreover, disruption of gonadal function and fertility by estrogens may be permanent after extended exposure. ==== GnRH modulators ==== GnRH modulators are antigonadotropins and hence functional antiandrogens. In both males and females, gonadotropin-releasing hormone (GnRH) is produced in the hypothalamus and induces the secretion of the gonadotropins luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from the pituitary gland. The gonadotropins signal the gonads to make sex hormones such as testosterone and estradiol. GnRH modulators bind to and inhibit the GnRH receptor, thereby preventing gonadotropin release. As a result of this, GnRH modulators are able to completely shut-down gonadal sex hormone production, and can decrease testosterone levels in men and transgender women by about 95%, or to an equivalent extent as surgical castration. GnRH modulators are also commonly known as GnRH analogues. However, not all clinically used GnRH modulators are analogues of GnRH. There are two types of GnRH modulators: GnRH agonists and GnRH antagonists. These medications have the opposite action on the GnRH receptor but paradoxically have the same therapeutic effects. GnRH agonists, such as leuprorelin (Lupron), goserelin (Zoladex), and buserelin (Suprefact), are GnRH receptor superagonists, and work by producing profound desensitization of the GnRH receptor such that the receptor becomes non-functional. This occurs because GnRH is normally released in pulses, but GnRH agonists are continuously present, and this results in excessive downregulation of the receptor and ultimately a complete loss of function. At the initiation of treatment, GnRH agonists are associated with a "flare" effect on hormone levels due to acute overstimulation of the GnRH receptor. In men, LH levels increase by up to 800%, while testosterone levels increase to about 140 to 200% of baseline. Gradually however, the GnRH receptor desensitizes; testosterone levels peak after about 2 to 4 days, return to baseline after about 7 to 8 days, and are reduced to castrate levels within 2 to 4 weeks. Antigonadotropins such as estrogens and cyproterone acetate as well as nonsteroidal antiandrogens such as flutamide and bicalutamide can be used beforehand and concomitantly to reduce or prevent the effects of the testosterone flare caused by GnRH agonists. In contrast to GnRH agonists, GnRH antagonists, such as degarelix (Firmagon) and elagolix (Orilissa), work by binding to the GnRH receptor without activating it, thereby displacing GnRH from the receptor and preventing its activation. Unlike with GnRH agonists, there is no initial surge effect with GnRH antagonists; the therapeutic effects are immediate, with sex hormone levels being reduced to castrate levels within a few days. GnRH modulators are highly effective for testosterone suppression in transgender women and have few or no side effects when sex hormone deficiency is avoided with concomitant estrogen therapy. However, GnRH modulators tend to be very expensive (typically US$10,000 to US$15,000 per year in the United States), and are often denied by medical insurance. GnRH modulator therapy is much less economical than surgical castration, and is less convenient than surgical castration in the long-term as well. Because of their costs, many transgender women cannot afford GnRH modulators and must use other, often less effective options for testosterone suppression. GnRH agonists are prescribed as standard practice for transgender women in the United Kingdom however, where the National Health Service (NHS) covers them. This is in contrast to the rest of Europe and to the United States. Another drawback of GnRH modulators is that most of them are peptides and are not orally active, requiring administration by injection, implant, or nasal spray. However, non-peptide and orally active GnRH antagonists, elagolix (Orilissa) and relugolix (Relumina), were introduced for medical use in 2018 and 2019, respectively. But they are under patent protection and, as with other GnRH modulators, are very expensive at present. In adolescents of either sex, GnRH modulators can be used to suppress puberty. The eighth edition of the World Professional Association for Transgender Health's Standards of Care permit its use from Tanner stage 2 and recommends GnRH agonists as the preferred method of puberty blocking. ==== 5α-Reductase inhibitors ==== 5α-Reductase inhibitors are inhibitors of the enzyme 5α-reductase, and are a type of specific androgen synthesis inhibitor. 5α-Reductase is an enzyme that is responsible for the conversion of testosterone into the more potent androgen dihydrotestosterone (DHT). There are three different isoforms of 5α-reductase, types 1, 2, and 3, and these three isoforms show different patterns of expression in the body. Relative to testosterone, DHT is about 2.5- to 10-fold more potent as an agonist of the androgen receptor. As such, 5α-reductase serves to considerably potentiate the effects of testosterone. However, 5α-reductase is expressed only in specific tissues, such as skin, hair follicles, and the prostate gland, and for this reason, conversion of testosterone into DHT happens only in certain parts of the body. Furthermore, circulating levels of total and free DHT in men are very low at about one-tenth and one-twentieth those of testosterone, respectively, and DHT is efficiently inactivated into weak androgens in various tissues such as muscle, fat, and liver. As such, it is thought that DHT plays little role as a systemic androgen hormone and serves more as a means of locally potentiating the androgenic effects of testosterone in a tissue-specific manner. Conversion of testosterone into DHT by 5α-reductase plays an important role in male reproductive system development and maintenance (specifically of the penis, scrotum, prostate gland, and seminal vesicles), male-pattern facial/body hair growth, and scalp hair loss, but has little role in other aspects of masculinization. Besides the involvement of 5α-reductase in androgen signaling, it is also required for the conversion of steroid hormones such as progesterone and testosterone into neurosteroids like allopregnanolone and 3α-androstanediol, respectively. 5α-Reductase inhibitors include finasteride and dutasteride. Finasteride is a selective inhibitor of 5α-reductase types 2 and 3, while dutasteride is an inhibitor of all three isoforms of 5α-reductase. Finasteride can decrease circulating DHT levels by up to 70%, whereas dutasteride can decrease circulating DHT levels by up to 99%. Conversely, 5α-reductase inhibitors do not decrease testosterone levels, and may actually increase them slightly. 5α-Reductase inhibitors are used primarily in the treatment of benign prostatic hyperplasia, a condition in which the prostate gland becomes excessively large due to stimulation by DHT and causes unpleasant urogenital symptoms. They are also used in the treatment of androgen-dependent scalp hair loss in men and women. The medications are able to prevent further scalp hair loss in men and can restore some scalp hair density. Conversely, the effectiveness of 5α-reductase inhibitors in the treatment of scalp hair loss in women is less clear. This may be because androgen levels are much lower in women, in whom they may not play as important of a role in scalp hair loss. 5α-Reductase inhibitors are also used to treat hirsutism (excessive body/facial hair growth) in women, and are very effective for this indication. Dutasteride has been found to be significantly more effective than finasteride in the treatment of scalp hair loss in men, which has been attributed to its more complete inhibition of 5α-reductase and by extension decrease in DHT production. In addition to their antiandrogenic uses, 5α-reductase inhibitors have been found to reduce adverse affective symptoms in premenstrual dysphoric disorder in women. This is thought to be due to prevention by 5α-reductase inhibitors of the conversion of progesterone into allopregnanolone during the luteal phase of the menstrual cycle. 5α-Reductase inhibitors are sometimes used as a component of feminizing hormone therapy for transgender women in combination with estrogens and/or other antiandrogens. They may have beneficial effects limited to improvement of scalp hair loss, body hair growth, and possibly skin symptoms such as acne. However, little clinical research on 5α-reductase inhibitors in transgender women has been conducted, and evidence of their efficacy and safety in this group is limited. Moreover, 5α-reductase inhibitors have only mild and specific antiandrogenic activity, and are not recommended as general antiandrogens. 5α-Reductase inhibitors have minimal side effects and are well tolerated in both men and women. In men, the most common side effect is sexual dysfunction (0.9–15.8% incidence), which may include decreased libido, erectile dysfunction, and reduced ejaculate. Another side effect in men is breast changes, such as breast tenderness and gynecomastia (2.8% incidence). Due to decreased levels of androgens and/or neurosteroids, 5α-reductase inhibitors may slightly increase the risk of depression (~2.0% incidence). There are reports that a small percentage of men may experience persistent sexual dysfunction and adverse mood changes even after discontinuation of 5α-reductase inhibitors. Some of the possible side effects of 5α-reductase inhibitors in men, such as gynecomastia and sexual dysfunction, are actually welcome changes for many transgender women. In any case, caution may be warranted in using 5α-reductase inhibitors in transgender women, as this group is already at a high risk for depression and suicidality. === Progestogens === Progesterone, a progestogen, is the other of the two major sex hormones in women. It is mainly involved in the regulation of the female reproductive system, the menstrual cycle, pregnancy, and lactation. The non-reproductive effects of progesterone are fairly insignificant. Unlike estrogens, progesterone is not known to be involved in the development of female secondary sexual characteristics, and hence is not believed to contribute to feminization in women. One area of particular interest in terms of the effects of progesterone in women is breast development. Estrogens are responsible for the development of the ductal and connective tissues of the breasts and the deposition of fat into the breasts during puberty in girls. Conversely, high levels of progesterone, in conjunction with other hormones such as prolactin, are responsible for the lobuloalveolar maturation of the mammary glands during pregnancy. This allows for lactation and breastfeeding after childbirth. Although progesterone causes the breasts to change during pregnancy, the breasts undergo involution and revert to their pre-pregnancy composition and size after the cessation of breastfeeding. Every pregnancy, lobuloalveolar maturation occurs again anew. There are two types of progestogens: progesterone, which is the natural and bioidentical hormone in the body; and progestins, which are synthetic progestogens. There are dozens of clinically used progestins. Certain progestins, namely cyproterone acetate and medroxyprogesterone acetate and as described previously, are used at high doses as functional antiandrogens due to their antigonadotropic effects to help suppress testosterone levels in transgender women. Aside from the specific use of testosterone suppression however, there are no other indications of progestogens in transgender women at present. In relation to this, the use of progestogens in transgender women is controversial, and they are not otherwise routinely prescribed or recommended. Besides progesterone, cyproterone acetate, and medroxyprogesterone acetate, other progestogens that have been reported to have been used in transgender women include hydroxyprogesterone caproate, dydrogesterone, norethisterone acetate, and drospirenone. Progestins in general largely have the same progestogenic effects however, and in theory, any progestin could be used in transgender women. Clinical research on the use of progestogens in transgender women is very limited. Some patients and clinicians believe, on the basis of anecdotal and subjective claims, that progestogens may provide benefits such as improved breast and/or nipple development, mood, and libido in transgender women. There are no clinical studies to support such reports at present. No clinical study has assessed the use of progesterone in transgender women, and only a couple of studies have compared the use of progestins (specifically cyproterone acetate and medroxyprogesterone acetate) versus the use of no progestogen in transgender women. These studies, albeit limited in the quality of their findings, reported no benefit of progestogens on breast development in transgender women. This has also been the case in limited clinical experience. Progestogens have some antiestrogenic effects in the breasts, for instance decreasing expression of the estrogen receptor and increasing expression of estrogen-metabolizing enzymes, and for this reason, have been used to treat breast pain and benign breast disorders. Progesterone levels during female puberty do not normally increase importantly until near the end of puberty in cisgender girls, a point by which most breast development has already been completed. In addition, concern has been expressed that premature exposure to progestogens during the process of breast development is unphysiological and might compromise final breast growth outcome, although this notion presently remains theoretical. Though the role of progestogens in pubertal breast development is uncertain, progesterone is essential for lobuloalveolar maturation of the mammary glands during pregnancy. Hence, progestogens are required for any transgender woman who wishes to lactate or breastfeed. A study found full lobuloalveolar maturation of the mammary glands on histological examination in transgender women treated with an estrogen and high-dose cyproterone acetate. However, lobuloalveolar development reversed with discontinuation of cyproterone acetate, indicating that continued progestogen exposure is necessary to maintain the tissue. In terms of the effects of progestogens on sex drive, one study assessed the use of dydrogesterone to improve sexual desire in transgender women and found no benefit. Another study likewise found that oral progesterone did not improve sexual function in cisgender women. Progestogens can have adverse effects. Oral progesterone has inhibitory neurosteroid effects and can produce side effects such as sedation, mood changes, and alcohol-like effects. Many progestins have off-target activity, such as androgenic, antiandrogenic, glucocorticoid, and antimineralocorticoid activity, and these activities likewise can contribute unwanted side effects. Furthermore, the addition of a progestin to estrogen therapy has been found to increase the risk of blood clots, cardiovascular disease (e.g., coronary heart disease and stroke), and breast cancer compared to estrogen therapy alone in postmenopausal women. Although it is unknown if these health risks of progestins occur in transgender women similarly, it cannot be ruled out that they do. High-dose progestogens increase the risk of benign brain tumors including prolactinomas and meningiomas as well. Because of their potential detrimental effects and lack of supported benefits, some researchers have argued that, aside from the purpose of testosterone suppression, progestogens should not generally be used or advocated in transgender women or should only be used for a limited duration (e.g., 2–3 years). Conversely, other researchers have argued that the risks of progestogens in transgender women are likely minimal, and that in light of potential albeit hypothetical benefits, should be used if desired. In general, some transgender women respond favorably to the effects of progestogens, while others respond negatively. Progesterone is most commonly taken orally. However, oral progesterone has very low bioavailability, and produces relatively weak progestogenic effects even at high doses. In accordance, and in contrast to progestins, oral progesterone has no antigonadotropic effects in men even at high doses. Progesterone can also be taken by various parenteral (non-oral) routes, including sublingually, rectally, and by intramuscular or subcutaneous injection. These routes do not have the bioavailability and efficacy issues of oral progesterone, and accordingly, can produce considerable antigonadotropic and other progestogenic effects. Transdermal progesterone is poorly effective, owing to absorption issues. Progestins are usually taken orally. In contrast to progesterone, most progestins have high oral bioavailability, and can produce full progestogenic effects with oral administration. Some progestins, such as medroxyprogesterone acetate and hydroxyprogesterone caproate, are or can be used by intramuscular or subcutaneous injection instead. Almost all progestins, with the exception of dydrogesterone, have antigonadotropic effects. === Miscellaneous === Galactogogues such as the peripherally selective D2 receptor antagonist and prolactin releaser domperidone can be used to induce lactation in transgender women who wish to breastfeed. An extended period of combined estrogen and progestogen therapy is necessary to mature the lobuloalveolar tissue of the breasts before this can be successful. There are several published reports of lactation and/or breastfeeding in transgender women. The World Professional Association for Transgender Health (WPATH) Standards of Care for the Health of Transgender and Gender Diverse People Version 8 (SOC8), released in September 2022, recommends against therapeutic strategies including supraphysiological estradiol levels (>200 pg/mL), use of progesterone (including rectal progesterone), use of bicalutamide, and monitoring of the ratio of estrone to estradiol. This is due to lack of data to support these approaches in transfeminine people as well as potential risks. The WPATH SOC8 also recommends against the use of 5α-reductase inhibitors such as finasteride in transfeminine people. == Interactions == Many of the medications used in feminizing hormone therapy, such as estradiol, cyproterone acetate, and bicalutamide, are substrates of CYP3A4 and other cytochrome P450 enzymes. As a result, inducers of CYP3A4 and other cytochrome P450 enzymes, such as carbamazepine, phenobarbital, phenytoin, rifampin, rifampicin, and St. John's wort, among others, may decrease circulating levels of these medications and thereby decrease their effects. Conversely, inhibitors of CYP3A4 and other cytochrome P450 enzymes, such as cimetidine, clotrimazole, grapefruit juice, itraconazole, ketoconazole, and ritonavir, among others, may increase circulating levels of these medications and thereby increase their effects. The concomitant use of a cytochrome P450 inducer or inhibitor with feminizing hormone therapy may necessitate medication dosage adjustments. == Effects == The spectrum of effects of hormone therapy in transfeminine people depend on the specific medications and dosages used. In any case, the main effects of hormone therapy in transfeminine people are feminization and demasculinization, and are as follows: === Mental changes === The psychological effects of feminizing hormone therapy are harder to define than physical changes. Because hormone therapy is usually the first physical step taken to transition, the act of beginning it has a significant psychological effect, which is difficult to distinguish from hormonally induced changes. Changes in mood and well-being occur with hormone therapy in transgender women. Side effects of hormone therapy have the ability to significantly impact sexual functioning, either directly or indirectly through the various side effects, such as cerebrovascular disorders, obesity, and mood fluctuations. Some transgender women report a significant reduction in libido, depending on the dosage of antiandrogens. The effects of long-term hormonal regimens have not been conclusively studied and are difficult to estimate because research on the long-term use of hormonal therapy has not been noted. One study found that sex drive returned to baseline after three years of hormone therapy. It is possible to approximate outcomes of these therapies on transgender people based on their observed effect in cisgender men and women. Firstly, if one is to decrease testosterone in feminizing gender transition, it is likely that sexual desire and arousal would be inhibited; alternatively, if high doses of estrogen negatively impact sexual desire, which has been found in some research with cisgender women, it is hypothesized that combining androgens with high levels of estrogen would intensify this outcome. To date there have not been any randomized clinical trials looking at the relationship between type and dose of transgender hormone therapy, so the relationship between them remains unclear. Typically, the estrogens given for feminizing gender transition are 2 to 3 times higher than the recommended dose for HRT in postmenopausal women. Pharmacokinetic studies indicate taking these increased doses may lead to a higher boost in plasma estradiol levels; however, the long-term side effects have not been studied and the safety of this route is unclear. Several studies have found that hormone therapy in transgender women causes the structure of the brain to change in the direction of female proportions. In addition, studies have found that hormone therapy in transgender women causes performance in cognitive tasks, including visuospatial, verbal memory, and verbal fluency, to shift in a more female direction. === Fat distribution === In hormone therapy, trans women often experience slight weight gain as men generally carry higher levels of visceral fat compared to subcutaneous fat, and less fat overall compared to women. Over months and years, HRT causes the body to accumulate new fat in a feminine pattern (gynoid fat). Unlike abdominal fat, gynoid fat has little effect on overall health except in the case of severe excess or postural changes. Gynoid fat will accumulate in the hips, lower belly, thighs, buttocks, pubis, upper arms, and breasts while the body burns fat in the ribcage, upper waist, shoulders, and back. However, fat will not simply move from one spot to another. There must be sufficient caloric intake to deposit gynoid fat, and sufficient activity to burn android fat. === Breast development === Significant breast development in transgender women begins within two to three months of the start of hormone therapy and continues for up to two years. Breast development seems to be better in transgender women who have a higher body mass index. This indicates that weight gain in the early phases of hormone therapy may be beneficial not only for fat distribution, but for breast development. Different estrogens, such as estradiol valerate, conjugated estrogens, and ethinylestradiol, appear to produce equivalent results in terms of breast sizes in transgender women. The sudden discontinuation of estrogen therapy has been associated with onset of galactorrhea (lactation). Breast, nipple, and areolar development varies considerably depending on genetics, nutrition, age of HRT initiation, and many other factors. Development can take a couple years to nearly a decade for some. However, many transgender women report there is often a "stall" in breast growth during transition, or significant breast asymmetry. Transgender women on HRT often experience less breast development than cisgender women (especially if started after young adulthood). For this reason, many seek breast augmentation. Transgender patients opting for breast reduction are rare. Shoulder width and the size of the rib cage also play a role in the perceivable size of the breasts; both are usually larger in transgender women, causing the breasts to appear proportionally smaller. Thus, when a transgender woman opts to have breast augmentation, the implants used tend to be larger than those used by cisgender women. === Fertility === The effect of feminizing hormone therapy on fertility is not clear, but it is known that testosterone suppression can prevent sperm production. The age of starting and stopping hormone therapy seems to be a significant factor, but no direct causation has been found between length of treatment and ability to reproduce. There is some research showing effective restoration of fertility by alternative means than HRT cessation alone. Dr. Will Powers has demonstrated the effectiveness of clomifene in restoring spermatogenesis in trans women. His study also includes an in-depth description of other methods for fertility restoration. === Skin === Estrogens cause the accumulation of subcutaneous fat and an increased epidermal thickness, softening the skin. Some skin conditions, including melasma, are found in trans women at the same rate at cisgender women. Sebaceous gland activity lessens, reducing oil production on the skin and scalp. Consequently, the skin becomes less prone to acne. It also becomes drier, and lotions or oils may be necessary. === Skeleton === Sex hormones play an important role in bone growth and maintenance. The effects of hormone therapy on bone health are not fully understood, and may depend on whether hormone therapy is started before or after puberty. Bone density continue to grow and change over time. Significant changes to bone structure have been observed, and transgender women have statistically poorer bone health even before beginning the transition process, possibly due to a lack of physical exercise or other risk factors such as low vitamin D, eating disorders, and substance abuse. Approximately 14% of transgender women suffer from osteoporosis. Transgender women below the age of 50 show increased fracture risk compared to age-matched cisgender women, equal to the risk to cisgender men of equivalent age. Transgender women above the age of 50 have a similar fracture risk to post-menopausal women — higher than that of age-matched cis men. In both cases, trans women's fracture patterns follow that of cis women, suffering long-term stress fractures concentrated in the hip, spine, and arms, typical of chronic low bone mineral density, rather than the fracture patterns typical of external injury suffered by cis men. Current clinical guidelines are for bone health to be monitored regularly throughout the transition process, particularly if risk factors are present. Transgender individuals are encouraged to ingest at least 1g of Calcium and 1000 IU of Vitamin D daily, engage regularly in weight-bearing physical activity, and reduce alcohol and smoking consumption. The effects of hormone therapy on bone health are reversible should treatment be interrupted. However, withdrawing hormone therapy after gonadectomy can lead to bone loss, and poor compliance with prescribed hormone therapy after gonadectomy may account in part for the observed fracture risk. === Hair === Antiandrogens affect existing facial hair only slightly; patients may see slower growth and some reduction in density and coverage. This reduction of density is due to the decreasing hair diameter and slower terminal growth rate. Effects on hair size and density were noticeable in the first four months following the start of hormone therapy, but later subsided, with measurements staying constant. In patients in their teens or early twenties, antiandrogens prevent new facial hair from developing if testosterone levels are within the normal female range. Body hair (on the chest, shoulders, back, abdomen, buttocks, thighs, tops of hands, and tops of feet) turns, over time, from terminal ("normal") hairs to tiny, blonde vellus hairs. Arm, perianal, and perineal hair is reduced but may not turn to vellus hair on the latter two regions (some cisgender women also have hair in these areas). Underarm hair changes slightly in texture and length, and pubic hair becomes more typically female in pattern. Lower leg hair becomes less dense. All of these changes depend to some degree on genetics. Eyebrows do not change because they are not androgenic hair. Occasionally, hormones can have effects on scalp hair texture, depending on various genetic factors. === Eye morphology === The lens of the eye changes in curvature. Because of decreased androgen levels, the meibomian glands (the sebaceous glands on the upper and lower eyelids that open up at the edges) produce less oil. Because oil prevents the tear film from evaporating, this change may cause dry eyes. === Cardiovascular effects === The most significant cardiovascular risk for transgender women is the prothrombotic effect (increased blood clotting) of estrogens. This manifests most significantly as an increased risk for venous thromboembolism (VTE): deep vein thrombosis (DVT) and pulmonary embolism (PE), which occurs when blood clots from DVT break off and migrate to the lungs. Symptoms of DVT include pain or swelling of one leg, especially the calf. Symptoms of PE include chest pain, shortness of breath, fainting, and heart palpitations, sometimes without leg pain or swelling. VTE occurs more frequently in the first year of treatment with estrogens. The risk of VTE is higher with oral non-bioidentical estrogens such as ethinylestradiol and conjugated estrogens than with parenteral formulations of estradiol such as injectable, transdermal, implantable, and intranasal. Increased risk of VTE with estrogens is thought to be due to their influence on liver protein synthesis, specifically on the production of coagulation factors. Non-bioidentical estrogens such as conjugated estrogens and especially ethinylestradiol have markedly disproportionate effects on liver protein synthesis relative to estradiol. In addition, oral estradiol has a 4- to 5-fold increased impact on liver protein synthesis than does transdermal estradiol and other parenteral estradiol routes. Because the risks of warfarin – which is used to treat blood clots – in a relatively young and otherwise healthy population are low, while the risk of adverse physical and psychological outcomes for untreated transgender patients is high, prothrombotic mutations (such as factor V Leiden, antithrombin III, and protein C or S deficiency) are not absolute contraindications for hormonal therapy. A 2018 cohort study of 2842 transfeminine individuals in the United States treated with a mean follow-up of 4.0 years observed an increased risk of VTE, stroke, and heart attack relative to a cisgender reference population. The estrogens used included oral estradiol (1 to 10 mg/day) and other estrogen formulations. Other medications such as antiandrogens like spironolactone were also used. A 2019 systematic review and meta-analysis found an incidence rate of VTE of 2.3 per 1000 person-years with feminizing hormone therapy in transgender women. For comparison, the rate in the general population has been found to be 1.0–1.8 per 1000 person-years, and the rate in premenopausal women taking birth control pills has been found to be 3.5 per 1000 patient-years. There was significant heterogeneity in the rates of VTE across the included studied, and the meta-analysis was unable to perform subgroup analyses between estrogen type, estrogen route, estrogen dosage, concomitant antiandrogen or progestogen use, or patient characteristics (e.g., sex, age, smoking status, weight) corresponding to known risk factors for VTE. Due to the inclusion of some studies using ethinylestradiol, which is more thrombotic and is no longer used in transgender women, the researchers noted that the VTE risk found in their study may be an overestimate. In a 2016 study that specifically assessed oral estradiol, the incidence of VTE in 676 transgender women who were treated for an average of 1.9 years each was only one individual, or 0.15% of the group, with an incidence of 7.8 events per 10,000 person-years. The dosage of oral estradiol used was 2 to 8 mg/day. Almost all of the transgender women were also taking spironolactone (94%), a subset were also taking finasteride (17%), and fewer than 5% were also taking a progestogen (usually oral progesterone). The findings of this study suggest that the incidence of VTE is low in transgender women taking oral estradiol. Cardiovascular health in transgender women has been reviewed in recent publications. === Gastrointestinal === Estrogens may increase the risk of gallbladder disease, especially in older and obese people. === Cancer risk === Studies are mixed on whether the risk of breast cancer is increased with hormone therapy in transgender women. Two cohort studies found no increase in risk relative to cisgender men, whereas another cohort study found an almost 50-fold increase in risk such that the incidence of breast cancer was between that of cisgender men and cisgender women. There is no evidence that breast cancer risk in transgender women is greater than in cisgender women. Twenty cases of breast cancer in transgender women have been reported as of 2019. Cisgender men with gynecomastia have not been found to have an increased risk of breast cancer. It has been suggested that a 46,XY karyotype (one X chromosome and one Y chromosome) may be protective against breast cancer compared to having a 46,XX karyotype (two X chromosomes). Men with Klinefelter's syndrome (47,XXY karyotype), which causes hypoandrogenism, hyperestrogenism, and a very high incidence of gynecomastia (80%), have a dramatically (20- to 58-fold) increased risk of breast cancer compared to karyotypical men (46,XY), closer to the rate of karyotypical women (46,XX). The incidences of breast cancer in karyotypical men, men with Klinefelter's syndrome, and karyotypical women are approximately 0.1%, 3%, and 12.5%, respectively. Women with complete androgen insensitivity syndrome (46,XY karyotype) never develop male sex characteristics and have normal and complete female morphology, including breast development, yet have not been reported to develop breast cancer. The risk of breast cancer in women with Turner syndrome (45,XO karyotype) also appears to be significantly decreased, though this could be related to ovarian failure and hypogonadism rather than to genetics. Prostate cancer is extremely rare in gonadectomized transgender women who have been treated with estrogens for a prolonged period of time. Whereas as many as 70% of men show prostate cancer by their 80s, only a handful of cases of prostate cancer in transgender women have been reported in the literature. As such, and in accordance with the fact that androgens are responsible for the development of prostate cancer, HRT appears to be highly protective against prostate cancer in transgender women. The risks of certain types of benign brain tumors including meningioma and prolactinoma are increased with hormone therapy in transgender women. These risks have mostly been associated with the use of cyproterone acetate. Estrogens and progestogens can cause prolactinomas, which are benign, prolactin-secreting tumors of the pituitary gland. Milk discharge from the nipples can be a sign of elevated prolactin levels. If a prolactinoma becomes large enough, it can cause visual changes (especially decreased peripheral vision), headaches, depression or other mood changes, dizziness, nausea, vomiting, and symptoms of pituitary failure, like hypothyroidism. === Unaffected characteristics === Established changes to the bone structure of the face are also unaffected by HRT. A significant majority of craniofacial changes occur during adolescence. Post-adolescent growth is considerably slower and minimal by comparison. Facial hair develops during puberty and is only slightly affected by HRT. A person's voice is unaffected by feminizing hormone therapy. Transgender individuals who have undergone male puberty often opt for vocal training, though this may take many years of practice to achieve the desired results. Some may also opt for vocal surgery, though this is to be done in addition to vocal training, not instead of. == Monitoring == Especially in the early stages of feminizing hormone therapy, blood work is done frequently to assess hormone levels and liver function. The Endocrine Society recommends that patients have blood tests every three months in the first year of HRT for estradiol and testosterone, and that spironolactone, if used, be monitored every two to three months in the first year. Recommended ranges for total estradiol and total testosterone levels include but are not limited to the following: The optimal ranges for estrogen apply only to individuals taking estradiol (or an ester of estradiol), and not to those taking synthetic or other non-bioidentical preparations (e.g., conjugated estrogens or ethinylestradiol). Physicians also recommend broader medical monitoring, including complete blood counts; tests of renal function, liver function, and lipid and glucose metabolism; and monitoring of prolactin levels, body weight, and blood pressure. If prolactin levels are greater than 100 ng/mL, estrogen therapy should be stopped and prolactin levels should be rechecked after 6 to 8 weeks. If prolactin levels remain high, an MRI scan of the pituitary gland to check for the presence of a prolactinoma should be ordered. Otherwise, estrogen therapy may be restarted at a lower dosage. Cyproterone acetate is particularly associated with elevated prolactin levels, and discontinuation of cyproterone acetate lowers prolactin levels. In contrast to cyproterone acetate, estrogen and spironolactone therapy is not associated with increased prolactin levels. == History == Effective pharmaceutical female sex-hormonal medications, including androgens, estrogens, and progestogens, first became available in the 1920s and 1930s. One of the earliest reports of hormone therapy in transgender women was published by Danish endocrinologist Christian Hamburger in 1953. One of his patients was Christine Jorgensen, who he had treated starting in 1950. Additional reports of hormone therapy in transgender women were published by Hamburger, the German-American endocrinologist Harry Benjamin, and other researchers in the mid-to-late 1960s. However, Benjamin had several hundred transgender patients under his care by the late 1950s, and had treated transgender women with hormone therapy as early as the late 1940s or early 1950s. In any case, Hamburger is said to be the first to treat transgender women with hormone therapy. One of the first transgender health clinics was opened in the mid-1960s at the Johns Hopkins School of Medicine. By 1981, there were almost 40 such centers. A review of the hormonal regimens of 20 of the centers was published that year. The first International Symposium on Gender Identity, chaired by Christopher John Dewhurst, was held in London in 1969, and the first medical textbook on transgenderism, titled Transsexualism and Sex Reassignment and edited by Richard Green and John Money, was published by Johns Hopkins University Press in 1969. This textbook included a chapter on hormone therapy written by Christian Hamburger and Harry Benjamin. The Harry Benjamin International Gender Dysphoria Association (HBIGDA), now known as the World Professional Association for Transgender Health (WPATH), was formed in 1979, with the first version of the Standards of Care published the same year. The Endocrine Society published guidelines for the hormonal care of transgender people in 2009, with a revised version in 2017. Hormone therapy for transgender women was initially done using high-dose estrogen therapy with oral estrogens such as conjugated estrogens, ethinylestradiol, and diethylstilbestrol and with parenteral estrogens such as estradiol benzoate, estradiol valerate, estradiol cypionate, and estradiol undecylate. Progestogens, such as hydroxyprogesterone caproate, medroxyprogesterone acetate, and other progestins, were also sometimes included. The antiandrogen and progestogen cyproterone acetate was first used in transgender women by 1977. Its use was standard at the Center of Expertise on Gender Dysphoria (CEGD; Kennis- en Zorgcentrum Genderdysforie, or KZcG) in Amsterdam, the Netherlands by 1985. Spironolactone, another antiandrogen, was first used in transgender women by 1986. These agents were described as allowing the use of much lower doses of estrogen than previously required, and this was considered advantageous due to risks of high doses of estrogens such as cardiovascular complications. Antiandrogens were well-established in hormone therapy for transgender women by the early 1990s. Estrogen doses in transgender women were reduced following the introduction of antiandrogens. Ethinylestradiol, conjugated estrogens, and other non-bioidentical estrogens largely stopped being used in transgender women in favor of estradiol starting around 2000 due to their greater risks of blood clots and cardiovascular issues. In modern times, hormone therapy in transgender women is usually done with the combination of an estrogen and an antiandrogen. In some places however, such as Japan, use of antiandrogens is uncommon, and estrogen monotherapy, for instance with high-dose injectable estradiol esters, is still frequently used. == See also == Menopausal hormone therapy Androgen replacement therapy DIY transgender hormone therapy Hormone replacement therapy == References == == Further reading == == External links == Deutsch M (17 June 2016). "Guidelines for the Primary and Gender-Affirming Care of Transgender and Gender Nonbinary People" (2nd ed.). University of California, San Francisco: Center of Excellence for Transgender Health. p. 28. Bourns A (2015). "Guidelines and Protocols for Comprehensive Primary Care for Trans Clients" (PDF). Sherbourne Health Centre. Retrieved 15 August 2018. Transgender HRT Research Repository Archived 2022-09-14 at the Wayback Machine	Wikipedia/Feminizing_hormone_therapy
Masculinizing hormone therapy, also known as transmasculine hormone therapy, is a form of hormone therapy and gender affirming therapy which is used to change the secondary sexual characteristics of transgender people from what is typically perceived as feminine to what is typically perceived as masculine. It is a common type of transgender hormone therapy (another being feminizing hormone therapy), and is predominantly used to treat transgender men, transmasculine individuals, and other gender diverse people who were assigned female at birth. Some intersex people also receive this form of therapy, either starting in childhood to confirm the assigned sex or later if the assignment proves to be incorrect. The purpose of this form of therapy is to cause the development of secondary sex characteristics such as voice deepening, increased body hair, enhanced size and sensitivity of the clitoris, redistributed fat, and muscle distribution. It cannot undo many of the changes produced by puberty, which may necessitate surgery and other treatments to reverse. The medications used for FTM therapy include, mainly, androgens (namely testosterone) and GnRH analogues. While the therapy cannot undo the effects of a person's first puberty, developing secondary sex characteristics associated with a different sex can relieve some or all of the distress and discomfort associated with gender dysphoria, and can help the person to "pass" or be seen as their gender identity. Introducing exogenous (not internally produced) hormones into the body impacts it at every level and many patients report changes in energy levels, mood, appetite, etc. The goal of the therapy, and indeed all somatic treatments, is to provide patients with a more satisfying body that is more congruent with their gender identity. == History == == Requirements and accessibility == == Contraindications == Absolute medical contraindications include: active pregnancy or attempting to become pregnant active sex hormone-sensitive cancer Relative medical contraindications include: severe hypertension (high blood pressure) sleep apnea polycythemia prior history of hormone-sensitive (e.g. breast) cancer == Safety == Due to insufficient comprehensive research, there is no consensus on the long-term effects of testosterone administration. Though it is not always the case, testosterone for transmasculine people is often intended to be used long-term. A 2022 review entitled The efficacy, safety, and outcomes of testosterone use among transgender men patients: A review of the literature, while pointing out that more research is needed for newer therapies, concludes that: More conventional therapies, including intramuscular injections, subcutaneous injections, and transdermal gels, have been extensively studied and show promising efficacy and outcomes with limited safety concerns. == Interactions == Testosterone is metabolized by the cytochrome P450 enzyme system (specifically CYP3A isoforms) in the liver. There are certain drugs that increase or decrease the activity of cytochrome P450 enzymes and may cause increased or decreased levels of testosterone: Enzyme inducers – May cause decreased levels of testosterone (and other sex steroid) levels: Phenobarbital and phenytoin (seizure medicines), rifampin (antibiotic), and alcohol. Enzyme inhibitors – May cause increased levels of testosterone: Nefazodone, fluoxetine, paroxetine (antidepressants), itraconazole, fluconazole, and other azole antifungals, cimetidine (an anti-ulcer agent that can cause gynecomastia in men because of this effect), clarithromycin and other macrolide antibiotics, and protease inhibitors (HIV treatment). Testosterone can also alter the effects of other drugs: Increases the blood thinning effect of warfarin; Decreases the effectiveness of propranolol, a nonselective beta blocker used in the management of cardiovascular conditions; Increases the effect of some oral medicines for diabetes and can cause dangerously low blood sugar levels. Because of these interactions, it is advised that people taking masculinizing hormones make their healthcare providers aware of their hormone therapy when this is relevant to their treatment for other medical issues. == Medications == Medications used in hormone therapy for transgender men include androgens and anabolic steroids like testosterone (by injection and other routes) to produce masculinization, suppress estrogen and progesterone levels, and prevent/reverse feminization; GnRH agonists and antagonists to suppress estrogen and progesterone levels; progestins like medroxyprogesterone acetate to suppress menses; and 5α-reductase inhibitors to prevent/reverse scalp hair loss. === Testosterone === The elimination half-life of testosterone in the blood is about 70 minutes, so it is necessary to have a continuous supply of the hormone for masculinization. A study of 45 FtM individuals randomly assigned to receive testoviron depot (intramuscular, 100 mg/10 days), testosterone gel (50 mg/day), or testosterone undecanoate (intramuscular, 1000 mg) found increased lean body mass, decreased fat mass, decreased high-density plasma lipoprotein levels, increased low-density lipoprotein levels, and increased prothrombin time. No differences were found between the different formulations of testosterone, and at week 54 all subjects were amenorrheic (no longer experiencing menstrual periods). 1 year after treatment, general life satisfaction was increased in all subjects. ==== Injected ==== 'Depot' drug formulations are created by mixing a substance with the drug that slows its release and prolongs the action of the drug. The two primarily used forms in the United States are the testosterone esters testosterone cypionate (Depo-Testosterone) and testosterone enanthate (Delatestryl or Xyosted) which are almost interchangeable. Testosterone enanthate is purported to be slightly better with respect to even testosterone release, but this is probably more of a concern for bodybuilders who use the drugs at higher doses (250–1000 mg/week) than the replacement doses used by transgender men (50–100 mg/week). These testosterone esters are mixed with different oils, so some individuals may tolerate one better than the other. Testosterone enanthate costs more than testosterone cypionate and is more typically the one prescribed for hypogonadal males in the US. Testosterone cypionate is more popular in the US than elsewhere (especially amongst bodybuilders). Other formulations exist but are more difficult to come by in the US. A formulation of injected testosterone available in Europe and the US, testosterone undecanoate (Nebido, Aveed) provides significantly improved testosterone delivery with far less variation outside the eugonadal range than other formulations with injections required only four times yearly. However, each quarterly dose requires an injection of 4 mL of oil which may require multiple simultaneous injections. Testosterone undecanoate is also much more expensive as it is still under patent protection. Testosterone propionate is another testosterone ester that is widely available, including in the US, Canada, and Europe, but it is very short-acting compared to the other testosterone esters and must be administered once every 2 or 3 days, and for this reason, is rarely used. The adverse side effects of injected testosterone esters are generally associated with high peak levels in the first few days after an injection. Some side effects may be ameliorated by using a shorter dosing interval (weekly or every ten days instead of twice monthly with testosterone enanthate or testosterone cypionate). 100 mg weekly gives a much lower peak level of testosterone than does 200 mg every two weeks, while still maintaining the same total dose of androgen. This benefit must be weighed against the discomfort and inconvenience of doubling the number of injections. Injectable forms of testosterone can cause a lung problem called pulmonary oil microembolism (POME). Symptoms of POME include cough, shortness of breath, tightening of the throat, chest pain, sweating, dizziness, and fainting. A postmarketing analysis by the manufacturer of Aveed (testosterone undeconate injection) found that POME occurred at a rate of less than 1% per injection per year for Aveed. Injected testosterone esters should be started at a low dose and titrated upwards based on trough levels (blood levels drawn just before your next shot). A trough level of 500 ng/dL is sought. (Normal range for a cisgender man is 290 to 900 ng/dL). ==== Transdermal ==== Testosterone patches, creams, and gels are available. Both approximate normal physiological levels of testosterone better than the higher peaks associated with injection. Both can cause local skin irritation (more so with the patches). Patches slowly diffuse testosterone through the skin and are replaced daily. The cost varies, as with all medication, from country to country, it is about $150/month in the US, and about €60 in Germany. Transdermal testosterone has the advantage of delivering a consistent supply of hormones over a given period and having a simple method of diffusion. Transdermal testosterone is available throughout the world under the brand names Andromen Forte, Androgel, Testogel and Testim. They are absorbed quickly when applied and produce a temporary drug depot in the skin which diffuses into the circulation, peaking at 4 hours and decreasing slowly over the rest of the day. The cost varies, as with all medication, from country to country, from as little as $50/month to about $280/month. Transdermal testosterone poses a risk of inadvertent exposure to others who come in contact with the patient's skin. This is most important for patients whose intimate partners are pregnant or those who are parents of young children as both of these groups are more vulnerable to the masculinizing effects of androgens. Case reports of significant virilization of young children after exposure to topical androgen preparations (both prescription and 'supplement' products) used by their caregivers demonstrates this very real risk; the same principle also applies to estrogens. ==== Implants ==== Implants, as subcutaneous pellets, can be used to deliver testosterone (brand name Testopel). 6 to 12 pellets are inserted under the skin every three months. This must be done in a physician's office, but is a relatively minor procedure done under local anesthetic. Pellets cost about $60 each, so the cost is greater than injected testosterone when the cost of the physician visit and procedure are included. The primary advantages of Testopel are that it gives a much more constant blood level of testosterone yet requires attention only four times yearly. ==== Oral ==== Oral testosterone is provided exclusively as testosterone undecanoate. It is available in Europe and Canada, but not in the US. Once absorbed from the gastrointestinal tract, testosterone is shunted (at very high blood levels) to the liver where it can cause liver damage (albeit very rarely) and worsens some of the adverse effects of testosterone, like lower HDL cholesterol. In addition, the first-pass metabolism of the liver also may result in testosterone levels too low to provide satisfactory masculinization and suppress menses. Because of the short terminal half-life of testosterone, oral testosterone undecanoate must be administered two to four times per day, preferably with food (which improves its absorption). ==== Sublingual and buccal ==== In 2003, the FDA approved a buccal form of testosterone (Striant). Sublingual testosterone can also be made by some compounding pharmacies. Cost for Striant is greater than other formulations (US$180–210/month). Testosterone is absorbed through the oral mucosa and avoids the first-pass metabolism in the liver which is the cause of many of the adverse effects of oral testosterone undecanoate. The lozenges can cause gum irritation, taste changes, and headache but most side effects diminish after two weeks. The lozenge is 'mucoadhesive' and must be applied twice daily. === Alternative androgens === ==== Synthetic androgens ==== Synthetic androgens/anabolic steroids (AAS), like nandrolone (as an ester like nandrolone decanoate or nandrolone phenylpropionate), are agonists of the androgen receptor (AR) similarly to testosterone but are not usually used in HRT for transgender men or for androgen replacement therapy (ART) in cisgender men. However, they can be used in place of testosterone with similar effects, and can have certain advantages like less or no local potentiation in so-called androgenic tissues that express 5α-reductase like the skin and hair follicles (which results in a reduced rate of skin and hair-related side effects like excessive body hair growth and scalp hair loss), although this can also be disadvantageous in certain aspects of masculinization like facial hair growth and normal body hair growth). Although many AAS are not potentiated in androgenic tissues, they have similar effects to testosterone in other tissues like bone, muscle, fat, and the voice box. Also, many AAS, like nandrolone esters, are aromatized into estrogens to a greatly reduced extent relative to testosterone or not at all, and for this reason, are associated with reduced or no estrogenic effects (e.g., gynecomastia). AAS that are 17α-alkylated like methyltestosterone, oxandrolone, and stanozolol are orally active but carry a high risk of liver damage, whereas AAS that are not 17α-alkylated, like nandrolone esters, must be administered by intramuscular injection (via which they act as long-lasting depots similarly to testosterone esters) but have no more risk of liver damage than does testosterone. For the sake of clarification, the term "anabolic–androgenic steroid" is essentially synonymous with "androgen" (or with "anabolic steroid"), and that natural androgens like testosterone are also AAS. These drugs all share the same core mechanism of action of acting as agonists of the AR and have similar effects, although their potency, pharmacokinetics, oral activity, ratio of anabolic to androgenic effects (due to differing capacities to be locally metabolized and potentiated by 5α-reductase), capacity for aromatization (i.e., conversion into an estrogen), and potential for liver damage may all differ. ==== Dihydrotestosterone ==== Dihydrotestosterone (DHT) (referred to as androstanolone or stanolone when used medically) can also be used in place of testosterone as an androgen. The availability of DHT is limited; it is not available in the United States or Canada, for instance, but it is available in certain European countries, including the United Kingdom, France, Spain, Belgium, Italy, and Luxembourg. DHT is available in formulations including topical gel, buccal or sublingual tablets, and as esters in oil for intramuscular injection. Relative to testosterone, and similarly to many synthetic AAS, DHT has the potential advantages of not being locally potentiated in so-called androgenic tissues that express 5α-reductase (as DHT is already 5α-reduced) and of not being aromatized into an estrogen (it is not a substrate for aromatase). DHT is common androgen used by intersex men to initiate the development of masculine secondary sex characteristics, particularly for individuals with partial androgen insensitivity syndrome (who are often assigned female at birth). As the masculinizing effects of testosterone is limited in AIS, DHT more easily binds to androgen receptors and cannot be directly converted into estrogen via the androgen backdoor pathway, this is useful as an androgen treatment for AIS as testosterone can often result in unintentional feminizing effects such as breast growth and hip widening. DHT can be converted into testosterone which can be aromatased into estrogen however this is low. === Gonadotropin-releasing hormone modulator analogues === In all people, the hypothalamus releases gonadotropin-releasing hormone (GnRH) to stimulate the pituitary to produce luteinizing hormone (LH) and follicle-stimulating hormone (FSH) which in turn cause the gonads to produce sex steroids. In adolescents, GnRH analogues such as leuprorelin can be used to suspend the advance of sex steroid induced, inappropriate pubertal changes for a period without inducing any changes in the gender-appropriate direction. GnRH analogues work by initially overstimulating the pituitary gland then rapidly desensitizing it to the effects of GnRH. Over a period of weeks, gonadal androgen production is greatly reduced. The WPATH permits GnRH from Tanner stage 2. The sex steroids do have important other functions. The high cost of GnRH analogues is often a significant factor. === Antiestrogens === Antiestrogens (or so-called "estrogen blockers") like aromatase inhibitors (AIs) (e.g., anastrozole) or selective estrogen receptor modulators (SERMs) (e.g., tamoxifen) can be used to reduce the effects of high levels of endogenous estrogen (e.g., breast development, feminine fat distribution) in transgender men. In addition, in those who have not yet undergone or completed epiphyseal closure (which occurs during adolescence and is mediated by estrogen), antiestrogens can prevent hip widening as well as increase final height (estrogen limits height by causing the epiphyses to fuse). === Others === ==== 5α-Reductase inhibitors ==== 5α-Reductase inhibitors like finasteride and dutasteride can be used to slow or prevent scalp hair loss and excessive body hair growth in transgender men taking testosterone. However, they may also slow or reduce certain aspects of masculinization, such as facial hair growth, normal male-pattern body hair growth, and possibly clitoral enlargement. A potential solution is to start taking a 5α-reductase inhibitor after these desired aspects of masculinization have been well-established. ==== Progestogens ==== Progestogens can be used to control menstruation in transgender men. Depot medroxyprogesterone acetate (DMPA) may be injected every three months just as it is used for contraception. Generally after the first cycle, menses are greatly reduced or eliminated. This may be useful for transgender men prior to initiation of testosterone therapy. ==== Growth hormone ==== In those who have not yet started or completed epiphyseal closure, growth hormone can be administered, potentially in conjunction with an aromatase inhibitor or a GnRH analogue, to increase final height. == Effects == The main effects of testosterone in trans men are as follows: Reversible changes Increased libido Redistribution of body fat Cessation of ovulation and menstruation Increased musculature Increased sweat and changes in body odor Prominence of veins and coarser skin Acne (especially in the first few years of therapy) Alterations in blood lipids (cholesterol and triglycerides) Increased red blood cell count Irreversible changes Deepening of the voice Growth of facial and body hair Male-pattern baldness (in some individuals) Enlargement of the clitoris Growth spurt and closure of growth plates if given before the end of puberty Breast atrophy – possible shrinking and/or softening of breasts === Physical changes === ==== Skin changes ==== Increased activity of oil and sweat glands. Change in body odor – less sweet and musky, more metallic and acrid. If severe odor is a problem, an antibacterial soap like chlorhexidine may be used in the armpits when showering. After 1–2 weeks of daily use, a noticeable decrease in odor should occur. Acne: generally worse the first few years of testosterone therapy (mimicking a second puberty). Can be treated with standard acne therapy. Initial treatment is with increased cleansing (at least twice daily) with an anti-acne or oil reducing scrub. If this doesn't work, additional therapy may be prescribed by a physician. Some physicians see acne as a contraindication to increasing testosterone dose. ==== Hair changes ==== The action of testosterone on hair follicles is mainly due to the more potent androgen, dihydrotestosterone, DHT. With androgen therapy, genetics primarily determines how much hair will develop (and where) as well as whether male pattern baldness will develop. Testosterone is converted (within the cells of the hair follicle's dermal papilla) by 5α-reductase to DHT. There are two forms of this enzyme: type 1 and 2. However, type 2 is the form that is most important to the development of male pattern hair loss. Males with congenital 5α-reductase type 2 deficiency (but functional 5α-reductase type 1) never develop male-pattern hair loss. ==== Facial changes ==== Facial changes develop gradually over time, and sexual dimorphism (physical difference between the sexes) tends to increase with age. Within a population of similar body size and ethnicity: Brow: Males tend to develop heavier bony brows than females, thus HRT results in a more prominent brow. Cheeks: Female cheeks tend to be fuller and more rounded. Under the influence of estrogen, fat is deposited beneath the skin and overall facial and body contours become softer. This is reversed by androgens, resulting in a male-type fat distribution after hormone therapy. Nose: The tips of the nasal bones tend to grow more in males than females, creating a larger (longer or wider) nose. Thus, androgens result in the development of the nose. Jaw: The jaw in males tends to grow wider and more deeply sculptured than in females, thus the jaw widens under androgens. Larynx: At puberty, the bones and cartilage of the voicebox tend to enlarge less in females than males. In most males, the larynx becomes visible as a bony "Adam's apple," which is developed in transgender men under hormone therapy. Lips: Females, tend to have thicker, fleshier lips than males of the same size due to estrogen. Thus, after being administered androgens, transgender men may have a fat redistribution that results in smaller lips. ==== Endocrine and gynecological changes ==== Menses should cease within 5 months of testosterone therapy (often sooner). If bleeding continues past 5 months, transgender men are strongly encouraged to see a gynecologist. A retrospective chart review of 74 menstruating individuals treated with intramuscular injected testosterone found that 4 stopped after the first shot, 37 stopped within 6 months, 24 stopped after 6 months, and 9 required additional progesterone therapy. The time to menstrual cessation was individualized, with only a small correlation to testosterone dosage. Clitoromegaly occurs, and frequently reaches its apex within 2–3 years of therapy. Sizes generally range from 3–8 cm with 4–5 cm being about average. This is genetically determined, but some physicians advocate topical clitoral testosterone as an adjunct to growth before metoidioplasty. However, this testosterone is absorbed and should be calculated into one's total regimen. After long-term androgen therapy, ovaries may develop polycystic ovary syndrome (PCOS) morphology, as both PCOS and transgender men there is an up-regulation of testosterone receptors in the ovaries. Untreated PCOS is associated with a possibly increased risk of endometrial cancer as well as decreased fertility. It is unknown whether the risk of ovarian cancer is increased, decreased or unchanged in transgender men compared to women. It is unlikely to be determined in the near future because ovarian cancer is a relatively rare disease and the population of transgender men is too small to do the appropriate study. However, it has been recommended by some physicians that transgender men have an oophorectomy within 2–5 years of starting androgen therapy due to the possible increased risk. (Note: Testosterone dose can frequently be decreased after oophorectomy.) The risk of endometrial cancer is similarly unknown. A large multicenter study along with review of previous studies, noted no increased prevalence of endometrial hyperplasia or malignancy in transgender men undergoing hysterectomy. However while the endometrial linings in these studies were noted to be thin, they remained histologically active. Growth of prostate tissue has been documented in transmasculine individuals on testosterone therapy. Frequently the first sign of endometrial cancer is bleeding in post-menopausal women. Transgender men who have any bleeding after the cessation of menses with androgen therapy should be evaluated for age appropriate causes of abnormal uterine bleeding as per cisgender female guidelines. Adults with a uterus/cervix are advised to have a Pap smear per guidelines (Human papillomavirus infection). Use of testosterone is no exception to this rule. Some transgender men report a decrease in breast size with androgen therapy. However, no morphological changes were found when this was studied and likely it is due to loss of fat in the breasts. Androgen therapy (and suppression of estrogen production) may cause vaginal atrophy and dryness, which may result in dyspareunia (painful vaginal intercourse). This can be alleviated with topical estrogen cream. Most transgender men report a significantly increased libido. Some report that this decreases somewhat after several years on testosterone. While testosterone decreases ovulation, it is not an approved form of contraception; transgender men who engage in sex which places them at risk for pregnancy should be counseled on utilizing concomitant contraception. All contraceptive methods are acceptable for use. ==== Reproductive changes ==== As the age at which transgender people begin therapy decreases, retention of reproductive potential may become more important to some. If a transgender man has not undergone hysterectomy and oophorectomy, he may regain fertility on cessation of testosterone. With the ovarian changes of long-term androgen therapy, however, it may require months of cessation of testosterone and possibly assistive reproductive technology to become pregnant. Testosterone must be withheld for the duration of pregnancy. If a transgender man is planning on having a hysterectomy/oophorectomy, future reproduction may still be preserved by: Oocyte banking – hormonal stimulation to 'hyper-ovulate' with transvaginal oocyte harvest for freezing. Previously using the "slow-freezing" cryopreservation method there were very poor survival rates of banked oocytes. However, the advent of vitrification, a rapid freezing process, has made oocyte cryopreservation a viable option for fertility preservation. It allows the possibility for eggs to later be fertilized and be placed in a surrogate, as opposed to a transgender man having to carry the pregnancy himself. Embryo banking – oocyte harvest as above with immediate fertilization and banking of the embryo. The sperm donor must be chosen before oophorectomy. Allows the possibility for embryos to later be placed in a surrogate, as opposed to a transgender man having to carry the pregnancy himself. Ovarian tissue banking – Ovarian tissue is frozen after oophorectomy. Even after long-term androgen therapy, ovaries usually retain usable follicles. Eventual use of frozen ovaries will require replantation into the transgender man for stimulation and harvest, but may eventually be possible in a lab as techniques for tissue culture improve. This option does not usually allow for placement into a surrogate as it may require the use of immunosuppressants on the part of the surrogate. === Neurological changes === Headaches: Pre-existing migraine headaches can be significantly worsened with androgen therapy. Headaches can also become problematic in men without prior headache disorders. Epilepsy: some seizure disorders are androgen-dependent. These may be worsened or (very rarely) unmasked with androgen therapy. Sleep deprivation worsens almost all seizure disorders, so concurrent obstructive sleep apnea caused or worsened by androgen therapy may also be responsible. Recent studies have found that cross-hormone therapy in trans men results in an increase in brain volume up to male proportions. === Psychological changes === The psychological changes are harder to define, since HRT is usually the first physical action that takes place when transitioning. This fact alone has a significant psychological impact, which is hard to distinguish from hormonally induced changes. Most trans men report an increase of energy and an increased sex drive. Many also report feeling more confident. While a high level of testosterone is often associated with an increase in aggression, this is not a noticeable effect in most trans men. HRT doses of testosterone are much lower than the typical doses taken by steroid-using athletes, and create testosterone levels comparable to those of most cisgender men. These levels of testosterone have not been proven to cause more aggression than comparable levels of estrogen. Some transgender men report mood swings, increased anger, and increased aggressiveness after starting androgen therapy. Studies are limited and small scale, however, based on self reporting over a short period of time (7 months). In a study by Motta et al., trans men also reported better anger control. Many transgender men, however, report improved mood, decreased emotional lability, and a lessening of anger and aggression. A randomized clinical trial on the effects of testosterone therapy in a group of transgender and gender expansive adults found that the group given treatment had significantly reduced dysphoria, depression, and suicidality relative to the control group. === Health-related changes === ==== Cardiovascular changes ==== In cisgender men, testosterone levels that are either significantly above or below normal are associated with increase cardiovascular risk. This may be causative or simply a correlation. A single retrospective study in the medical literature of 293 trans men treated with testosterone (range of 2 months to 41 years) by the Amsterdam Gender Dysphoria Clinic from 1975 to 1994 showed no increase in cardiovascular mortality or morbidity when compared with the general female Dutch population. (As with all scientific studies, this does not conclusively prove that no causal link exists. A small to moderate detrimental effect remains a possibility, though a very large effect is more unlikely.) Androgen therapy can adversely affect the blood lipid profile by causing decreases in HDL (good) cholesterol, increases in LDL (bad) cholesterol, and increases in triglycerides. Androgen therapy redistributes the fat toward abdominal obesity, which is associated with increased cardiovascular risk rather than fat carried on the buttocks and hips. Androgen therapy can cause weight gain and decreased insulin sensitivity (perhaps worsening a predisposition to develop Type II diabetes). Androgen therapy effects are not all negative, however. Acutely it causes dilation of the coronary arteries, and in men with testosterone levels within the normal physiological range, higher levels are actually associated with a slight decrease in cardiovascular disease. Supra-physiological levels of androgens (generally due to abuse) are associated with significantly increased risks of strokes and heart attacks (even in the young). Cardiovascular risk factors are more than additive. (If high blood pressure is worth 10 and smoking is worth 10, together they are worth more than 20.) So for transgender men, the addition of risk with androgen therapy makes improving modifiable risk factors more important. The most important modifiable risk factor for many men is smoking. In pre-clinical models, testosterone XHT has been shown to lead to adverse cardiovascular effects, but adding a low-dose estrogen to that hormone therapy completely mitigated those effects. (Goetz LG, et al. "Addition of Estradiol to Cross-sex Testosterone Therapy Reduces Atherosclerosis Plaque Formation in Female ApoE -/- Mice." Endocrinology. 2017) ==== Gastrointestinal changes ==== There is a risk of liver damage and liver cancer with all testosterone formulations, but this is minimal with all forms except oral or unless very high levels are administered. However, as with any drug that carries even a small risk of liver damage, liver function tests (or at least ALT) should be periodically monitored. ==== Metabolic changes ==== Testosterone increases body weight (and increases appetite). The form that this weight gain will take depends on diet and exercise as well as genetic factors. Since testosterone has anabolic effects, gain of lean muscle mass will be easier than it previously was for transgender men. Moderate amounts of exercise will cause greater gains and will ameliorate some of the adverse effects of testosterone. Many transgender men report an increased energy level, decreased need for sleep, and increased alertness after testosterone therapy. In cisgender men, abnormally high or low levels of testosterone are both associated with insulin resistance (which eventually can result in Type II diabetes). So mid-normal levels of testosterone are the target for androgen therapy. In women, increased levels of either estrogen or androgens are associated with decreased insulin sensitivity (which may predispose to diabetes). In a study of transgender males and females, decreased insulin sensitivity was found in both populations after four months of hormonal treatment. ==== Bone changes ==== Both estrogens and androgens are necessary for both cisgender males and females for healthy bone. (Young healthy women produce about 10 mg of testosterone monthly. Higher bone mineral density in males is associated with higher serum estrogen.) Bone is not static. It is constantly being reabsorbed and created. Osteoporosis results when bone formation occurs at a rate less than bone resorption. Estrogen is the predominant sex hormone that slows bone loss (even in men). Both estrogen and testosterone help stimulate bone formation (T, especially at puberty). Testosterone may cause an increase in cortical bone thickness in transgender men (however this does not necessarily translate to a greater mechanical stability). Transgender men who have been oophorectomized must continue androgen therapy to avoid premature osteoporosis. Estrogen supplementation is theoretically not usually necessary, as some of the injected testosterone will be aromatized into estrogen sufficient to maintain bone (as it does in cisgender men). However, a single small study of trans men after oophorectomy demonstrated that androgens alone may be insufficient to slow bone loss. It is likely the case that pre-oophorectomy, residual estrogen production is protective. However, after oophorectomy, some trans men may have insufficient estrogen to slow bone loss. Pre-clinical research has suggested the importance of low-dose estrogen supplementation for those beginning cross-sex hormone therapy (XHT) during adolescence. Some physicians advocate a Dexa (bone density) scan at the time of oophorectomy and every year or two thereafter to diagnose osteoporosis before it becomes severe enough to be symptomatic. This is important because the treatment of osteoporosis is most effective if done early. Daily calcium supplementation and possibly Vitamin D3 and K2 are probably a good idea for most transgender men, but it is even more important after removal of the ovaries. ==== Obstructive sleep apnea ==== OSA may be worsened or unmasked by androgen therapy. Risk is higher in transgender men who are obese, smoke, or have COPD (Chronic Obstructive Pulmonary Disease). Untreated OSA may have significant adverse effects on the heart, blood pressure, mood, and may cause headaches and worsen seizure disorders. Symptoms of OSA are noisy sleeping (snoring), excessive daytime sleepiness, morning headache, personality changes, and problems with judgment, memory, and attention. ==== Polycythemia ==== Increased red blood cell mass usually from overproduction by the bone marrow. Testosterone (frequently in large doses) was previously used to treat anemia from bone marrow failure. A transgender man's hematocrit (the percentage of whole blood made up of red blood cells) should be judged against normal age-adjusted values for men. Therapy is via phlebotomy (periodic therapeutic blood draws similar to blood donation). Tendency to become polycythemic worsens with age. Worse with injected testosterone (especially with longer intervals between doses) than with oral, transdermal, or Testopel. (Increase in RBCs occurs with the very high peaks from the injection. So decreasing dose and interval to 7–10 days instead of 14 may help.) Severe polycythemia predisposes to both venous and arterial thrombosis (blood clots) such as: deep venous thrombosis, pulmonary embolism, heart attack, and stroke. Aspirin may decrease the risk. == Hormone levels == During HRT, especially in the early stages of treatment, blood tests should be consistently done to assess hormone levels and liver function. Gianna Israel and colleagues have suggested that for pre-oophorectomy trans men, therapeutic testosterone levels should optimally fall within the normal male range, whereas estrogen levels should optimally fall within the normal female range. Before oophorectomy, it is difficult and frequently impractical to fully suppress estrogen levels into the normal male range, especially with exogenous testosterone aromatizing into estrogen, hence why the female ranges are referenced instead. In post-oophorectomy trans men, Israel and colleagues recommend that both testosterone and estrogen levels fall exactly within the normal male ranges. See the table below for all of the precise values they suggest. The optimal ranges listed for testosterone only apply to individuals taking bioidentical hormones in the form of testosterone (including esters) and do not apply to those taking synthetic AAS (e.g., nandrolone) or dihydrotestosterone. == See also == Androgen replacement therapy Feminizing hormone therapy Hormone replacement therapy == References == == External links == Tom Waddell Clinic Transgender Protocol - masculinizing and feminizing clinical protocols aimed at providers Medical Therapy and Health Maintenance for Transgender Men: A Guide For Health Care Providers Archived 2016-11-30 at the Wayback Machine: a free online medical book. Hudson's FTM Resource Guide: A comprehensive guide to gender transition for persons assigned female at birth Information for the Female to Male Crossdresser and Transsexual (1985): One of the earliest widely distributed guides to transmasculine transition, written by transgender activist Lou Sullivan	Wikipedia/Masculinizing_hormone_therapy
Laser medicine is the use of lasers in medical diagnosis, treatments, or therapies, such as laser photodynamic therapy, photorejuvenation, and laser surgery. The word laser stands for "light amplification by stimulated emission of radiation". == History == The laser was invented in 1960 by Theodore Maiman, and its potential uses in medicine were subsequently explored. Lasers benefit from three interesting characteristics: directivity (multiple directional functions), impulse (possibility of operating in very short pulses), and monochromaticity. Several medical applications were found for this new instrument. In 1961, just one year after the laser's invention, Dr. Charles J. Campbell successfully used a ruby laser to destroy an angiomatous retinal tumor with a single pulse. In 1963, Dr. Leon Goldman used the ruby laser to treat pigmented skin cells and reported on his findings. The argon-ionized laser (wavelength: 488–514 nm) has since become the preferred laser for the treatment of retinal detachment. The carbon dioxide laser was developed by Kumar Patel and others in the early 1960s and is now a common and versatile tool not only for medicinal purposes but also for welding and drilling, among other uses. The possibility of using optical fiber (over a short distance in the operating room) since 1970 has opened many laser applications, in particular endocavitary, thanks to the possibility of introducing the fiber into the channel of an endoscope. During this time, the argon laser began to be used in gastroenterology and pneumology. Dr. Peter Kiefhaber was the first to "successfully perform endoscopic argon laser photocoagulation for gastrointestinal bleeding in humans". Kiefhaber is also considered a pioneer in using the Nd:YAG laser in medicine, also using it to control gastrointestinal bleeding. In 1976, Dr. Hofstetter employed lasers for the first time in urology. The late 1970s saw the rise of photodynamic therapy, thanks to laser dye. (Dougherty, 1972) Since the early 1980s, applications have particularly developed, and lasers have become indispensable tools in ophthalmology, gastroenterology, and facial and aesthetic surgery. In 1981, Goldman and Dr. Ellet Drake, along with others, founded the American Society for Laser Medicine and Surgery to mark the specialization of certain branches of medicine thanks to the laser. In the same year, the Francophone Society of Medical Lasers (in French, Société Francophone des Lasers Médicaux) was founded for the same purpose and was first led by Maurice Bruhat. After the end of the 20th century, a number of centers dedicated to laser medicine opened, first in the OCDE, and then more generally since the beginning of the 21st century. The Lindbergh Operation was a historic surgical operation between surgeons in New York (United States) and doctors and a patient in Strasbourg (France) in 2001. Among other things, they utilized lasers. == Advantages == The laser presents multiple unique advantages that make it very popular among various practitioners. Due to its directional precision, a laser precisely cuts and cauterizes tissues without damaging neighboring cells. It's the safest technique and most precise cutting and cauterizing ever practiced in medicine. Laboratories use lasers extensively, especially for spectroscopy analysis and more generally for the analysis of biochemical samples. It makes it possible to literally "see" and more quickly determine the composition of a cell or sample on a microscopic scale. The electrical intensity of a laser is easily controllable in a safe way for the patient but also variable at will, which gives it a very wide and still partially explored range of uses (in 2021). == Disadvantages == The principal disadvantage is not medical but rather economic: its cost. Although its price has dropped significantly in developed countries since its inception, it remains more expensive than most other common technical means due to materials, the technicality of the equipment necessary for the operation of any laser therapy, and the fact that it requires only certain specific training. For example, in France (as in other countries with a social security system), dental, endodontal or periodontal laser treatment is classified outside the nomenclature and not reimbursed by social security. == Lasers == Lasers used in medicine include, in principle, any type of laser, but especially the following: CO2 lasers, used to cut, vaporize, ablate, and photocoagulate soft tissue. diode lasers dye lasers excimer lasers fiber lasers gas lasers free electron lasers semiconductor diode lasers == Applications in medicine == Examples of procedures, practices, devices, and specialties where lasers are utilized include the following: angioplasty cancer diagnosis cancer treatment dentistry cosmetic dermatology such as scar revision, skin resurfacing, laser hair removal, and tattoo removal dermatology, to treat melanoma frenectomy gingivectomy lithotripsy laser mammography medical imaging microscopy ophthalmology (includes Lasik and laser photocoagulation) optical coherence tomography optogenetics prostatectomy plastic surgery, in laser liposuction, in the treatment of skin lesions (congenital and acquired), and in scar management (burns and surgical scars) surgery, to cut, ablate, and cauterize tissue == See also == Dental laser Endovenous laser therapy Laser-assisted new attachment procedure Laser surgery Light therapy Low level laser therapy Neuromodulation Neurostimulation Photodynamic therapy Photomedicine == References == == External links == Media related to Laser medicine at Wikimedia Commons	Wikipedia/Laser_therapy
Symptomatic treatment, supportive care, supportive therapy, or palliative treatment is any medical therapy of a disease that only affects its symptoms, not the underlying cause. It is usually aimed at reducing the signs and symptoms for the comfort and well-being of the patient, but it also may be useful in reducing organic consequences and sequelae of these signs and symptoms of the disease. In many diseases, even in those whose etiologies are known (e.g., most viral diseases, such as influenza and Rift Valley fever), symptomatic treatment is the only treatment available so far. For more detail, see supportive therapy. For conditions like cancer, arthritis, neuropathy, tendinopathy, and injury, it can be useful to distinguish treatments that are supportive/palliative and cannot alter the natural history of the disease (disease modifying treatments). == Examples == Examples of symptomatic treatments: Analgesics, to reduce pain Anti-inflammatory agents, for inflammation caused by arthritis Antitussives, for cough Antihistaminics (also known as antihistamines), for allergy Antipyretics, for fever Enemas for constipation Treatments that reduce unwanted side effects from drugs == Uses == When the etiology (the cause, set of causes, or manner of causation of a disease or condition) for the disease is known, then specific treatment may be instituted, but it is generally associated with symptomatic treatment, as well. When the etiology is unknown, then symptomatic treatment may be the only realistic option. Symptomatic treatments are often used to manage side effects, such as drug withdrawal syndromes. Symptomatic treatment is not always recommended, and in fact, it may be dangerous, because it may mask the presence of an underlying etiology which will then be forgotten or treated with great delay. Examples: Low-grade fever for 15 days or more is sometimes the only symptom of bacteremia by staphylococcus bacteria. Suppressing it by symptomatic treatment will hide the disease from effective diagnosis and treatment with antibiotics. The consequence may be severe (rheumatic fever, nephritis, endocarditis, etc.) Chronic headache may be caused simply by a constitutional disposition or be the result of a brain tumor or a brain aneurysm. Finally, symptomatic treatment is not exempt from adverse effects, and may be a cause of iatrogenic consequences (i.e., ill effects caused by the treatment itself), such as allergic reactions, stomach bleeding, central nervous system effects (nausea, dizziness, etc.). == See also == Palliative care – program of supportive care for people with serious illnesses == References ==	Wikipedia/Symptomatic_treatment
Therapy freedom is the freedom of physicians to apply whichever therapy their medical knowledge makes them believe to be appropriate. That often means: Physician have the legal right to prescribe an unlicensed drug. In the 1960s, some of today's drugs considered essential human medicines could be purchased without a prescription. At that time, governments began to impose strict regulations on drugs to ensure the quality of drugs and the effectiveness of treatment. Nowadays, many countries have established drug regulatory agencies. An unlicensed medicine refers to its prescription for use without a marketing authorization issued by the licensing authority of the country. A comprehensive research in Australia, Czech Republic, India, Israel, Italy, Netherlands, Spain, Serbia, Sweden, UK, and USA showed that their rate of prescription (unlicensed medicine) has been reported to range from 0.3 to 35% depending on the country. In many countries, unlicensed therapy should only be prescribed when: no licensed alternative meets the patient's medical necessity and "the clinical benefits are considered to outweigh the potential risks of treatment". Possible restrictions on this issue in each jurisdiction should also be taken into account. From the EU perspective, "if the medical product is provided for “humanitarian reasons to a group of patients suffering from a debilitating and chronic or serious illness or whose disease is considered to be life-threatening” (Article 83, subsection 2 of the EU regulation number 726/2004), it is regarded as a special form, the so called “compassionate use." For example in Italy, the use of the so-called "compassionate use" is foreseen for a medicinal product undergoing clinical trials, outside of the trial itself, in patients suffering from serious or rare diseases or who are in danger of life, when, in the opinion of the doctor, there are no further valid therapeutic alternatives, or in the case in which the patient cannot be included in a clinical trial or, for the purposes of therapeutic continuity, for patients already treated with clinical benefit in the context of a clinical trial of at least phase II concluded. The medicinal product in question must be the subject of an application for marketing authorization or be subjected to trials (Art. 83 paragraph 2 of EC Regulation 726/2004 of the European Parliament and of the Council of 31 March 2004). In Germany, the prescribers have a wide margin of discretion in choosing the therapy that they consider medically necessary. However, they must be guided by the current state of scientific knowledge and exercise due care. The Federal Constitutional Court confirmed this scope in a decision from 2005. From the UK perspective, physicians can prescribe unauthorized drugs, even if they are unlicensed in the UK, in a case if they are licensed elsewhere, or if they have been fabricated in the UK by a certified factory. A health insurance company is obliged to pay for the treatment, regardless of whether or not it considers the treatment to be appropriate. Your health insurer should reimburse medical expenses due to your health insurance package; it would pay the care compensation following the signed health insurance agreement and local restrictions on this issue in each jurisdiction. Therapy freedom, however, is limited to cases of no treatment existing that is both well-established and more efficacious. Therapy freedom is established in Germany, where it is known as Therapiefreiheit. == References ==	Wikipedia/Therapy_freedom
Radionics—also called electromagnetic therapy (EMT) and the Abrams method—is a form of alternative medicine that claims that disease can be diagnosed and treated by applying electromagnetic radiation (EMR), such as radio waves, to the body from an electrically powered device. It is similar to magnet therapy, which also applies EMR to the body but uses a magnet that generates a static electromagnetic field. The concept behind radionics originated with two books published by American physician Albert Abrams in 1909 and 1910. Over the next decade, Abrams became a millionaire by leasing EMT machines, which he designed himself. This so-called treatment contradicts the principles of physics and biology and therefore is widely considered pseudoscientific. The United States Food and Drug Administration does not recognize any legitimate medical use for radionic devices. Several systematic reviews have shown radionics is no more effective than placebo and falls into the category of pseudoscience. == History == Beginning around 1909, Albert Abrams (1864–1924) began to claim that he could detect "energy frequencies" in his patient's bodies. The idea was that a healthy person will have certain energy frequencies moving through their body that define health, while an unhealthy person will exhibit other, different energy frequencies that define disorders. He said he could cure people by "balancing" their discordant frequencies and claimed that his devices are sensitive enough that he could tell someone's religion by looking at a drop of blood. He developed thirteen devices and became a millionaire leasing his devices, and the American Medical Association described him as the "dean of gadget quacks". His devices were definitively proven useless by an independent investigation commissioned by Scientific American in 1924. He used "frequency" not in its standard meaning, but to describe an imputed energy type, which does not correspond to any property of energy in the scientific sense. In one form of radionics popularised by Abrams, some blood on a bit of filter paper is attached to a device Abrams called a "dynamizer", which is attached by wires to a string of other devices and then to the forehead of a healthy volunteer, facing west in a dim light. By tapping on his abdomen and searching for areas of "dullness", disease in the donor of the blood is diagnosed by proxy. Handwriting analysis is also used to diagnose disease under this scheme. Having done this, the practitioner may use a special device known as an oscilloclast or any of a range of other devices to broadcast vibrations at the patient in order to attempt to heal them. Other notable quack devices in radionics have included the Ionaco and the Hieronymus machine. Some people claim to have the paranormal or parapsychological ability to detect "radiation" within the human body, which they call radiesthesia. According to the theory, all human bodies give off unique or characteristic "radiations" as do all other physical bodies or objects. Such radiations are often termed an "aura". Radiesthesia is cited as the explanation of such phenomena as dowsing by rods and pendulums in order to locate buried substances, diagnose illnesses, and the like. Radiesthesia has been described as a mixture of occultism and pseudoscience by critics. Modern practitioners conceptualize these devices merely as a focusing aid to the practitioner's proclaimed dowsing abilities, and claim that there is no longer any need for the device to have any demonstrable function. Indeed, Abrams' black boxes had no purpose of their own, being merely obfuscated collections of wires and electronic parts. Contemporary proponents of radionics or EMT claim that where there is an imbalance of electromagnetic fields or frequencies, within the body, that it causes diseases or other illnesses by disrupting the body's chemical makeup. These practitioners believe that applications of electromagnetic energy from outside the body can correct these imbalances. Like magnet therapy, electromagnetic therapy has been proposed by practitioners of alternative medicine for a variety of purposes, including, according to the American Cancer Society, "ulcers, headaches, burns, chronic pain, nerve disorders, spinal cord injuries, diabetes, gum infections, asthma, bronchitis, arthritis, cerebral palsy, heart disease, and cancer". Another variant of radionics or EMT is magnetic resonance therapy. == Scientific assessment == The claims for radionic devices contradict the accepted principles of biology and physics. No scientifically verifiable mechanisms of function for these devices has been posited, and they are often described as "magical" in operation. No plausible biophysical basis for the "putative energy fields" has been proposed, and neither the fields themselves nor their purported therapeutic effects have been convincingly demonstrated. No radionic device has been found efficacious in the diagnosis or treatment of any disease, and the U.S. Food and Drug Administration does not recognize any legitimate medical uses of any such device. According to David Helwig in The Gale Encyclopedia of Alternative Medicine, "most physicians dismiss radionics as quackery". Internally, a radionic device is very simple and may not even form a functional electrical circuit. The wiring in the analysis device is simply used as a mystical conduit. A radionic device does not use or need electric power, though a power cord may be provided, ostensibly to determine a "base rate" on which the device operates to attempt to heal a subject. Typically, little attempt is made to define or describe what, if anything, is flowing along the wires and being measured. Energy in the physical sense, i.e., energy that can be sensed and measured, is viewed as subordinate to intent and "creative action". Claims about contemporary EMT devices are similar to those made by the older generation of "radionics" devices, are also not supported by evidence, and are also pseudoscientific. Even though some of the early works in bioelectromagnetics have been applied in clinical medicine, the use of electromagnetic energy in mainstream medicine is completely unrelated to alternative devices or methods that use externally applied electrical forces. The American Cancer Society says that "relying on electromagnetic treatment alone and avoiding conventional medical care may have serious health consequences". In some cases the devices may be ineffective and harmful. === Reviews === Several systematic reviews have shown EMT is not a useful therapy: In 2009 no significant difference from control was found for management of pain or stiffness for osteoarthritis. In 2011 a systematic literature review on the use of pulsed electromagnetic field (PEMT) body mats used in a wide range of conditions found insufficient evidence for them to be recommended and recommended further high‐quality, double‐blind trials. In 2014 insufficient for the efficacy of EMT as a therapy for urinary incontinence. In 2014 EMT was found to have no difference from control for stimulation of bone growth in acute fractures. In 2015 Cochrane Database of Systematic Reviews found no evidence that EMT was useful in healing pressure ulcers or venous stasis ulcers. A 2016 guideline, in addition to reviews in 2016, 2013 and 2022, did not find EMT useful for various forms of pain. == EMT devices == The FDA has banned some commercially available EMT devices. In 2008 the VIBE machine from Vibe Technologies had a Class I recall that was completed in 2012. Other ineffectual EMT therapy devices that have been marketed include: "BioResonance Tumor Therapy", developed by Martin Keymer and purported to stimulate the P53 gene to cure cancer. "Cell Com System", a device created by Hugo Nielsen that is used on hands and feet to regulate communications between cells in the body. "Rife machine", a device created by Royal Rife, which is also known as frequency therapy or frequency generator and marketed as treating cancer. "Zapping Machine", a device created by Hulda Regehr Clark, claimed to cure cancer by using low-level electrical current to kill parasites within the body that are supposed to cause cancer. "EMP Pad", a device manufactured by EMPPad, advertised by Noel Edmonds, that is claimed to slow ageing, reduce pain, lift depression and stress and tackles cancer. "UVLrx", a device manufactured by UVLrx Therapeutics that provides ultraviolet treatment of blood to treat HIV/AIDS, Hepatitis C, Dengue fever and Lyme disease, as well as many other conditions. "ReBuilder", a device manufactured by Rebuilder, is claimed to reverse neuropathy (nerve damage) by using tiny electrical signals to wake up nerves. "Electro Physiological Feedback Xrroid (EPFX)", a device manufactured by Desiré Dubounet that is claimed to cure cancer, as well as other serious conditions by sending electromagnetic frequencies into the body. == Notable practitioners == == See also == Biophoton – a term used by EMT proponents Electropoise Neuromodulation Neurostimulation Psionics Pulsed electromagnetic field therapy == References == == Further reading == Stephen Barrett, William T. Jarvis. (1993). The Health Robbers: A Close Look at Quackery in America. Prometheus Books. ISBN 0-87975-855-4. Eric Jameson. (1961). The Natural History of Quackery. Charles C. Thomas Publisher. Bob McCoy. (2004). Radionics. In Quack!: Tales of Medical Fraud from the Museum of Questionable Medical Devices. Santa Monica Press. pp. 71–94. ISBN 1-891661-10-8. James Harvey Young. (1965). Device Quackery in America. Bulletin of the History of Medicine 39: 154–162. == External links == Regulatory Actions related to EMT Devices – Stephen Barrett M.D. via Quackwatch Index of EMT Devices – Stephen Barrett M.D. via devicewatch.org Radionics in the Skeptic's dictionary	Wikipedia/Magnetic_resonance_therapy
Recreational therapy or therapeutic recreation (TR) is a systematic process that utilizes recreation, leisure, and other activities as interventions to address the assessed needs of individuals with illnesses and/or disabling conditions, as a means to psychological and physical health, recovery and well-being. Recreational therapy may also be simply referred to as recreation therapy, but in short, it is the utilization and enhancement of leisure. The work of recreational therapists differs from other professionals on the basis of using leisure activities alone to meet well-being goals, they work with clients to enhance motor, social and cognitive functioning, build confidence, develop coping skills, and integrate skills learned in treatment settings into community settings. Intervention areas vary widely and are based upon enjoyable and rewarding interests of the client. Examples of intervention modalities include creative arts (e.g., crafts, music, dance, drama, among others), games, sports like adventure programming, exercises like dance/movement, and skill enhancement activities (Motor, locomotion, sensory, cognition, communication, and behavior). "Today, the United States Department of Labor projects that there are over 19,000 recreational therapists in the United States. As of January 2023, there are 19,278 professionals who hold active, inactive, or eligible for re-entry status on the NCTRC registry. The CTRS credential is the most professionally advanced credential for the field of therapeutic recreation." There are four approaches in therapeutic recreation: Recreation services: Providing recreation services to people with disabilities for experiencing leisure and its benefits, often this takes a rehabilitation tone in approach for helping clients to reach an optimal level of health and well-being. Therapeutic approach: The purpose of this approach is curative in nature. It attempts to lessen and ameliorate the effects of illness' and disabilities, it also can be prescriptive for improving certain functional capacities. Umbrella or combined approach: Use of recreation as a subjective continuation of enjoyable activities as well as a recreation service for bringing purposeful change. Leisure ability approach: An approach that operates leisure activities therapeutically and engages the clients fully for participation with good dissemination on the benefits of structured leisure/ leisure awareness education (Gun & Peterson, 1978). Eight domains of leisure are: leisure awareness, leisure attitudes, leisure skills, community integration skills, community participation, cultural and social behaviors, interpersonal skills. == Educational programs == A bachelor's degree in recreational therapy is required for most entry-level positions. These programs typically cover areas such as treatment and program planning, human body, physiology, kinesiology, and professional ethics. Some programs offer the opportunity to specialize in occupational therapy, and in the intervention of those that are mentally or physically challenged. Most employers prefer to hire candidates who are Certified Therapeutic Recreation Specialists (CTRS). Therapists become certified through the National Council for Therapeutic Recreation Certification (NCTRC) or through a provincial regulatory body such as, Therapeutic Recreation Ontario (TRO). To qualify for certification under the Academic Path, applicants must have a bachelor's degree in TR, complete an internship under the supervision of a CTRS, and pass a written exam. There is also an Equivalency Path A and B for certification. The requirements are slightly different and include a bachelor's degree outside of TR, paid work experience, and successful completion of the written exam. === Pre-Internship Requirements === An individual must be enrolled in a regionally accredited baccalaureate degree program (or higher). Degrees include; "(a) therapeutic recreation (recreation therapy); (b) recreation or leisure with an option in therapeutic recreation; (c) therapeutic recreation, recreation, or leisure in combination with other fields of study (e.g., Therapeutic Recreation and Health Studies; Recreation and Sport Management; Leisure and Tourism); and (d) a major in another field of study with a concentration/emphasis/sub-plan/option/minor/certificate in recreation therapy/therapeutic recreation". A a minimum of 90 credit hours towards attaining the degree must be completed. A minimum of 18 semester or 24 quarter credit hours of Recreational Therapy/Therapeutic Recreation (RT/TR) specific courses have to be completed: A minimum of 6 courses in RT/TR are required (two of the required must be taught by applicant as an educator). Each individual must take 3 semester hours or 4 quarter hours coursework in each of the areas; anatomy and physiology, abnormal psychology, human growth and development across the lifespan, and the remaining semester hours or quarter hours should be fulfilled in the areas of social sciences and humanities. === Internship Requirements === The duration of the Internship is a minimum of 560 hours over the course of 14 consecutive weeks (or more). If you go under 20 hours in a week (Sun-Sat), the internship must restart. Supervision by internship supervisor must have active CTRS (Certified Therapeutic Recreation Specialist) and have been certified for at least one year prior to supervising interns. Internship completion must appear on official academic transcript. The CTRS credential, is evidence that the individual completed and met the qualifications for the NCTRC's CTRS Certification Standards. This is a limited license that requires individuals to continue education and trainings. === Continuing Education === Recreation Therapists with the Certified Therapeutic Recreation Specialist (CTRS) credential are required to complete 50 clock hours (5.0 CEUs) of continuing education within a 5 year span as part of the overall requirements to renew national certification through NCTRC. NCTRC has outlined several ways a CTRS can earn continuing education Continuing Education. These include: a.) Academic Courses b.) Teleconferences/Audio Seminars like ATRA's webinar series. c.) Internet Course Programs: Some online programs identified are on the Therapeutic Recreation Directory website: Therapeutic Recreation Directory: CEU Opportunities. The largest online providers for RT continuing education are: 1) ATRA- American Therapeutic Recreation Association Webinars 2) Rec Therapy Today 3) SMART CEUs Hub- Success Makers Are Rec Therapists- Unlimited NCTRC Pre-Approved CEUs d.) Conferences: American Therapeutic Recreation Association (ATRA) and state branches of ATRA. Recreation therapists can attend conferences provided by related professional organizations and earn CEUs (pending the session meets Therapeutic Recreation (TR) knowledge areas required by NCTRC. e.) Internships & Externships: Supervised guidance to practice. == Professional Organizations == The American Therapeutic Recreation Association (ATRA) and the Canadian Therapeutic Recreation Association (CTRA) are the largest national membership organizations representing the interests and needs of recreational therapists in the U. S. and Canada. ATRA is the only organization that represents the therapeutic recreation profession in the United States."ATRA, was incorporated in the District of Columbia in 1984 as a non-profit, grassroots organization in response to a growing concern about the dramatic changes in the healthcare industry. As a result of this response, ATRA has grown from a membership of 60 individuals in June 1984 to 2,200 in 2014." == Credentialing == Certification: The National Council for Therapeutic Recreation Certification, a charter member of the National Organization for Competency Assurance (NOCA), also provides a certification that expires after 5 years. "NCTRC was founded to protect the consumer of recreational therapy services and the public at large, resulting in many benefits to the public, the profession, the individual practitioner, and the organization." Those who are certified must apply for re-certification at the end of the expiration period. Specialty certification is now available in five areas. Health and human service professionals who acquire a higher level of knowledge and more advanced skills provide the consumer with a greater depth of service compared to individuals who practice at less advanced levels. Specialization is well recognized within professional practice and has become the norm within the health and human service delivery system today. The median salary for recreational therapists in the United States was estimated $51,330 a year in 2022. This number may vary slightly based on specific geographic region, years of experience, and type of employing agency. Licensure: There are currently five states that require a Recreational Therapy licensure (Utah, North Carolina, New Hampshire, New Jersey and Oklahoma). To practice Recreational Therapy in these states, professionals must possess a current, valid state license. In addition to the five currently licensed states, numerous other states are currently moving toward developing licensure. Through the Joint Task Force on Recreational Therapy Licensure sponsored by the American Therapeutic Recreation Association and the National Council for Therapeutic Recreation Certification, significant progress is being made in the licensure arena. Licensure is being pursued by the profession as a further means of protecting the public from potential harm. == References == == Further reading == Robertson, T. & Long, T. (Eds.) (2007). Foundations of Therapeutic Recreation. Champaign, IL: Human Kinetics. Stumbo, N. J.& Peterson, C. A.(2009). Therapeutic recreation program design: Principles and procedures. Toronto, ON: Pearson Benjamin Cummings. Dattilo, J. & McKenney, A. (2011). Facilitation Techniques in Therapeutic Recreation (2nd ed). State College, PA: Venture Publishing. Carter, M., Van Andel, G., & Robb, G. (2003). Therapeutic Recreation A Practical Approach. Prospect Heights, IL: Waveland Press, Inc. Austin, D. R., Crawford, M.E., McCormick, B.P. & Van Puymbroeck, M. (2015). Recreational Therapy: An Introduction (4thed). Urbana, IL: Sagamore Publishing. Kunstler, R., & Stavola Daly, F. (2010). Therapeutic recreation leadership and programming. Champaign, IL: Human Kinetics. == External links == American Therapeutic Recreation Association (ATRA) National Therapeutic Recreation Society U.S. Bureau of Labor: Recreational Therapist	Wikipedia/Recreational_therapy
Writing therapy is a form of expressive therapy that uses the act of writing and processing the written word in clinical interventions for healing and personal growth. Writing therapy posits that writing one's feelings gradually eases feelings of emotional trauma; studies have found this therapy primarily beneficial for alleviating stress caused by previously undisclosed adverse events and for those suffering from medical conditions associated with the immune system. Writing therapeutically can take place individually or in a group and can be administered in person with a therapist or remotely through mailing or the Internet. The field of writing therapy includes many practitioners in a variety of settings, usually administered by a therapist or counselor. Writing group leaders also work in hospitals with patients dealing with mental and physical illnesses. In university departments, they aid student self-awareness and self-development. Online and distance interventions are useful for those who prefer to remain anonymous and/or are not ready to disclose their most private thoughts and anxieties in a face-to-face situation. As with most forms of therapy, writing therapy is adapted and used to work with a wide range of psychoneurotic issues, including bereavement, desertion and abuse. Many interventions take the form of classes where clients write on specific themes chosen by the therapist or counselor. Assignments may include writing unsent letters to selected individuals, alive or dead, followed by imagined replies from the recipient, or a dialogue with the recovering alcoholic's bottle of alcohol. == Research == === Expressive writing paradigm === Expressive writing is a form of writing therapy developed primarily by James W. Pennebaker in the late 1980s. The seminal expressive writing study instructed participants in the experimental group to write about a 'past trauma', expressing their very deepest thoughts and feelings surrounding it. In contrast, control participants were asked to write as objectively and factually as possible about neutral topics (e.g., a particular room or their plans for the day) without revealing their emotions or opinions. Both groups wrote continuously for 15 minutes per day for 4 consecutive days. If participants felt they could not write any more details, they were instructed to return to the beginning, potentially repeating what they wrote or writing it in a different manner. The following quote provides an example of writing instructions for expressive writing: For the next 4 days, I would like you to write your very deepest thoughts and feelings about the most traumatic experience of your entire life or an extremely important emotional issue that has affected you and your life. In your writing, I'd like you to really let go and explore your deepest emotions and thoughts. You might tie your topic to your relationships with others, including parents, lovers, friends, or relatives; to your past, your present or your future; or to who you have been, who you would like to be or who you are now. You may write about the same general issues or experiences on all days of writing or about different topics each day. All of your writing will be completely confidential. Don't worry about spelling, grammar or sentence structure. The only rule is that once you begin writing, you continue until the time is up. Pennebaker and his team took several measurements before and after, but the most striking finding was that relative to the control group, the experimental group made significantly fewer visits to a physician in the following months. Although many reported being upset by the writing experience, they also found it valuable and meaningful.: 167 Pennebaker has either written or co-written over 130 articles on expressive writing. One publication suggested expressive writing may boost the immune system, perhaps explaining the reduction in physician visits. This was shown by measuring lymphocyte response to the foreign mitogens phytohaemagglutinin (PHA) and concanavalin A (ConA) just prior to and six weeks after writing. The significantly increased lymphocyte response led to speculation that expressive writing enhances immunocompetence. The results of a preliminary study of 40 people diagnosed with Major Depressive Disorder suggests that routinely engaging in expressive writing may be effective in reducing symptoms of depression. Pennebaker's experiments have been widely replicated and validated. Following on from Pennebaker's original work, there has been a renewed interest in the therapeutic value of abreaction. This was first discussed by Josef Breuer and Freud in Studies on Hysteria but not much explored since. At the heart of Pennebaker's theory is the idea that actively inhibiting thoughts and feelings about traumatic events requires effort, serves as a cumulative stressor on the body, and is associated with increased physiological activity, obsessive thinking or ruminating about the event, and longer-term disease. ==== Criticism ==== As Baikie and Wilhelm note in following quote, the theory has intuitive appeal but mixed empirical support. Studies have shown that expressive writing results in significant improvements in various biochemical markers of physical and immune functioning (Pennebaker et al, 1988; Esterling et al, 1994; Petrie et al, 1995; Booth et al, 1997). This suggests that written disclosure may reduce the physiological stress on the body caused by inhibition, although it does not necessarily mean that disinhibition is the causal mechanism underlying these biological effects. On the other hand, participants writing about previously undisclosed traumas showed no differences in health outcomes from those writing about previously disclosed traumas (Greenberg & Stone, 1992) and participants writing about imaginary traumas that they had not actually experienced, and therefore could not have inhibited, also demonstrated significant improvements in physical health (Greenberg et al, 1996). Therefore, although inhibition may play a part, the observed benefits of writing are not entirely due to reductions in inhibition. In a 2013 article by Nazarian and Smyth, the salivary cortisol for 5 writing instructions for the expressive writing task were measured: cognitive processing, exposure, self-regulation, and benefit-finding, standard expressive writing. None of the conditions significantly influenced cortisol compared to control group, but instructions did impact mood differentially depending on the condition. The cognitive processing as measured post-intervention was influenced not only by the cognitive processing instructions but also, by exposure and benefit-finding. These results demonstrate a spillover effect from instructions to outcomes. === Other theories related to writing therapy === In related research, Travagin, Margola, Dennis, and Revenson compared cognitive-processing instructions to standard expressive writing for adolescents with peer problems. This research demonstrated better long-term social adjustment compared to standard expressive writing and greater increased positive affect for those adolescents who reported more peer problems than most. An additional line of inquiry, which has particular bearing on the difference between talking and writing, derives from Robert Ornstein's studies into the bicameral structure of the brain. Julie Gray, founder of Stories Without Borders notes that "People who have experienced trauma in their lives, whether or not they consider themselves writers, can benefit from creating narratives out of their stories. It is helpful to write it down, in other words, in safety and in non-judgment. Trauma can be quite isolating. Those who have suffered need to understand how they feel and also to try to communicate that to others." == Potential clinical benefits == Additional research since the 1980s has demonstrated that expressive writing may act as an agent to increase long-term health. Expressive writing can result in physiological, psychological, and biological outcomes, and is part of the emerging medical humanities field. Experiments demonstrate quantitative physiological readouts such as changes in immune counts, and blood pressure, in addition to qualitative readouts relating to psychiatric symptoms. Past attempts at implementing expressive writing interventions in clinical settings indicate that there are potential benefits for treatment plans. However, the specifics of such expressive writing procedures or protocols, and the populations most likely to benefit are not entirely clear. === Expressive writing === One of the most important aspects of expressive writing used in therapy is the short-term, and long-term effects on the individuals participating. Karen Baikie and Kay Wilhelm go into a brief description of the effects people will have after completing a therapeutic expressive writing session. While some people have experienced negative feelings, physical and mental, instantly after using expressive writing as a tool to cope, following up with clients after a longer amount of time to measure those effects finds evidence of many mental and physical health benefits. These benefits include but are not limited to "reduced blood pressure, improved mood, reduced depressive symptoms, and fewer post-traumatic intrusion/avoidance symptoms." This study also showed that these positive long-term emotional outcomes correlated to positive physical outcomes such as improved memory, improved performance at work, quicker re-employment, and many more. While the short-term effects of this therapeutic practice may seem daunting, they are just the steppingstones for individuals to begin a cycle of growth. === For cancer patients === Illness and disease are experienced on multiple different fronts: biological, psychological, and social. Recent research has explored how narrative medicine and expressive writing, independently, may play a therapeutic role in chronic diseases such as cancer. Comparisons in practice have been made between expressive writing and psychotherapy. Similarly, practices such as integrative, holistic, humanistic, or complementary medicine have already been incorporated into the field. Expressive writing is self-administered with minimal prompting. With further research and refinement, it may be used as a more cost-effective alternative to psychotherapy. Recent experiments, systematic reviews, and meta-analyses examining the effects of expressive writing on ameliorating negative cancer symptoms yielded primarily non-significant initial results. However, analysis of sub-groups and moderating variables suggest that particular symptoms, or situations, may benefit some more than others with the implementation of an expressive writing intervention. For example, a review by Antoni and Dhabhar (2019) examined how psychosocial stress negatively impacts the immune response of patients with cancer. Even if an expressive writing intervention cannot directly impact cancer prognosis, it may play an important role in mediating factors such as chronic stress, trauma, depression, and anxiety. === War trauma victims === It is widely acknowledged that trauma is prevalent among veterans, and research indicates that writing therapy can play a significant role in their self-healing journey. A primary contributor to trauma is the sense of powerlessness. Writing facilitates self-healing against this sense of helplessness through the strategy of mythologization. Neil P Baird defines mythologization as the process of establishing standardized narratives that transform uncontrollable events into ones that are contained and predictable. Janis Haswell expands on this concept by highlighting how individuals can utilize writing to manipulate and reshape the traumatic events they have experienced. This allows them to convey the emotional truths of their pasts to not only themselves but to others through the words on a page.Marian M MacCurdy has argued that there is a link between trauma and the brain, where traumatic events exist in the brain as images, rather than a clear and direct story, which causes difficulty for victims to describe their experiences fully. When victims decide to write these experiences down, it allows them to take control of the story and piece together the images they have held in their brains, which can help lead them to healing parts of that trauma. Mark Bracher emphasizes the benefits of literacy in general for self-healing. His research indicates that literacy acknowledges the challenges veterans face during their deployment. This acknowledgement can in turn boost their morale and contribute to them feeling valued. Additionally, it aids in diminishing the recollection of distressing memories and reinforces one's sense of self-identity. Nancy Miller explores further the reinforcement of self-identity by examining Kim Phuc, a victim of napalm burns during the Vietnam War. In Kim's biographical memoir, she sought to transform her portrayal from that of a helpless child frightened by war into a tale of forgiveness. Her objective with her writing was to illustrate how she overcame her trauma from war through her deliberate effort to reshape her past with a more optimistic perspective. === Recovering from addiction === Writing therapy may play a significant role in recovery for individuals with a substance use disorder. Writing exercises have been found to have the potential to improve those in addiction recovery the ability to cope with their conditions, and overall health.When a person in addiction recovery is given writing exercises to complete, it can allow them to reflect on their past actions and figure out what they must do differently to improve their behavior. When they put together their stories, and discover that other people can relate to them, any negative feelings they may have felt, can potentially decrease as they get deeper into the writing therapy process. Studies done involving creative writing and people who deal with substance abuse have shown to become more confident and develop a higher self-esteem. When therapists introduce creative writing as a healing tool, there are higher chances of a better relationship between the therapist and the patient. == Forms == === Distance therapies === With the accessibility provided by the Internet, the reach of writing therapies has increased considerably, as clients and therapists can work together from anywhere in the world, provided they can write the same language. They simply "enter" into a private "chat room" and engage in an ongoing text dialogue in "real-time". Participants can also receive therapy sessions via e-text and/or voice with video, and complete online questionnaires, handouts, workout sheets, and similar exercises. This requires the services of a counselor or therapist, albeit sitting at a computer. Given the huge disjunction between the amount of mental illness compared with the paucity of skilled resources, new ways have been sought to provide therapy other than drugs. In the more advanced societies pressure for cost-effective treatments, supported by evidence-based results, has come from both insurance companies and government agencies. Hence the decline in long-term intensive psychoanalysis and the rise of much briefer forms, such as cognitive therapy. While distance therapy has been deemed to be beneficial, therapists and patients have mentioned the downsides of treatment through a phone or video call. Some of these downsides include patients struggling to find a secluded place in their homes where they are comfortable being vulnerable. Therapists have also mentioned that distance therapy can be more draining than in-person therapy and more difficult to focus, for both the therapist and the patient. When they interact through a screen, the therapist has less ability to examine the patient's body language. ==== Via the Internet ==== Currently, the most widely used mode of Internet writing therapy is via e-mail (see analytic psychotherapist Nathan Field's paper "The Therapeutic Action of Writing in Self-Disclosure and Self-Expression"). It is asynchronous; i.e. messages are passed between therapist and client within an agreed time frame (for instance, one week), but at any time within that week. Where both parties remain anonymous the client benefits from the online disinhibition effect; that is to say, feels freer to disclose memories, thoughts, and feelings that they might withhold in a face-to-face situation. Both client and therapist have time for reflecting on the past and recapturing forgotten memories, time for privately processing their reactions and giving thought to their own responses. With e-therapy, space is eliminated, and time is expanded. Overall, it considerably reduces the amount of therapeutic input, as well as the speed and pressure that therapists habitually have to work under. The anonymity and invisibility provides a therapeutic environment that comes much closer than classical analysis to Freud's ideal of the "analytic blank screen". Sitting behind the patient on the couch still leaves room for a multitude of clues to the analyst's individuality; e-therapy provides almost none. Whether distance and reciprocal anonymity reduces or increases the level of transference has yet to be investigated. In a 2016 randomized controlled trial, expressive writing was tested against direction to an online support group for individuals with anxiety and depression. No difference between the groups was found. Both groups showed a moderate improvement over time but of a magnitude comparable to what one would expect to see over the time period concerned without intervention. === Journaling === The oldest and most widely practiced form of self-help through writing is that of keeping a personal journal or diary—as distinct from a diary or calendar of daily appointments—in which the writer records their most meaningful thoughts and feelings. One individual benefit is that the act of writing puts a powerful brake on the torment of endlessly repeating troubled thoughts to which everyone is prone. Kathleen Adams states that through the act of journal writing, the writer is also able to "literally [read] his or her own mind" and thus "to perceive experiences more clearly and thus feels a relief of tension". Self-concealment Self-disclosure Reflective writing === Poetry === Poetry has been a very powerful form of writing for many and there are beneficial factors that correspond with writing and reading poetry. Alicia Ostriker explains how personal experience and memories, whether traumatic or repressed, can be tackled by the person through the artistic ability of writing and facing these emotions that have been neglected in order to release and ease a writer's pain. Robert Baden elaborates how poetry allows a wide range of emotions to be portrayed to describe the feeling or what the writer had felt within their experience to later allow others to engage and relate to their work. Baden expands this concept with the idea that no emotion is too grand or too small for poetry, which allows others to engage with the healing experience. Baden also points out that for there to be an act of healing and release between the emotions that have been held within the conscience, the writer must recognize that there must be a strong enough need to be vulnerable and willing to be able to confront these emotions and trust that the audience will then be able to relate and potentially make others want to use this written release within their own lives. Vasiliki Antzoulis believes that writers should be vulnerable because ignorance should never be the course of action when experiencing all kinds of emotions. Without the ability to talk about what the writer is experiencing, it becomes more difficult to understand what each of these emotions represents and how they affect the writer's current views of life. Dale M. Bauer provides insight that poetry has the power to allow people to be able to talk about inner suffering without judgment and rather gain the ability to have others be able to compare and connect with the writer's experience. Bauer goes on to say that these experiences, no matter if they are good or bad, correspond with the human experience. Being able to have others relate to them allows the writer to feel supported and reflect on what has been shared and what they have obtained with this release and be able to begin healing. Veteran Writer, Liam Corley, healed significantly from his trauma through the means of poetry. By sharing this method with fellow veterans and examining its positive impacts, Corley’s research indicates the concise nature and inherent significance of poetry works greatly for self-healing. This is because poetry fulfills the crucial need for self-expression and assists in providing a voice to those who have felt silenced. James W. Pennebaker has discovered that "writing about trauma allows writers to externalize an event, thereby detaching themselves from the experience" (Writing to Heal 98). Pennebaker argues that once the writer can free themselves from what has been weighing them down, they are then able to begin healing and decide whether they are going to learn from the experience, or if it is something that has been long overdue for a release. Benjamin Batzer recognized that only the writer knows what they have gone through, so the first steps into healing and coping with what life has given, we must first be able to talk about these experiences to take back the power and decide the next point of action. == See also == Medical humanities Graphic medicine Narrative criticism Storytelling Narration Slow medicine Health humanities Reflective writing == References == == Further reading ==	Wikipedia/Writing_therapy
Contrast bath therapy is a form of treatment where a limb or the entire body is immersed in hot (but not boiling) water followed by the immediate immersion of the limb or body in cold ice water. This procedure is repeated several times, alternating hot and cold. The only evidence of benefit is anecdotal and no plausible mechanism has been confirmed. == Theory == The theory behind contrast bath therapy is that the hot water causes vasodilation of the blood flow in the limb or body followed by the cold water which causes vasoconstriction. The lymph system, unlike the circulatory system, lacks a central pump. By alternating hot and cold, it is believed that lymph vessels dilate and contract to "pump" and move stagnant fluid out of the injured area and that this positively affects the inflammation process, which is the body's primary mechanism for healing damaged tissue. == Treatment == Contrast bathing can be used to reduce swelling around injuries or to aid recovery from exercise. It can also significantly improve muscle recovery following exercise by reducing the levels of blood lactate concentration. For any injury presenting with palpable swelling and heat, and visible redness - such as a strain/sprain - contrast baths are contraindicated during the acute inflammation stage. Acute inflammation begins at the time of injury and lasts for approximately 72 hours. == Effectiveness in athletic recovery == The current evidence base suggests that contrast water therapy (CWT) is superior to using passive recovery or rest after exercise; the magnitudes of these effects may be most relevant to an elite sporting population. There seems to be little difference in recovery outcome between CWT and other popular recovery interventions such as cold water immersion and active recovery. In a review on immersion therapy in general, Ian Wilcock, John Cronin, and Wayne Hing suggest that most of the benefits of contrast therapy are from the hydrostatic pressure from the water, not the variations in temperature. == See also == Ice bath == References ==	Wikipedia/Contrast_bath_therapy
Immersion therapy is a psychological technique which allows a patient to overcome fears (phobias), but can be used for anxiety and panic disorders. == Details == First a fear-hierarchy is created: the patient is asked a series of questions to determine the level of discomfort the fear causes in various conditions. Can the patient talk about the object of their fear, can the patient tolerate a picture of it or watch a movie which has the object of their fear, can they be in the same room with the object of their fear, and/or can they be in physical contact with it? Once these questions have been ordered beginning with least discomfort to most discomfort, the patient is taught a relaxation exercise. Such an exercise might be tensing all the muscles in the patient's body then relaxing them and saying "relax", and then repeating this process until the patient is calm. Next, the patient is exposed to the object of their fear in a condition with which they are most comfortable - such as merely talking about the object of their fear. Then, while in such an environment, the patient performs the relaxation exercise until they are comfortable at that level. After that, the patient moves up the hierarchy to the next condition, such as a picture or movie of the object of fear, and then to the next level in the hierarchy and so on until the patient is able to cope with the fear directly. This specific therapy can create a safe space, where individuals are able to become comfortable with their fears, anxieties or traumatic experiences. One may say it is linked to exposure, as the patient is immersed into an experience until they eventually become much more relaxed in it. Although it may take several sessions to achieve a resolution, the technique is regarded as successful. Many research studies are being conducted in regard to achieving immersion therapy goals in a virtual computer based program, although results are not conclusive. 'Immersive therapy through virtual reality represents a novel strategy used in psychological interventions, but there is still a need to strengthen the evidence on its effects on health professionals' mental health' (Linares-Chamorro et al., 2022). == Virtual therapy == As mentioned previously, Immersion Therapy can occur in the form of a virtual reality (VR) therapy. This usually involves transporting the user to a simulated environment, creating a realistic real life setting, and combining video, audio, haptic and motion sensory input to create an immersive experience. Virtual therapy may use videos in either a 2D or 3D immersion using a head-mounted display (Hodges et al., 2002). There have been many studies looking at this type of therapy and combatting anxiety and phobias, such as acrophobia. It assesses a patient's cognitive, emotional and physiological functioning. It can be useful for both prevention and treatment of psychiatric conditions. This method goes beyond the simple exposure therapy, as it can be a more comprehensive treatment compared to other interventions. A study conducted in Olot, Spain aimed to look at levels of anxiety and the wellbeing of female hospital staff. A sample size of 35 female health professionals undertook immersive therapy for 8 weeks. The way the anxiety levels were measured was through the Hamilton scale and well-being through the Eudemon scale. This specific immersive therapy was executed through Virtual Reality, in which the VR experience used a projection device with light and sound control that provided an immersive experience, creating an environment that enhanced self awareness to approach anxiety management. Results suggested that a significant improvement was found in anxiety and wellbeing, both statistically and clinically. Another study in the UK looking at helping acrophobia. Researchers recruited 100 adults with a fear of heights, if they scored more than 29 on the heights interpretation questionnaire, suggested they had a fear of heights. Participants were randomly allocated by computer to either an automated VR delivered in roughly six 30 minute sessions, administered about 2-3 times a week over 2 weeks and a control group was present which received no treatment. The virtual coach worked alongside the VR programmed and would mention things like "We're discovering what happens when we venture into a situation we'd normally try to avoid." The aim of the virtual coach was to put the participants' expectations to the test and experiencing citations where they would usually feel anxious. Then the tasks began, where they underwent different levels of heights in different activities. Overall, participants in the control group compared to the VR group had reduced fear of heights by the end of the treatment. Although, this is evidence to suggest how virtual computer based immersion therapy works, the research within this area of Psychology is scare, thus more testing needs to occur, to fully implement this type of technology. === Advantages === Immersive virtual reality may be identified as something that is a potentially revolutionary tool for psychological treatment of mental disorders, which may gradually be adopted in regular clinical practice in the coming years. (Geraets et al., 2021). Virtual reality has significantly been evolving over the last few years due to many advancements in technology, thus enabling us to understand the constant need for new research to take place. The benefits of Immersive virtual reality therapy could significantly enhance effective psychological interventions. Treatments can be given automatically, without a therapist's physical presence, resulting in a more low cost route. Another benefit of VR is that it can offer 'direct therapeutic intervention', which is often lacking in conventional clinical settings, allowing for treatments to be delivered faster and more efficiently. Patients can be placed in simulated environments whilst wearing a VR headset, teaching them how to react more effectively. Additionally, patients are more open to experimenting with new therapies because they are aware they are in a secure stimulation setting, in which the exposure to the stimuli can occur in different stages and not just one go. VR has been used successfully over the past 25 years for assessment, understanding, and treatment of mental health disorders.The increased accessibility and affordability of VR mean that this technique is now ready to move from specialist laboratories into clinics (Freeman et al., 2018). Immersive therapy can provide a distinctive and engaging experience that allows for overcoming fears, gaining self-confidence and creating coping strategies. It allows people to experience real life situations in a controlled and safe setting. It is much more interactive and rather than just talking about their phobia or anxiety, they can actually relive it but overcome it too, generating a greater sense of self-confidence, reducing the feelings of anxieties and managing their feelings during stressful situations. == See also == Flooding (psychology) Exposure therapy == References ==	Wikipedia/Immersion_therapy
Cancer immunotherapy (immuno-oncotherapy) is the stimulation of the immune system to treat cancer, improving the immune system's natural ability to fight the disease. It is an application of the fundamental research of cancer immunology (immuno-oncology) and a growing subspecialty of oncology. Cancer immunotherapy exploits the fact that cancer cells often have tumor antigens, molecules on their surface that can bind to antibody proteins or T-cell receptors, triggering an immune system response. The tumor antigens are often proteins or other macromolecules (e.g., carbohydrates). Normal antibodies bind to external pathogens, but the modified immunotherapy antibodies bind to the tumor antigens marking and identifying the cancer cells for the immune system to inhibit or kill. The clinical success of cancer immunotherapy is highly variable between different forms of cancer; for instance, certain subtypes of gastric cancer react well to the approach whereas immunotherapy is not effective for other subtypes. In 2018, American immunologist James P. Allison and Japanese immunologist Tasuku Honjo received the Nobel Prize in Physiology or Medicine for their discovery of cancer therapy by inhibition of negative immune regulation. == History == "During the 17th and 18th centuries, various forms of immunotherapy in cancer became widespread... In the 18th and 19th centuries, septic dressings enclosing ulcerative tumours were used for the treatment of cancer. Surgical wounds were left open to facilitate the development of infection, and purulent sores were created deliberately... One of the most well-known effects of microorganisms on ... cancer was reported in 1891, when an American surgeon, William Coley, inoculated patients having inoperable tumours with [ Streptococcus pyogenes ]." "Coley [had] thoroughly reviewed the literature available at that time and found 38 reports of cancer patients with accidental or iatrogenic feverish erysipelas. In 12 patients, the sarcoma or carcinoma had completely disappeared; the others had substantially improved. Coley decided to attempt the therapeutic use of iatrogenic erysipelas..." "Coley developed a toxin that contained heat-killed bacteria [ Streptococcus pyogenes and Serratia marcescens ]. Until 1963, this treatment was used for the treatment of sarcoma." "Coley injected more than 1000 cancer patients with bacteria or bacterial products." 51.9% of [Coley's] patients with inoperable soft-tissue sarcomas showed complete tumour regression and survived for more than 5 years, and 21.2% of the patients had no clinical evidence of tumour at least 20 years after this treatment..." Research continued in the 20th century under Maria O'Connor Hornung at Tulane Medical School. In the 1980's, researchers at the National Cancer Institute's Center for Cancer Research (CCR) began exploring the then-heretical idea that a patient’s immune system could be harnessed to fight cancer. These researchers included Michael Potter, Ira Pastan, and Steven Rosenberg who developed approaches including monoclonal antibody-based immunotoxins, checkpoint blockade drugs, cytokine-based therapies, and adoptive cell therapy studies. == Types and categories == There are several types of immunotherapy used to treat cancer: Immune checkpoint inhibitors: drugs that block immune system checkpoints to allow immune cells to respond more strongly to the cancer. T-cell transfer therapy: a treatment that takes T-cells from the tumor and selects or changes them in the lab to better attack cancer cells, then reintroduces them into the patient. Monoclonal antibodies: designed to bind to specific targets on cancer cells, marking cancer cells so that they will be better seen and destroyed by the immune system. Treatment vaccines: also known as therapeutic cancer vaccines, help the immune system learn to recognize and react to mutant proteins specific to the tumor and destroy cancer cells containing them. Immune system modulators: agents that enhance the body’s immune response against cancer. Immunotherapies can be categorized as active or passive based on their ability to engage the host immune system against cancer. Active immunotherapy specifically targets tumor cells via the immune system. Examples include therapeutic cancer vaccines (also known as treatment vaccines, which are designed to boost the body's immune system to fight cancer), CAR-T cells, and targeted antibody therapies. In contrast, passive immunotherapy does not directly target tumor cells, but enhances the ability of the immune system to attack cancer cells. Examples include checkpoint inhibitors and cytokines. Active cellular therapies aim to destroy cancer cells by recognition of distinct markers known as antigens. In cancer vaccines, the goal is to generate an immune response to these antigens through a vaccine. Currently, only one vaccine (sipuleucel-T for prostate cancer) has been approved. In cell-mediated therapies like CAR-T cell therapy, immune cells are extracted from the patient, genetically engineered to recognize tumor-specific antigens, and returned to the patient. Cell types that can be used in this way are natural killer (NK) cells, lymphokine-activated killer cells, cytotoxic T cells, and dendritic cells. Finally, specific antibodies can be developed that recognize cancer cells and target them for destruction by the immune system. Examples of such antibodies include rituximab (targeting CD-20), trastuzumab (targeting HER-2), and cetuximab (targeting EGFR). Passive antibody therapies aim to increase the activity of the immune system without specifically targeting cancer cells. For example, cytokines directly stimulate the immune system and increase immune activity. Checkpoint inhibitors target proteins (immune checkpoints) that normally dampen the immune response. This enhances the ability of the immune system to attack cancer cells. Current research is identifying new potential targets to enhance immune function. Approved checkpoint inhibitors include antibodies such as ipilimumab, nivolumab, and pembrolizumab. == Cellular immunotherapy == === Dendritic cell therapy === Dendritic cell therapy provokes anti-tumor responses by causing dendritic cells to present tumor antigens to lymphocytes, which activates them, priming them to kill other cells that present the antigen. Dendritic cells are antigen-presenting cells (APCs) in the mammalian immune system. In cancer treatment, they aid cancer antigen targeting. The only approved cellular cancer therapy based on dendritic cells is sipuleucel-T. One method of inducing dendritic cells to present tumor antigens is by vaccination with autologous tumor lysates or short peptides (small parts of the protein that correspond to the protein antigens on cancer cells). These peptides are often given in combination with adjuvants (highly immunogenic substances) to increase the immune and anti-tumor responses. Other adjuvants include proteins or other chemicals that attract and/or activate dendritic cells, such as granulocyte-macrophage colony-stimulating factor (GM-CSF). The most common sources of antigens used for dendritic cell vaccine in glioblastoma (GBM) as an aggressive brain tumor were whole tumor lysate, CMV antigen RNA and tumor-associated peptides like EGFRvIII. Dendritic cells can also be activated in vivo by making tumor cells express GM-CSF. This can be achieved by either genetically engineering tumor cells to produce GM-CSF or by infecting tumor cells with an oncolytic virus that expresses GM-CSF. Another strategy is to remove dendritic cells from the blood of a patient and activate them outside the body. The dendritic cells are activated in the presence of tumor antigens, which may be a single tumor-specific peptide/protein or a tumor cell lysate (a solution of broken-down tumor cells). These cells (with optional adjuvants) are infused and provoke an immune response. Dendritic cell therapies include the use of antibodies that bind to receptors on the surface of dendritic cells. Antigens can be added to the antibody and can induce the dendritic cells to mature and provide immunity to the tumor. Dendritic cell receptors such as TLR3, TLR7, TLR8 or CD40 have been used as antibody targets. Dendritic cell-NK cell interface also has an important role in immunotherapy. The design of new dendritic cell-based vaccination strategies should also encompass NK cell-stimulating potency. It is critical to systematically incorporate NK cells monitoring as an outcome in antitumor DC-based clinical trials. ==== Drugs ==== Sipuleucel-T (Provenge) was approved for treatment of asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer in 2010. The treatment consists of removal of antigen-presenting cells from blood by leukapheresis and growing them with the fusion protein PA2024 made from GM-CSF and prostate-specific prostatic acid phosphatase (PAP) and reinfused. This process is repeated three times. === Adoptive T-cell therapy === Adoptive T cell therapy is a form of passive immunization by the transfusion of T-cells. They are found in blood and tissue and typically activate when they find foreign pathogens. Activation occurs when the T-cell's surface receptors encounter cells that display parts of foreign proteins (either on their surface or intracellularly). These can be either infected cells or other antigen-presenting cells (APCs). The latter are found in normal tissue and in tumor tissue, where they are known as tumor-infiltrating lymphocytes (TILs). They are activated by the presence of APCs such as dendritic cells that present tumor antigens. Although these cells can attack tumors, the tumor microenvironment is highly immunosuppressive, interfering with immune-mediated tumour death. Multiple ways of producing tumour-destroying T-cells have been developed. Most commonly, T-cells specific to a tumor antigen can be removed from a tumor sample (TILs) or filtered from blood. The T-cells can optionally be modified in various ways, cultured and infused into patients. T cells can be modified via genetic engineering, producing CAR-T cell or TCR T cells or by exposing the T cells to tumor antigens in a non-immunosuppressive environment, that they recognize as foreign and learn to attack. Another approach is transfer of haploidentical γδ T cells or natural killer cells from a healthy donor. The major advantage of this approach is that these cells do not cause graft-versus-host disease. The disadvantage is that transferred cells frequently have impaired function. ==== Tumor-derived T cell therapy ==== The simplest example involves removing TILs from a tumor, culturing but not modifying them, and infusing the result back into the tumour. The first therapy of this type, Lifileucel, achieved US Food and Drug Administration (FDA) approval in February 2024. ==== CAR-T cell therapy ==== The premise of CAR-T immunotherapy is to modify T cells to recognize cancer cells in order to target and destroy them. Scientists harvest T cells from people, genetically alter them to add a chimeric antigen receptor (CAR) that specifically recognizes cancer cells, then infuse the resulting CAR-T cells into patients to attack their tumors. Tisagenlecleucel (Kymriah), a chimeric antigen receptor (CAR-T) therapy, was approved by the FDA in 2017 to treat acute lymphoblastic leukemia (ALL). This treatment removes CD19 positive cells (B-cells) from the body (including the diseased cells, but also normal antibody-producing cells). Axicabtagene ciloleucel (Yescarta) is another CAR-T therapeutic, approved in 2017 for treatment of diffuse large B-cell lymphoma (DLBCL). ==== Multifunctional alginate scaffolds ==== Multifunctional alginate scaffolds for T cell engineering and release (MASTER) is a technique for in situ engineering, replication and release of genetically engineered T cells. It is an evolution of CAR T cell therapy. T cells are extracted from the patient and mixed with a genetically engineered virus that contains a cancer-targeting gene (as with CAR T). The mixture is then added to a MASTER (scaffold), which absorbs them. The MASTER contains antibodies that activate the T cells and interleukins that trigger cell proliferation. The MASTER is then implanted into the patient. The activated T cells interact with the viruses to become CAR T cells. The interleukins stimulate these CAR T cells to proliferate, and the CAR T cells exit the MASTER to attack the cancer. The technique takes hours instead of weeks. And because the cells are younger, they last longer in the body, show stronger potency against cancer, and display fewer markers of exhaustion. These features were demonstrated in mouse models. The treatment was more effective and longer-lasting against lymphoma. ==== T cell receptor T cell therapy ==== == Antibody therapy == === Antibody types === ==== Conjugation ==== Two types are used in cancer treatments: Naked monoclonal antibodies are antibodies without added elements. Most antibody therapies use this antibody type. Conjugated monoclonal antibodies are joined to another molecule, which is either cytotoxic or radioactive. The toxic chemicals are those typically used as chemotherapy drugs, but other toxins can be used. The antibody binds to specific antigens on cancer cell surfaces, directing the therapy to the tumor. Radioactive compound-linked antibodies are referred to as radiolabelled. Chemolabelled or immunotoxins antibodies are tagged with chemotherapeutic molecules or toxins, respectively. Research has also demonstrated conjugation of a TLR agonist to an anti-tumor monoclonal antibody. ==== Fc regions ==== Fc's ability to bind Fc receptors is important because it allows antibodies to activate the immune system. Fc regions are varied: they exist in numerous subtypes and can be further modified, for example with the addition of sugars in a process called glycosylation. Changes in the Fc region can alter an antibody's ability to engage Fc receptors and, by extension, will determine the type of immune response that the antibody triggers. For example, immune checkpoint blockers targeting PD-1 are antibodies designed to bind PD-1 expressed by T cells and reactivate these cells to eliminate tumors. Anti-PD-1 drugs contain not only a Fab region that binds PD-1 but also an Fc region. Experimental work indicates that the Fc portion of cancer immunotherapy drugs can affect the outcome of treatment. For example, anti-PD-1 drugs with Fc regions that bind inhibitory Fc receptors can have decreased therapeutic efficacy. Imaging studies have further shown that the Fc region of anti-PD-1 drugs can bind Fc receptors expressed by tumor-associated macrophages. This process removes the drugs from their intended targets (i.e. PD-1 molecules expressed on the surface of T cells) and limits therapeutic efficacy. Furthermore, antibodies targeting the co-stimulatory protein CD40 require engagement with selective Fc receptors for optimal therapeutic efficacy. Together, these studies underscore the importance of Fc status in antibody-based immune checkpoint targeting strategies. ==== Human/non-human antibodies ==== Antibodies can come from a variety of sources, including human cells, mice, and a combination of the two (chimeric antibodies). Different sources of antibodies can provoke different kinds of immune responses. For example, the human immune system can recognize mouse antibodies (also known as murine antibodies) and trigger an immune response against them. This could reduce the effectiveness of the antibodies as a treatment and cause an immune reaction. Chimeric antibodies attempt to reduce murine antibodies' immunogenicity by replacing part of the antibody with the corresponding human counterpart. Humanized antibodies are almost completely human; only the complementarity determining regions of the variable regions are derived from murine sources. Human antibodies have been produced using unmodified human DNA. === Mechanism of action === ==== Antibody-dependent cell-mediated cytotoxicity (ADCC) ==== Antibody-dependent cell-mediated cytotoxicity (ADCC) requires antibodies to bind to target cell surfaces. Antibodies are formed of a binding region (Fab) and the Fc region that can be detected by immune system cells via their Fc surface receptors. Fc receptors are found on many immune system cells, including NK cells. When NK cells encounter antibody-coated cells, the latter's Fc regions interact with their Fc receptors, releasing perforin and granzyme B to kill the tumor cell. Examples include rituximab, ofatumumab, elotuzumab, and alemtuzumab. Antibodies under development have altered Fc regions that have higher affinity for a specific type of Fc receptor, FcγRIIIA, which can dramatically increase effectiveness. === Anti-CD47 therapy === Many tumor cells overexpress CD47 to escape immunosurveilance of host immune system. CD47 binds to its receptor signal-regulatory protein alpha (SIRPα) and downregulate phagocytosis of tumor cell. Therefore, anti-CD47 therapy aims to restore clearance of tumor cells. Additionally, growing evidence supports the employment of tumor antigen-specific T cell response in response to anti-CD47 therapy. A number of therapeutics are being developed, including anti-CD47 antibodies, engineered decoy receptors, anti-SIRPα antibodies and bispecific agents. As of 2017, wide range of solid and hematologic malignancies were being clinically tested. === Anti-GD2 antibodies === Carbohydrate antigens on the surface of cells can be used as targets for immunotherapy. GD2 is a ganglioside found on the surface of many types of cancer cell including neuroblastoma, retinoblastoma, melanoma, small cell lung cancer, brain tumors, osteosarcoma, rhabdomyosarcoma, Ewing's sarcoma, liposarcoma, fibrosarcoma, leiomyosarcoma and other soft tissue sarcomas. It is not usually expressed on the surface of normal tissues, making it a good target for immunotherapy. As of 2014, clinical trials were underway. ==== Complement Activation ==== The complement system includes blood proteins that can cause cell death after an antibody binds to the cell surface (the classical complement pathway, among the ways of complement activation). Generally, the system deals with foreign pathogens but can be activated with therapeutic antibodies in cancer. The system can be triggered if the antibody is chimeric, humanized, or human; as long as it contains the IgG1 Fc region. Complement can lead to cell death by activation of the membrane attack complex, known as complement-dependent cytotoxicity; enhancement of antibody-dependent cell-mediated cytotoxicity; and CR3-dependent cellular cytotoxicity. Complement-dependent cytotoxicity occurs when antibodies bind to the cancer cell surface, the C1 complex binds to these antibodies and subsequently, protein pores are formed in cancer cell membrane. Blocking Antibody therapies can also function by binding to proteins and physically blocking them from interacting with other proteins. Checkpoint inhibitors (CTLA-4, PD-1, and PD-L1) operate by this mechanism. Briefly, checkpoint inhibitors are proteins that normally help to slow immune responses and prevent the immune system from attacking normal cells. Checkpoint inhibitors bind these proteins and prevent them from functioning normally, which increases the activity of the immune system. Examples include durvalumab, ipilimumab, nivolumab, and pembrolizumab. === FDA-approved antibodies === ==== Alemtuzumab ==== Alemtuzumab (Campath-1H) is an anti-CD52 humanized IgG1 monoclonal antibody indicated for the treatment of fludarabine-refractory chronic lymphocytic leukemia (CLL), cutaneous T-cell lymphoma, peripheral T-cell lymphoma and T-cell prolymphocytic leukemia. CD52 is found on >95% of peripheral blood lymphocytes (both T-cells and B-cells) and monocytes, but its function in lymphocytes is unknown. It binds to CD52 and initiates its cytotoxic effect by complement fixation and ADCC mechanisms. Due to the antibody target (cells of the immune system), common complications of alemtuzumab therapy are infection, toxicity and myelosuppression. ==== Atezolizumab ==== ==== Atezolizumab/hyaluronidase ==== ==== Avelumab ==== ==== Durvalumab ==== Durvalumab (Imfinzi) is a human immunoglobulin G1 kappa (IgG1κ) monoclonal antibody that blocks the interaction of programmed cell death ligand 1 (PD-L1) with the PD-1 and CD80 (B7.1) molecules. Durvalumab is approved for the treatment of patients with locally advanced or metastatic urothelial carcinoma who: have disease progression during or following platinum-containing chemotherapy. have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. On 16 February 2018, the Food and Drug Administration approved durvalumab for patients with unresectable stage III non-small cell lung cancer (NSCLC) whose disease has not progressed following concurrent platinum-based chemotherapy and radiation therapy. ==== Elotuzumab ==== ==== Ipilimumab ==== Ipilimumab (Yervoy) is a human IgG1 antibody that binds the surface protein CTLA4. In normal physiology T-cells are activated by two signals: the T-cell receptor binding to an antigen-MHC complex and T-cell surface receptor CD28 binding to CD80 or CD86 proteins. CTLA4 binds to CD80 or CD86, preventing the binding of CD28 to these surface proteins and therefore negatively regulates the activation of T-cells. Active cytotoxic T-cells are required for the immune system to attack melanoma cells. Normally inhibited active melanoma-specific cytotoxic T-cells can produce an effective anti-tumor response. Ipilimumab can cause a shift in the ratio of regulatory T-cells to cytotoxic T-cells to increase the anti-tumor response. Regulatory T-cells inhibit other T-cells, which may benefit the tumor. ==== Nivolumab ==== Nivolumab is a human IgG4 antibody that prevents T-cell inactivation by blocking the binding of programmed cell death 1 ligand 1 or programmed cell death 1 ligand 2 (PD-L1 or PD-L2), a protein expressed by cancer cells, with PD-1, a protein found on the surface of activated T-cells. Nivolumab is used in advanced melanoma, metastatic renal cell carcinoma, advanced lung cancer, advanced head and neck cancer, and Hodgkin's lymphoma. ==== Ofatumumab ==== Ofatumumab is a second generation human IgG1 antibody that binds to CD20. It is used in the treatment of chronic lymphocytic leukemia (CLL) because the cancerous cells of CLL are usually CD20-expressing B-cells. Unlike rituximab, which binds to a large loop of the CD20 protein, ofatumumab binds to a separate, small loop. This may explain their different characteristics. Compared to rituximab, ofatumumab induces complement-dependent cytotoxicity at a lower dose with less immunogenicity. ==== Pembrolizumab ==== As of 2019, pembrolizumab, which blocks PD-1, programmed cell death protein 1, has been used via intravenous infusion to treat inoperable or metastatic melanoma, metastatic non-small cell lung cancer (NSCLC) in certain situations, as a second-line treatment for head and neck squamous cell carcinoma (HNSCC), after platinum-based chemotherapy, and for the treatment of adult and pediatric patients with refractory classic Hodgkin's lymphoma (cHL). It is also indicated for certain patients with urothelial carcinoma, stomach cancer and cervical cancer. ==== Rituximab ==== Rituximab is a chimeric monoclonal IgG1 antibody specific for CD20, developed from its parent antibody Ibritumomab. As with ibritumomab, rituximab targets CD20, making it effective in treating certain B-cell malignancies. These include aggressive and indolent lymphomas such as diffuse large B-cell lymphoma and follicular lymphoma and leukemias such as B-cell chronic lymphocytic leukemia. Although the function of CD20 is relatively unknown, CD20 may be a calcium channel involved in B-cell activation. The antibody's mode of action is primarily through the induction of ADCC and complement-mediated cytotoxicity. Other mechanisms include apoptosis and cellular growth arrest. Rituximab also increases the sensitivity of cancerous B-cells to chemotherapy. ==== Trastuzumab ==== == Immune checkpoint antibody therapy or immune checkpoint blockade == Immune checkpoints affect the immune system function. Immune checkpoints can be stimulatory or inhibitory. Tumors can use these checkpoints to protect themselves from immune system attacks. Checkpoint therapies approved as of 2012 block inhibitory checkpoint receptors. Blockade of negative feedback signaling to immune cells thus results in an enhanced immune response against tumors. As of 2020, immune checkpoint blockade therapies have varied effectiveness. In Hodgkin lymphoma and natural killer T-cell lymphoma, response rates are high, at 50–60%. Response rates are quite low for breast and prostate cancers, however. A major challenge are the large variations in responses to immunocheckpoint inhibitors, some patients showing spectacular clinical responses while no positive effects are seen in others. A plethora of possible reasons for the absence of efficacy in many patients have been proposed, but the biomedical community has still to begin to find consensus in this respect. For instance, a recent paper documented that infection with Helicobacter pylori would negatively influence the effects of immunocheckpoint inhibitors in gastric cancer., but this notion was quickly challenged by others. One ligand-receptor interaction under investigation is the interaction between the transmembrane programmed cell death 1 protein (PDCD1, PD-1; also known as CD279) and its ligand, PD-1 ligand 1 (PD-L1, CD274). PD-L1 on the cell surface binds to PD1 on an immune cell surface, which inhibits immune cell activity. Among PD-L1 functions is a key regulatory role on T cell activities. It appears that (cancer-mediated) upregulation of PD-L1 on the cell surface may inhibit T cells that might otherwise attack. PD-L1 on cancer cells also inhibits FAS- and interferon-dependent apoptosis, protecting cells from cytotoxic molecules produced by T cells. Antibodies that bind to either PD-1 or PD-L1 and therefore block the interaction may allow the T-cells to attack the tumor. === CTLA-4 blockade === The first checkpoint antibody approved by the FDA was ipilimumab, approved in 2011 to treat melanoma. It blocks the immune checkpoint molecule CTLA-4. As of 2012, clinical trials have also shown some benefits of anti-CTLA-4 therapy on lung cancer or pancreatic cancer, specifically in combination with other drugs. In on-going trials the combination of CTLA-4 blockade with PD-1 or PD-L1 inhibitors is tested on different types of cancer. However, as of 2015 it is known that patients treated with checkpoint blockade (specifically CTLA-4 blocking antibodies), or a combination of check-point blocking antibodies, are at high risk of having immune-related adverse events such as dermatologic, gastrointestinal, endocrine, or hepatic autoimmune reactions. These are most likely due to the breadth of the induced T-cell activation when anti-CTLA-4 antibodies are administered by injection in the bloodstream. A 2024 cohort study of ICI use during pregnancy showed no overreporting of specific adverse effects on pregnancy, fetal, and/or newborn outcomes, interestingly. Using a mouse model of bladder cancer, researchers have found that a local injection of a low dose anti-CTLA-4 in the tumour area had the same tumour inhibiting capacity as when the antibody was delivered in the blood. At the same time the levels of circulating antibodies were lower, suggesting that local administration of the anti-CTLA-4 therapy might result in fewer adverse events. === PD-1 inhibitors === Initial clinical trial results with IgG4 PD1 antibody nivolumab were published in 2010. It was approved in 2014. Nivolumab is approved to treat melanoma, lung cancer, kidney cancer, bladder cancer, head and neck cancer, and Hodgkin's lymphoma. A 2016 clinical trial for non-small cell lung cancer failed to meet its primary endpoint for treatment in the first-line setting, but is FDA-approved in subsequent lines of therapy. Pembrolizumab (Keytruda) is another PD1 inhibitor that was approved by the FDA in 2014. Pembrolizumab is approved to treat melanoma and lung cancer. Antibody BGB-A317 is a PD-1 inhibitor (designed to not bind Fc gamma receptor I) in early clinical trials. === PD-L1 inhibitors === In May 2016, PD-L1 inhibitor atezolizumab was approved for treating bladder cancer. Anti-PD-L1 antibodies currently in development include avelumab and durvalumab, in addition to an inhibitory affimer. === CISH === === Combinations === Many cancer patients do not respond to immune checkpoint blockade. Response rate may be improved by combining that with additional therapies, including those that stimulate T cell infiltration. For example, targeted therapies such as radiotherapy, vasculature targeting agents, and immunogenic chemotherapy can improve immune checkpoint blockade response in animal models. Combining immunotherapies such as PD1 and CTLA4 inhibitors can create to durable responses. Combinatorial ablation and immunotherapy enhances the immunostimulating response and has synergistic effects for metastatic cancer treatment. Combining checkpoint immunotherapies with pharmaceutical agents has the potential to improve response, and as of 2018 were a target of clinical investigation. Immunostimulatory drugs such as CSF-1R inhibitors and TLR agonists have been effective. Two independent 2024 clinical trials reported that combinations of JAK inhibitors with anti–PD-1 immunotherapy could improve efficacy. A phase 2 trial investigated the combination as a first-line therapy for metastatic non-small-cell lung cancer. Administration of itacitinib after treatment with pembrolizumab improved therapeutic response. A separate phase 1/2 trial with patients with relapsed/refractory Hodgkin’s lymphoma combined ruxolitinib and nivolumab, yielding improved clinical efficacy in patients who had previously failed checkpoint blockade immunotherapy. == Cytokine therapy == Cytokines are proteins produced by many types of cells present within a tumor. They can modulate immune responses. The tumor often employs them to allow it to grow and reduce the immune response. These immune-modulating effects allow them to be used as drugs to provoke an immune response. Two commonly used cytokines are interferons and interleukins. Interleukin-2 and interferon-α are cytokines, proteins that regulate and coordinate the behavior of the immune system. They have the ability to enhance anti-tumor activity and thus can be used as passive cancer treatments. Interferon-α is used in the treatment of hairy-cell leukaemia, AIDS-related Kaposi's sarcoma, follicular lymphoma, chronic myeloid leukaemia and malignant melanoma. Interleukin-2 is used in the treatment of malignant melanoma and renal cell carcinoma. === Interferon === Interferons are produced by the immune system. They are usually involved in anti-viral response, but also have use for cancer. They fall in three groups: type I (IFNα and IFNβ), type II (IFNγ) and type III (IFNλ). IFNα has been approved for use in hairy-cell leukaemia, AIDS-related Kaposi's sarcoma, follicular lymphoma, chronic myeloid leukaemia and melanoma. Type I and II IFNs have been researched extensively and although both types promote anti-tumor immune system effects, only type I IFNs have been shown to be clinically effective. IFNλ shows promise for its anti-tumor effects in animal models. Unlike type I IFNs, Interferon gamma is not approved yet for the treatment of any cancer. However, improved survival was observed when Interferon gamma was administered to patients with bladder carcinoma and melanoma cancers. The most promising result was achieved in patients with stage 2 and 3 of ovarian carcinoma. The in vitro study of IFN-gamma in cancer cells is more extensive and results indicate anti-proliferative activity of IFN-gamma leading to the growth inhibition or cell death, generally induced by apoptosis but sometimes by autophagy. === Interleukin === Interleukins have an array of immune system effects. Interleukin-2 is used in the treatment of malignant melanoma and renal cell carcinoma. In normal physiology it promotes both effector T cells and T-regulatory cells, but its exact mechanism of action is unknown. == Genetic pre-treatment testing for therapeutic significance == Because of the high cost of many of immunotherapy medications and the reluctance of medical insurance companies to prepay for their prescriptions various test methods have been proposed, to attempt to forecast the effectiveness of these medications. In some cases the FDA has approved genetic tests for medication specific to certain genetic markers. For example, the FDA approved BRAF-associated medication for metastatic melanoma, to be administered to patients after testing for the BRAF genetic mutation. As of 2018, the detection of PD-L1 protein seemed to be an indication of cancer susceptible to several immunotherapy medications, but research found that both the lack of this protein or its inclusion in the cancerous tissue was inconclusive, due to the little-understood varying quantities of the protein during different times and locations within the infected cells and tissue. In 2018, some genetic indications such as Tumor Mutational Burden (TMB, the number of mutations within a targeted genetic region in the cancerous cell's DNA), and microsatellite instability (MSI, the quantity of impaired DNA mismatch leading to probable mutations), have been approved by the FDA as good indicators for the probability of effective treatment of immunotherapy medication for certain cancers, but research is still in progress. As of 2020, the patient prioritization for immunotherapy based on TMB was still highly controversial. Tests of this sort are being widely advertised for general cancer treatment and are expensive. In the past, some genetic testing for cancer treatment has been involved in scams such as the Duke University Cancer Fraud scandal, or claimed to be hoaxes. == Research == === Oncolytic virus === An oncolytic virus is a virus that preferentially infects and kills cancer cells. As the infected cancer cells are destroyed by oncolysis, they release new infectious virus particles or virions to help destroy the remaining tumour. Oncolytic viruses are thought not only to cause direct destruction of the tumour cells, but also to stimulate host anti-tumour immune responses for long-term immunotherapy. The potential of viruses as anti-cancer agents was first realized in the early twentieth century, although coordinated research efforts did not begin until the 1960s. A number of viruses including adenovirus, reovirus, measles, herpes simplex, Newcastle disease virus and vaccinia have now been clinically tested as oncolytic agents. T-Vec is the first FDA-approved oncolytic virus for the treatment of melanoma. A number of other oncolytic viruses are in Phase II-III development. === Polysaccharides === Certain compounds found in mushrooms, primarily polysaccharides, can up-regulate the immune system and may have anti-cancer properties. For example, beta-glucans such as lentinan have been shown in laboratory studies to stimulate macrophage, NK cells, T cells and immune system cytokines and have been investigated in clinical trials as immunologic adjuvants. === Neoantigens === Many tumors express mutations. These mutations potentially create new targetable antigens (neoantigens) for use in T-cell immunotherapy. The presence of CD8+ T cells in cancer lesions, as identified using RNA sequencing data, is higher in tumors with a high mutational burden. The level of transcripts associated with the cytolytic activity of natural killer cells and T cells positively correlates with mutational load in many human tumors. In non–small cell lung cancer patients treated with lambrolizumab, mutational load shows a strong correlation with clinical response. In melanoma patients treated with ipilimumab, the long-term benefit is also associated with a higher mutational load, although less significantly. The predicted MHC binding neoantigens in patients with a long-term clinical benefit were enriched for a series of tetrapeptide motifs that were not found in tumors of patients with no or minimal clinical benefit. However, human neoantigens identified in other studies do not show the bias toward tetrapeptide signatures. === Polysaccharide-K === In the 1980s, Japan's Ministry of Health, Labour and Welfare approved polysaccharide-K extracted from the mushroom, Coriolus versicolor, to stimulate the immune systems of patients undergoing chemotherapy. It is a dietary supplement in the US and other jurisdictions. == See also == Cancer vaccine Antigen 5T4 Coley's toxins Combinatorial ablation and immunotherapy Cryoimmunotherapy Photoimmunotherapy Radioimmunotherapy == References == == External links == A primer on "Immunotherapy to Treat Cancer", NIH Immunotherapy – Using the Immune System to Treat Cancer Archived 4 April 2017 at the Wayback Machine Cancer Research Institute – What is Cancer Immunotherapy Association for Immunotherapy of Cancer Society for Immunotherapy of Cancer "And Then There Were Five". Economist. "Discover the Science of Immuno-Oncology". Bristol-Myers Squibb. Archived from the original on 10 October 2014. Retrieved 13 March 2014. Eggermont A, Finn O (September 2012). "Advances in immuno-oncology. Foreword". Annals of Oncology. 23 (Suppl 8): viii5. doi:10.1093/annonc/mds255. PMID 22918929. "Cancer Immunotherapy in Gujarat"	Wikipedia/Cell_transfer_therapy
Speleotherapy (Greek σπήλαιον spḗlaion "cave") is an alternative medicine respiratory therapy involving breathing inside subterranean environments, such as a cave. == History == Some sources claim that Hippocrates believed that salt-based therapies, including inhaling steam from saltwater, provided relief of respiratory symptoms. There are claims of improvements in the breathing of miners in Roman times and medieval times. Speleotherapy hospitals existed in Italy in the 19th century. In the middle of the 19th century, a clinic, founded in Mammoth Cave (Kentucky, USA), was intended for tuberculosis patients. However, a few months after the death of five of the patients, the hospital was closed. The history of modern speleotherapy dates back to the 1950s. At this time, speleotherapeutic hospitals arose in several Eastern and Central European countries. Residents of Ennepetal in Germany used the Kluterthöhle cave as a bomb shelter during WW2. Karl Hermann Spannagel began researching the therapeutic effect of caves. Speleotherapeutic facilities in karst caves were started in Hungary and Czechoslovakia. In 1968, in Solotvyn (now in Ukraine), the first speleotherapy clinic was opened on the territory of the USSR. In 1982, a climate chamber was patented, equipped with a salt filter-saturator to recreate the conditions of salt mines on the earth's surface. == Indications == The treatment is claimed to be used for bronchial asthma, bronchitis, allergic and chronic runny nose, allergic and chronic sinus diseases, various allergies and skin diseases, fibrosing alveolitis and croup. However, as of 2022, the evidence is inconclusive to support these claims. == Speleotherapy in the Czech Republic == The first speleotherapy in the Czechoslovakia was carried out by Mgr. Štefan Roda in Slovakia in the Tombašek Cave in the High Tatras (1969). In 1973–1976, doctors Timová and Valtrová from the Children's Clinic in Banská Bystrica treated childhood asthmatics with speleotherapy with favourable results, which were published in the medical literature. From 1981 to 1985, speleotherapy became the subject of official scientific research tasks, carried out under the responsibility of the Ministry of Health and the Geographical Institute of the Czechoslovak Academy of Sciences. In 1985, speleotherapy was recognized as an official climatic treatment method. According to the chairman of the International Union of Speleology's Standing Commission on Speleotherapy, Prof. Svetozar Dluholucky, M.D., speleotherapy is "a natural way of treating asthma and allergies, which it would be a sin not to use." He has conducted research in Bystrianska Cave since 1974, according to which there has been a fivefold decrease in respiratory diseases and asthma in the children studied. In 1997, he conducted further research on 111 asthmatic children with the same results. Allergists and immunologists remain sceptical, however. There are two speleotherapy centres in the Czech Republic: the Children's Treatment Centre in Ostrov u Macochy and the Children's Treatment Centre for Respiratory Diseases in Zlaté Hory. The children's sanatorium in Mladč-Vojtěchov was closed in 2014. == Research == Hoyrmír Malota led a research team that tested patients of the speleotherapeutic sanatorium in Mladeč in 1985-1987 and came to the clinically verified knowledge "that individual factors of the underground environment, or their complex connected by internal and external interactions, stimulate and modulate the immune system of the human organism directly. He confirmed that repeated exposure to the underground environment - without the use of anti-asthmatic, antihistamine, or immunomodulatory pharmaceutical preparations - induces positive and measurable changes in secretory and lymphatic lysosomes and immunoglobins after only a few days of exposure to the degree that any existing artificial immunomodulators cannot achieve." Some factors characterizing cave endoclimates are controversial. While cave aerosols may theoretically contain high Ca and Mg ions, in practice, they are not present in the treatment sites known to date; Ca and Mg concentrations are everywhere the same as in the ambient air. It has been shown that the concentrations of Ca and Mg in cave air are not so significantly elevated as to be considered a therapeutic factor. The elevated CO2 concentration, or the absence of allergens in the cave (the presence of some molds in very small amounts), or the absence of ozone is also questionable. According to the Cochrane Collaboration, three studies involving 124 children with asthma met the inclusion criteria for the 2001 meta-study. Still, only one study was of adequate methodological quality. Two studies reported that speleotherapy had a beneficial short-term effect on lung function. The other results could not be reliably evaluated. Due to the small number of studies, no reliable conclusion can be drawn from the available evidence on whether speleotherapy interventions are effective in treating chronic asthma. Randomized controlled trials with long-term follow-up are needed. No evidence of the effectiveness of speleotherapy was found from randomized controlled trials and further research is needed. According to a 2017 Romanian systematic review, speleotherapy is a valuable treatment method for asthma and other respiratory problems. Still, only a few studies can be found in international databases, reflecting the specificity of this field. On the other hand, basic studies in laboratory animals and in vitro cell cultures have demonstrated the efficacy and usefulness of speleotherapy. == References == == External links == Dunning, Brian (20 August 2013). "Skeptoid #376: Salt Therapies". Skeptoid.	Wikipedia/Speleotherapy
Information Therapy was first cited in the literature to mean “information leading patients in the direction of discovering more about their disease.” Later, the term was modified to mean “the therapeutic provision of information to people for the amelioration of physical and mental health and wellbeing,” that could lead to a decrease in the utilization of healthcare resources. In their book Information therapy: Prescribed Information as a Reimbursable Medical Service, authors Donald W. Kemper and Molly Mettler defined the term to mean the right information, to the right person, at the right time, to help make better decisions or to improve a health behavior. Healthwise, Incorporated, a nonprofit organization founded by Kemper and Mettler to develop and supply health educational content for the general public, trademarked the symbol "Ix" to represent the term information therapy. Studies show that information therapy can improve the knowledge and medical decision-making abilities of patients, as well as reduce patient anxiety. Human factors engineer, Jeff Greene invented a web-based system that combines information therapy with a patented patient-doctor aligned-incentive mechanism, called the MedEncentive Mutual Accountability and Information Therapy (MAIT) Program. In a five-year study of an employer health plan, the MAIT Program was found to be associated with reductions in annual hospitalizations, emergency room visits, and per capita expenditures of 32%, 14%, and 11%, respectively. Greene coined the term “reward-induced information therapy” to mean providing people with the right information, at the right time, in the right way so they are more knowledgeable and motivated to make better decisions about their health behaviors and medical treatment options. == References ==	Wikipedia/Information_therapy
Ozone therapy is an alternative medical treatment that introduces ozone or ozonides to the body. The United States Food and Drug Administration (FDA) prohibits all medical uses of ozone "in any medical condition for which there is no proof of safety and effectiveness", stating "ozone is a toxic gas with no known useful medical application in specific, adjunctive, or preventive therapy. For ozone to be germicidal, it must be present in a concentration far greater than that which can be safely tolerated by man and animals." Ozone therapy has been sold as an unproven treatment for various illnesses, including cancer, a practice which has been characterized as "pure quackery". The therapy can cause serious adverse effects, including death. == Proposed uses == Ozone therapy consists of the introduction of ozone into the body via various methods, usually involving its mixture with various gases and liquids before injection, with potential routes including the vagina, rectum, into a muscle, under the skin, or directly into a vein. Ozone can also be introduced via autohemotherapy, in which blood is drawn from the patient, exposed to ozone, and re-injected into the patient. This therapy has been proposed as a primary or adjunct therapy for various diseases, including osteoarthritis, herniated disk, chronic wounds, hepatitis B and C, herpes zoster, HIV-AIDS, multiple sclerosis, cancer, heart disease, Alzheimer's dementia, and Lyme disease, though supportive evidence for some of these applications is limited. The American Cancer Society warned in 2010 that evidence for the efficacy of ozone therapy against cancer is inconclusive, and the therapy may be dangerous. For treatment of HIV/AIDS, although ozone deactivates the viral particles in vitro, well-designed studies have shown there is no benefit for living patients. The United States Food and Drug Administration initially stated in 1976, and reiterated its position in 2006, that when inhaled, ozone is a toxic gas that has no demonstrated safe medical application, though their position statements primarily deal with its potential for causing inflammation and pulmonary edema in the lungs. They also emphasize that for ozone to be effective as a germicide, it must be present at concentrations far greater than can be safely tolerated by humans or other animals. More recent reviews have highlighted that different routes of administration may result in different therapeutic and side-effect profiles. Some reviews have suggested ozone as a potential treatment for herniated discs and diabetic neuropathy. There is some controversy about its use by athletes to increase performance despite numerous adverse side effects within the pulmonary and/or skeletal muscle systems. Although its use is not disallowed in and of itself, it can be mixed with banned substances for administration prior to injection. == Safety == Ozone therapy has potentially serious adverse effects, and as of 2012 at least five deaths had been reported due to the therapy's use on people with cancer. From 1975 to 1983 in Germany, research revealed six deaths, four cases of visual disturbance, three cases of paraplegias, four gas embolisms in the pulmonary circuit, two myocardial infarction, four pulmonary embolisms, two cases of apoplexy paralysis, and two cases of cardiac arrhythmia following ozone therapy. More commonly, pulmonary edema is the most prevalent adverse effect of ozone treatment. In the muscular system, many cases of tendon rupture, osteoarthritis, myositis, synovitis, joint infections, and muscle tears have been documented as results of ozone therapy. In the integumentary system, benign skin discoloration is most common. These all occurred following direct injection of O2/O3 gas: a method now regarded as malpractice by most ozone practitioners. In each case, the clinical picture corresponded either to gas embolism, or allergic shock. The fact that one case of apparent allergic shock followed the injection of a minute quantity of gas raises the unknown possibility that other methods of administration might also carry the risk of allergic shock. Much of the concern related to ozone therapy revolves around the safety of blood ozonation. When inhaled by mammals in high levels, ozone reacts with compounds in tissues lining the lungs and triggers a cascade of pathological effects, including pulmonary edema, however, ozone therapy does not usually involve inhalation of ozone gas. It has been argued that while peroxides (a product of ozone) are naturally generated inside phagocyte cells to kill bacteria, outside the cell they can damage tissue. Proponents suggest that its effects are tissue-dependent, though the subject is still debated. Other serious incidents reported include transmission of hepatitis C. Ozone-based treatments can be associated with central nervous system toxicity, termed Ozone Induced Encephalopathy (OIE). == Regulation and ethics == The FDA prohibits the medical use of ozone "in any medical condition for which there is no proof of safety and effectiveness", stating that "ozone is a toxic gas with no known useful medical application in specific, adjunctive, or preventive therapy. For ozone to be germicidal, it must be present in a concentration far greater than that which can be safely tolerated by man and animals." Beginning in 1991 the FDA has prosecuted and sent to jail several people presenting themselves as medical doctors and selling ozone therapy products as a medical cure or operating medical clinics using ozone therapy for healing human illness. Arrests following similar activity have been made in other countries as well, including Uganda and Thailand. Ozone therapy is sold as an expensive alternative cancer treatment in Germany. David Gorski has described the practice as "pure quackery". Proponents of the therapy falsely claim it is a recognized therapy there, but the German medical establishment has not approved ozone therapy. In 2009, a panel of experts consulted by Forbes recommended that ozone therapy be included on a "list of the most egregious, dangerous, aggressively marketed health scams." Ozone therapy was banned in Malaysia in 2017. The Malaysian Health Ministry determined that the treatment could cause serious harm and had no scientific support as a treatment for any condition. On 7 August 2023, the Brazilian government legalized ozone therapy as a complementary therapy, ignoring a request for veto due to lack of scientific evidence made in an open letter from the Brazilian National Academy of Medicine. == History == In 1856, just 16 years after its discovery, ozone was first used in a healthcare setting to disinfect operating rooms and sterilize surgical instruments. By the end of the 19th century the use of ozone to disinfect drinking water of bacteria and viruses was well established in mainland Europe. In 1892 The Lancet published an article describing the administration of ozone for treatment of tuberculosis. During World War I, ozone was tested at Queen Alexandra Military Hospital in London as a possible disinfectant for wounds. The gas was applied directly to wounds for as long as 15 minutes. This resulted in damage to both bacterial cells and human tissue. Other sanitizing techniques, such as irrigation with antiseptics, were preferable. The psychoanalyst Wilhelm Reich was a proponent of ozone therapy, which was supposed to enhance an imaginary life force he called orgone. Reich developed a device utilizing ozonides in his work on bioenergetic analysis. == See also == Ozone health effects Air ioniser List of unproven and disproven cancer treatments == References == == External links == Ozone Generators that are Sold as Air Cleaners - factsheet at US EPA	Wikipedia/Ozone_therapy
Cognitive emotional behavioral therapy (CEBT) is an extended version of cognitive behavioral therapy (CBT) aimed at helping individuals to evaluate the basis of their emotional distress and thus reduce the need for associated dysfunctional coping behaviors (e.g., eating behaviors including binging, purging, restriction of food intake, and substance misuse). This psychotherapeutic intervention draws on a range of models and techniques including dialectical behavior therapy (DBT), mindfulness meditation, acceptance and commitment therapy (ACT), and experiential exercises. CEBT has been used primarily for individuals with eating disorders, as it offers an alternative when standard CBT is unsuccessful in relieving symptoms. Research indicates that CEBT may help reduce emotional eating, depression, and anxiety and also improve self-esteem. CEBT was developed in 2006 by British psychologist Emma Gray (née Corstorphine). Its key components include psychological education; techniques to enhance awareness of emotions and motivation to change; and strategies to restructure beliefs about the experience and expression of emotions. Although (CEBT) was initially developed to help individuals with eating disorders, its effectiveness in helping people to better understand and manage their emotions has meant that it is increasingly being used by psychologists as a 'pretreatment' to prepare patients for the process of therapy for a range of problems including anxiety, depression, obsessive compulsive disorder (OCD), and post traumatic stress disorder (PTSD), which can often be emotionally challenging. == Techniques == Dialectical behavior therapy (DBT) - DBT is a type of psychotherapy used to treat various disorders. The purpose of this therapy is to help create positive changes in a person's behavior. DBT focuses mainly on treating individuals who have bulimia, drug-dependence, borderline personality disorder, depression, or other psychological disorders. Mindfulness meditation - Mindfulness meditation is a technique that increases and improves awareness. This technique aims to lower stress and improve our attention. It is a form of focusing on what is presently happening. Mindfulness meditation aims at improving mental health through helping those with disorders be able to manage their emotions. Acceptance and commitment therapy (ACT) - Acceptance and commitment therapy is a treatment aimed at helping people to accept the feelings and experiences they go through. Oftentimes people must deal with unpleasant feelings, thoughts or experiences and in response they avoid those emotions as a way of coping. In regards to the way we react, ACT helps with acceptance, making a decision to make changes, and going through with that commitment. Experiential exercises - Experiential exercises play an important part in CEBT because it allows individuals to become actively involved in the learning process. Experiencing what is being taught can have a positive impact on those individuals who experience emotional and behavioral difficulties. These exercises are often used in different types of therapy in order to help individuals learn about diversity, acceptance, injustice, and so forth. Experiential exercises can be incorporated in the treatment of individuals dealing with disorders. These exercises help people to know how to react or cope in certain situations. == Background == In 2006, Dr. Emma Gray (née Corstorphine) started the idea of Cognitive emotional behavioral therapy (CEBT). CEBT uses techniques from other types of treatment such as Cognitive behavior therapy and Dialectical behavioral therapy. The main goal of CEBT is to help individuals learn to cope with their emotions, reduce stress and anxiety, and make changes to their behavior. Gray noted that emotion plays a crucial part in disorders, therefore it needs to be further addressed in terms of treatment. Cognitive behavioral therapy aims to treat where a patient needs the most help, whether that is emotional, behavioral, cognitive, etc. CBT has been practiced since the 1960s. There is a greater focus on cognitive psychology and its impact on behavior. In 2003 there began to be suggestions that CBT needed to be expanded to meet the needs of even more specific vulnerabilities such as emotion, social environments, relationships, etc. Gray saw the need for an approach that has a greater focus on the emotional components. Gray's research specifically analyzes cognitive emotional behavioral therapy (CBT) for eating disorders. She found that CBT and related techniques for bulimia were not effective. CBT mainly uses treatments aimed at discovering cognitive or behavioral issues to be the source. Gray's findings show that therapy focused on emotion helped individuals manage their emotions and difficulties. Research has shown that emotional distress is a major cause of bulimia. Additional studies show that what triggers bulimia is oftentimes one's emotional state and their relationships. CEBT helps these individuals with disorders to cope with their emotions and develop the skills necessary to positively handle their situation. == Case == Gray (née Corstorphine) analyzes a case to determine whether cognitive emotional behavior therapy for eating disorders (CEBT-ED) is effective. In this case, a 22-year-old woman named Anna, who has bulimia and anorexia, goes through CBT and is able to regulate some of her eating patterns and lower the number of times she purges. It was acknowledged that Anna had emotional trauma due to the environment she grew up in. Her self esteem and expression of emotion were repressed because of her family. CEBT-ED allowed her to feel encouraged to show her emotions and discover the source of her difficulties. CEBT is an effective way of easing the symptoms of cognitive and emotional disorders when the typical CBT does not provide sufficient exercises and training. Emotion is the primary issue of eating disorders. In Anna's case CBT would have been helpful but would have focused mainly on changing negative or unreasonable thoughts. At the center of Anna's problem was her emotional trauma as a child and her difficulty in expressing how she felt. To address Anna's specific needs, CBT was not enough, but CEBT allowed room for self-reflection to find the root of her issues. CEBT helped her to identify and understand her emotions, allowing her to learn skills that would help her cope with these emotions and relieve the symptoms of her issues. == References == == Further reading == Corstorphine, E. (2006) Cognitive-emotional-behavioural therapy for the eating disorders: Working with beliefs about emotions. European Eating Disorders Research, 14, 448–461. Corstorphine (2008). Modifying cognitive behavioural therapy for the treatment of eating disorders – using schema modes to work with emotions. In J. Buckroyd (Ed.) Psychological responses to treatment in eating disorders and obesity. Wiley	Wikipedia/Cognitive_emotional_behavioral_therapy
The red garra (Garra rufa), also known as the doctor fish or nibble fish, is a species of cyprinid that is native to a wide range of freshwater habitats in subtropical parts of Western Asia. This small fish typically is up to about 14 centimeters (5.5 inches) in total length, but locally individuals can reach as much as 24 cm (9.5 in). In the wild, Garra rufa feed on detritus, algae and tiny animals (arthropods and other zooplankton). == Distribution, habitat and taxonomy == As traditionally defined, Garra rufa is native to Turkey, Syria, Jordan, Israel, Palestine, Iraq and Iran. Some of the main systems where it is found are the Kızıl, Seyhan, Ceyhan, Orontes, Queiq, Jordan, Tigris–Euphrates, Kor, and Mond river basins, but the species also inhabits other coastal river basins in the Levant and Iran, as well as the endorheic Lake Maharlu system. It lives in rivers, streams, canals, reservoirs, ponds and lakes, although it tends to avoid stagnant waters. It often is common or abundant, even in areas that are heavily influenced by humans like polluted canals. The taxonomy of this species has been labelled with uncertainty. As traditionally defined (sensu lato), there are some morphological variations over its relatively large range and it has been recognized for several years that it likely was a species complex. Several subspecies have been described, but their validity is questionable and in the last few decades authorities have generally not recognized them. Nevertheless, reviews published since 2014 have provided genetic and morphologic evidence for recognizing some of them as separate species, while other new species have been described from the species complex. This includes G. turcica (formerly a subspecies) from its Turkish range, except the Tigris–Euphrates system, G. jordanica (new species) from the northern Dead Sea basin, including the Jordan River, in Israel, Jordan and Syria, G. gymnothorax (formerly a subspecies) from the Karun, Balarud and Bashar systems in Iran, G. mondica (new species) of the Mond River basin in Iran, and G. amirhosseini (new species) from the Sartang-e-Bijar Spring in the Tigris River system in Iran. G. jordanica and G. turcica have entirely separate ranges from true G. rufa (thus limiting its range to the Tigris–Euphrates system and river systems in Iran), but the others do overlap in range with true G. rufa or at least occur in the same river basins. Other members of the G. rufa complex are G. barreimiae, G. elegans, G. ghorensis, G. longipinnis, G. nana, G. persica, G. rossica and G. sahilia, but these were generally recognized as valid species many years ago. Finally the complex includes four cavefish: G. lorestanensis, G. tashanensis, G. typhlops and G. widdowsoni. == Fish pedicure == Doctor fish facilities at spa resorts exist in many countries worldwide. In 2006, doctor fish spa resorts opened in Kangal, Turkey, Hakone, Japan, and Umag, Croatia, where the fish are used to clean the bathers at the spa. In 2008, two widely known doctor fish pedicure services were opened in the United States in Fairfax County, Virginia, and in Milwaukee, Wisconsin. Wisconsin ordered the closure of the doctor fish service shortly after its opening. In 2010, the first spa opened in the United Kingdom in Sheffield. In 2011, the UK Health Protection Agency issued a report assigning a "very low" risk of transferring infection from the procedure. The practice is banned in several of the states in the United States and Canadian provinces as cosmetology regulators believe the practice is unsanitary, with the Wall Street Journal saying that "cosmetology regulations generally mandate that tools need to be discarded or sanitized after each use. But epidermis-eating fish are too expensive to throw away". The procedure is legal in Quebec, with a few clinics in Montreal. The animal rights organization People for the Ethical Treatment of Animals (PETA), which opposes all human use of animals, denounces the practice, citing callous methods of international transportation and suggesting that the fish are deliberately starved between treatments to force them to eat an abnormal amount of food. Garra rufa seen in the spa and aquarium trade mostly originate from commercial facilities in Israel and to a lesser degree Turkey. Since Israeli and many (but not all) Turkish populations of "G. rufa" now are recognized as G. jordanica and G. turcica instead, this leads to questions over the true identity of most of the fish seen in the trade. It is legally protected from capture from the wild in Turkey due to concerns of overharvesting. Despite its ability to survive in polluted waters, the species requires clean, well-oxygenated and moving waters to thrive in an aquarium. For treatment of skin diseases, aquarium specimens are not well-suited as the skin-feeding behavior fully manifests only under conditions where the food supply can be scarce and unpredictable. When used as a prelude intended to enhance the effects of ultraviolet light expoure in psoriasis treatment, fish pedicure is known as ichthyotherapy. == See also == Cleaner fish == References ==	Wikipedia/Ichthyotherapy
Phonemic neurological hypochromium therapy (PNHT) is a technique that uses insemination devices to implement chromium (Cr3+) into the hypothalamic regions of the brain. It has been proposed by Dr. Nicole Kim to offset delayed phonemic awareness in children between the ages of 3 and 8. The causes of delayed phonemic awareness have been linked to an inability to break down chromium triastenitephosphate. PNHT has been successfully implemented into in vivo mice with some controversial side effects, including; polydactyly, regurgitation, fatigue, and nausea. While Russia, Poland, and Ukraine have approved this procedure, the United States Food and Drug Administration (USFDA) has not yet granted its approval. == Preparation == PNHT functions on the premise that the hypothalamic region of the human brain lacks the critical molecule chromium picolinate, a molecule typically produced by cytochromase B7[1]. The hypothalamus of a developing child may lack cytochromase B7, thereby causing a delay in phonemic awareness. The PNHT process involves passing a chromium mixture (CrAt3PO4) dissolved in a "mobile phase" through a stationary phase, which separates the chromium picolinate to be measured from other molecules in the mixture based on differential partitioning between the mobile and stationary phases. Subtle differences in a compound's partition coefficient result in differential retention on the stationary phase and thus changing the separation. == Experiment == In vitro and animal studies[1,2] have shown chromium to have a positive effect on insulin sensitivity. One of the intracellular proteins influencing the insulin receptor is the oligopeptide apolipoprotein, low molecular weight, chromium-binding substance (apo-chromomodulin) [2]. In vitro, this peptide has the ability to increase tyrosine kinase activity eightfold, depending on the chromium concentration [3]. This in turn promotes insulin receptor activity, thus eliciting improved insulin sensitivity. Therefore, for some time now, chromium has been thought to play a beneficial role in glucose metabolism and, as early as 1957, was referred to as a “glucose tolerance factor” [4]. It has been marketed as such by some companies in the US. There are studies that support this proposed effect. Anderson et al. [5] studied the effects of chromium treatment in a group of Chinese patients with type 2 diabetes. They reported an average decrease in HbA1c (A1C) of almost 2 percentage points after only four months of treatment with 1,000 μg chromium daily. Since then, the effects of chromium on glycemic control, lipid profile, weight, and muscular strength have been investigated, both in nondiabetic healthy subjects and in patients with type 2 diabetes. == References == 2. Shindea UA, Sharma G, Xu YJ, Dhalla NS, Goyal RK: Insulin sensitising action of chromium picolinate in various experimental models of diabetes mellitus. J Trace Elem Med Biol 18: 23–32, 2004 3. Davis CM, Vincent JB: Chromium oligopeptide activates insulin receptor tyrosine kinase activity. Biochemistry 36: 4382–4385, 1997 4. Sun Y, Ramirez J, Woski SA, Vincent JB: The binding of trivalent chromium to low-molecular-weight chromium-binding substance (LMWCr) and the transfer of chromium from transferrin and chromium picolinate to LMWCr. J Biol Inorg Chem 5: 129–136, 2000 5. Schwarz K, Mertz W: A glucose tolerance factor and its differentiation from factor 3. Arch Biochem Biophys 72: 515–518, 1957	Wikipedia/Phonemic_neurological_hypochromium_therapy
Manual therapy, or manipulative therapy, is a treatment primarily used by physical therapists, occupational therapists, and massage therapists to treat musculoskeletal pain and disability. It mostly includes kneading and manipulation of muscles, joint mobilization and joint manipulation. It is also used by Rolfers, athletic trainers, osteopaths, and physicians. == Definitions == Irvin Korr, J. S. Denslow and colleagues did the original body of research on manual therapy. Korr described it as the "Application of an accurately determined and specifically directed manual force to the body, in order to improve mobility in areas that are restricted; in joints, in connective tissues or in skeletal muscles." According to the Orthopaedic Manual Physical Therapy Description of Advanced Specialty Practice manual therapy is defined as a clinical approach utilizing specific hands-on techniques, including but not limited to manipulation/mobilization, used by the physical therapist to diagnose and treat soft tissues and joint structures for the purpose of modulating pain; increasing range of motion (ROM); reducing or eliminating soft tissue inflammation; inducing relaxation; improving contractile and non-contractile tissue repair, extensibility, and/or stability; facilitating movement; and improving function. A consensus study of US chiropractors defined manual therapy (generally known as the "chiropractic adjustment" in the profession) as "Procedures by which the hands directly contact the body to treat the articulations and/or soft tissues." == Use and method == In Pakistan, Western Europe, North America and Australasia, manual therapy is usually practiced by members of specific health care professions (e.g. Chiropractors, Occupational Therapists, Osteopaths, Osteopathic physicians, Physiotherapists/Physical Therapists, Massage Therapists and Physiatrists). However, some lay practitioners (not members of a structured profession), such as bonesetters also provide some forms of manual therapy. A survey released in May 2004 by the National Center for Complementary and Integrative Health focused on who used complementary and alternative medicine (CAM), what was used, and why it was used in the United States by adults during 2002. Massage was the fifth most commonly use CAM in the United States in 2007. === Techniques === Myofascial therapy targets the muscle and fascial systems, promotes flexibility and mobility of the body's connective tissues. It is said to mobilize adhesions and reduce severity/sensitivity of scarring. A critical analysis finds that the relevance of fascia to therapy doubtful. Massage may be used as part of a treatment. Proponents claim this may reduce inflammation. Science writer Paul Ingraham notes that there is no evidence to support the claim. Friction massage is said to increase mobilization of adhesions between fascial layers, muscles, compartments and other soft tissues. They are thought to create an inflammatory response and instigate focus to injured areas. A 2002 systematic review found that no additional benefit was incurred from the inclusion of deep tissue friction massage in a therapeutic regimen, although the conclusions were limited by the small sample sizes in available randomized clinical trials. Soft Tissue Technique is firm, direct pressure to relax hypertonic muscles and stretch tight fascial structures. A 2015 review concluded that the technique is ineffective for lower back pain, and the quality of research testing its effectiveness is poor. Trigger point techniques claim to address myofascial trigger points, though the explanation of how this works is controversial. === Stretching === From the main article's effectiveness section: Apart from before running, stretching does not appear to reduce risk of injury during exercise. Some evidence shows that pre-exercise stretching may increase range of movement. The Mayo Clinic advises against bouncing, and to hold for thirty seconds. They suggest warming up before stretching or stretching post-exercise. === Taping === Manual therapy practitioners often use therapeutic taping to relieve pressure on injured soft tissue, alter muscle firing patterns or prevent re-injury. Some techniques are designed to enhance lymphatic fluid exchange. After a soft tissue injury to muscles or tendons from sports activities, over exertion or repetitive strain injury swelling may impede blood flow to the area and slow healing. Elastic taping methods may relieve pressure from swollen tissue and enhance circulation to the injured area. According to the medical and skeptical community there is no known benefit from this technique and it is a pseudoscience. == Styles of manual therapy == There are many different styles of manual therapy. It is a fundamental feature of ayurvedic medicine, traditional Chinese medicine and some forms of alternative medicine as well as being used by mainstream medical practitioners. Hands-on bodywork is a feature of therapeutic interactions in traditional cultures around the world. == Efficacy == In 2018, the Journal of Orthopaedic & Sports Physical Therapy stated that due to the wide range of issues with various parts of the body and different techniques used, as well as a lack of modeling behavior, it can be difficult to tell just how effective manual therapy can be for a patient. More recent research published in 2024 explained that historically, traditional manual therapy had no basis deeming it an effective modality for treatment of musculoskeletal diseases and pain. This faulty modality was centered around the clinician’s palpation, patho-anatomical reasoning, and technique specificity. The previously known manual therapy is shifting into a highly effective modern day physical therapy, which is not dependent on perfect palpation, and rather utilizes a patient-centered care model. Based on clinical trials and current data, modern day manual therapy is deemed effective when used in conjunction with other modalities for patients suffering with musculoskeletal diseases. The modern practice of manual therapy is centered around values such as safety, comfort, efficiency, communication, and patient-centeredness. Through this new approach, clinicians are encouraging their patient’s to assess their outcomes and progress and reevaluate their pain, thereby aligning the practice of manual therapy with the holistic approach to healthcare. Results for migraines, headaches, and asthma are mixed due to a lack of clinical trials, though at least one article states that manual therapy is effective for asthma. Manual therapy was shown to be effective for treating back pain, with trigger point therapy being used for myofascial pain, and manual manipulation for lower back pain. The therapeutic pressure relieves pain and increases range of motion. While patient’s may complain of muscle soreness post treatment, this effect is expected and it is not deemed adverse. == See also == Body psychotherapy McKenzie method Osteopathy Physical therapy Qigong Siddha medicine Fascial Manipulation == References == == Further reading == === Journals === The Journal of Manual and Manipulative Therapy Journal of Manipulative and Physiological Therapeutics - PubMed access found here === Books === Karel Lewit (1999). Manipulative therapy in rehabilitation of the locomotor system. Oxford: Butterworth-Heinemann. ISBN 0-7506-2964-9. Umasankar Mohanty (2017). Clinical Symposia In Manual Therapy. Mangalore: MTFI Healthcare Publications. ISBN 978-81-908154-1-3. Weiselfish-Giammatteo, S., J. B. Kain; et al. (2005). Integrative manual therapy for the connective tissue system: myofascial release. Berkeley, Calif: North Atlantic Books.{{cite book}}: CS1 maint: multiple names: authors list (link) Kimberly Burnham (2007). Integrative Manual Therapy. West Hartford, CT: The Burnham Review. Umasankar Mohanty (2010). Manual therapy of the pelvic complex. Mangalore: MTFI Healthcare Publications. ISBN 978-81-908154-0-6. == External links == American Academy of Orthopaedic Manual Physical Therapists American Organization for Bodywork Therapies of Asia Manual Therapy Foundation of India International Federation of Orthopaedic Manipulative Therapists	Wikipedia/Manual_therapy
Host modulatory therapy is an emerging treatment concept in the management of periodontitis that aims to reduce tissue destruction and stabilise or even regenerate the periodontium by modifying the host response. Historically treatment of periodontitis has been focused on reducing the bacterial challenge. However the outcomes of the conventional treatment procedures like scaling and root planning (SRP) are not always stable or predictable. Periodontal disease is seen as a balance between (1) a persisting bacterial challenge and the proinflammatory destructive events in the tissue and (2) resolution of inflammation and downregulation of destructive processes. The goal is to maximize treatment response by reducing inflammation and inhibiting destructive processes in the tissues which will result in enhanced periodontal stability after conventional periodontal treatments like SRP. Host modulatory therapy is a means of treating the host's side of the host-bacteria interaction. == Agents == Non steroidal Anti Inflammatory Drugs They inhibit prostaglandin E2 formation (PGE2) that is produced by neutrophils, fibroblasts and gingival epithelial cells in response to bacteria. PGE2 upregulates bone resorption by osteoclasts and their levels are higher in patients with periodontal disease than in healthy individuals. Bisphosphonate Sub antimicrobial doxycycline Sub antimicrobial doxycycline is 20 mg doxycycline (Periostat) approved and indicated as an adjunct to SRP in the treatment of chronic periodontitis. It is given twice daily for three months for a maximum of nine months. This dosage of doxycycline has cytokine and osteoclasts inhibitory action rather than being antimicrobial. Enamel Matrix Protein These agents not only help improve wound healing but also stimulate regeneration of the lost bone, periodontal ligament and cementum restoring the complete periodontal attachment apparatus. Currently Emdogain is the only approved host modulatory agent of this type. Growth Factors Bone Morphogenic Proteins == References ==	Wikipedia/Host_modulatory_therapy
Hormone replacement therapy (HRT), also known as menopausal hormone therapy or postmenopausal hormone therapy, is a form of hormone therapy used to treat symptoms associated with female menopause. Effects of menopause can include symptoms such as hot flashes, accelerated skin aging, vaginal dryness, decreased muscle mass, and complications such as osteoporosis (bone loss), sexual dysfunction, and vaginal atrophy. They are mostly caused by low levels of female sex hormones (e.g. estrogens) that occur during menopause. Estrogens and progestogens are the main hormone drugs used in HRT. Progesterone is the main female sex hormone that occurs naturally and is also manufactured into a drug that is used in menopausal hormone therapy. Although both classes of hormones can have symptomatic benefit, progestogen is specifically added to estrogen regimens, unless the uterus has been removed, to avoid the increased risk of endometrial cancer. Unopposed estrogen therapy promotes endometrial hyperplasia and increases the risk of cancer, while progestogen reduces this risk. Androgens like testosterone are sometimes used as well. HRT is available through a variety of different routes. The long-term effects of HRT on most organ systems vary by age and time since the last physiological exposure to hormones, and there can be large differences in individual regimens, factors which have made analyzing effects difficult. The Women's Health Initiative (WHI) is an ongoing study of over 27,000 women that began in 1991, with the most recent analyses suggesting that, when initiated within 10 years of menopause, HRT reduces all-cause mortality and risks of coronary disease, osteoporosis, and dementia; after 10 years the beneficial effects on mortality and coronary heart disease are no longer apparent, though there are decreased risks of hip and vertebral fractures and an increased risk of venous thromboembolism when taken orally. "Bioidentical" hormone replacement is a development in the 21st century and uses manufactured compounds with "exactly the same chemical and molecular structure as hormones that are produced in the human body." These are mainly manufactured from plant steroids and can be a component of either registered pharmaceutical or custom-made compounded preparations, with the latter generally not recommended by regulatory bodies due to their lack of standardization and formal oversight. Bioidentical hormone replacement has inadequate clinical research to determine its safety and efficacy as of 2017. The current indications for use from the United States Food and Drug Administration (FDA) include short-term treatment of menopausal symptoms, such as vasomotor hot flashes or vaginal atrophy, and prevention of osteoporosis. == Medical uses == Approved uses of HRT in the United States include short-term treatment of menopausal symptoms such as hot flashes and vaginal atrophy, and prevention of osteoporosis. The American College of Obstetrics and Gynecology (ACOG) approves of HRT for symptomatic relief of menopausal symptoms, and advocates its use beyond the age of 65 in appropriate scenarios. The North American Menopause Society (NAMS) 2016 annual meeting mentioned that HRT may have more benefits than risks in women before the age of 60. A consensus expert opinion published by The Endocrine Society stated that when taken during perimenopause or the initial years of menopause, HRT carries fewer risks than previously published, and reduces all cause mortality in most scenarios. The American Association of Clinical Endocrinologists (AACE) has also released position statements approving of HRT when appropriate. Women receiving this treatment are usually post-, peri-, or surgically induced menopausal. Menopause is the permanent cessation of menstruation resulting from loss of ovarian follicular activity, defined as beginning twelve months after the final natural menstrual cycle. This twelve month time point divides menopause into early and late transition periods known as 'perimenopause' and 'postmenopause'. Premature menopause can occur if the ovaries are surgically removed, as can be done to treat ovarian or uterine cancer. Demographically, the vast majority of data available is in postmenopausal American women with concurrent pre-existing conditions and an average age of over 60 years. === Menopausal symptoms === HRT is often given as a short-term relief from menopausal symptoms during perimenopause. Potential menopausal symptoms include: Hot flashes – vasomotor symptoms Vulvovaginal atrophy – atrophic vaginitis and dryness Dyspareunia – painful sexual intercourse due to vaginal atrophy and lack of lubrication Bone loss – decreased bone mineral density, which can eventually lead to osteopenia, osteoporosis, and associated fractures Decreased sexual desire Defeminization – diminished feminine fat distribution and accelerated skin aging Sleep disturbances and joint pain The most common of these are loss of sexual drive and vaginal dryness. The use of hormone therapy for heart health among menopausal women has declined significantly over the past few decades. In 1999, nearly 27% of menopausal women in the U.S. used estrogen, but by 2020, that figure had dropped to less than 5%. Recent evidence in 2024 suggests evidence supporting the cardiovascular benefits of hormone therapy, including improvements in insulin resistance and other heart-related markers. This adds to a growing body of research highlighting hormone therapy’s effectiveness, not only for heart health but also for managing menopausal symptoms like hot flashes, disrupted sleep, vaginal dryness, and painful intercourse. Despite its proven benefits, many menopausal women avoid hormone therapy, often due to lingering misconceptions about its risks and societal discomfort with openly discussing menopause. === Sexual function === HRT can help with the lack of sexual desire and sexual dysfunction that can occur with menopause. Epidemiological surveys of women between 40 and 69 years suggest that 75% of women remain sexually active after menopause. With increasing life spans, women today are living one third or more of their lives in a postmenopausal state, a period during which healthy sexuality can be integral to their quality of life. Decreased libido and sexual dysfunction are common issues in postmenopausal women, an entity referred to hypoactive sexual desire disorder (HSDD); its signs and symptoms can both be improved by HRT. Several hormonal changes take place during this period, including a decrease in estrogen and an increase in follicle-stimulating hormone. For most women, the majority of change occurs during the late perimenopausal and postmenopausal stages. Decreases in sex hormone-binding globulin (SHBG) and inhibin (A and B) also occur. Testosterone is present in women at a lower level than men, peaking at age 30 and declining gradually with age; there is less variation during the menopausal transition relative to estrogen and progesterone. A global consensus position statement has advised that postmenopausal testosterone replacement to premenopausal levels can be effective for HSDD. Safety information for testosterone treatment is not available beyond two years of continuous therapy however and dosing above physiologic levels is not advised. Testosterone patches have been found to restore sexual desire in post menopausal women. There is insufficient data to evaluate the impact of testosterone replacement on heart disease, breast cancer, with most trials having included women taking concomitant estrogen and progesterone and with testosterone therapy itself being relatively short in duration. In the setting of this limited data, testosterone therapy has not been associated with adverse events. Not all women are responsive, especially those with preexisting sexual difficulties. Estrogen replacement can restore vaginal cells, pH levels, and blood flow to the vagina, all of which tend to deteriorate at the onset of menopause. Pain or discomfort with sex appears to be the most responsive component to estrogen. It also has been shown to have positive effects on the urinary tract. Estrogen can also reduce vaginal atrophy and increase sexual arousal, frequency and orgasm. The effectiveness of hormone replacement can decline in some women after long-term use. A number of studies have also found that the combined effects of estrogen/androgen replacement therapy can increase libido and arousal over estrogen alone. Tibolone, a synthetic steroid with estrogenic, androgenic, and progestogenic properties that is available in Europe, has the ability to improve mood, libido, and physical symptomatology. In various placebo-controlled studies, improvements in vasomotor symptoms, emotional response, sleep disturbances, physical symptoms, and sexual desire have been seen, though it also carries a similar risk profile to conventional HRT. === Muscle and bone === There is a significant decrease in hip fracture risk during treatment that to a lesser degree persists after HRT is stopped. It also helps collagen formation, which in turn improves intervertebral disc and bone strength. Hormone replacement therapy in the form of estrogen and androgen can be effective at reversing the effects of aging on muscle. Lower testosterone is associated with lower bone density and higher free testosterone is associated with lower hip fracture rates in older women. Testosterone therapy, which can be used for decreased sexual function, can also increase bone mineral density and muscle mass. == Side effects == Side effects in HRT occur with varying frequency and include: == Health effects == === Heart disease === The effect of HRT in menopause appears to be divergent, with lower risk of heart disease when started within five years, but no impact after ten. For women who are in early menopause and have no issues with their cardiovascular health, HRT comes with a low risk of adverse cardiovascular events. There may be an increase in heart disease if HRT is given twenty years post-menopause. This variability has led some reviews to suggest an absence of significant effect on morbidity. Importantly, there is no difference in long-term mortality from HRT, regardless of age. A Cochrane review suggested that women starting HRT less than 10 years after menopause had lower mortality and coronary heart disease, without any strong effect on the risk of stroke and pulmonary embolism. Those starting therapy more than 10 years after menopause showed little effect on mortality and coronary heart disease, but an increased risk of stroke. Both therapies had an association with venous clots and pulmonary embolism. HRT with estrogen and progesterone also improves cholesterol levels. With menopause, HDL decreases, while LDL, triglycerides and lipoprotein a increase, patterns that reverse with estrogen. Beyond this, HRT improves heart contraction, coronary blood flow, sugar metabolism, and decreases platelet aggregation and plaque formation. HRT may promote reverse cholesterol transport through induction of cholesterol ABC transporters. Atherosclerosis imaging trials show that HRT decreases the formation of new vascular lesions, but does not reverse the progression of existing lesions. HRT also results in a large reduction in the pro-thrombotic lipoprotein a. Studies on cardiovascular disease with testosterone therapy have been mixed, with some suggesting no effect or a mild negative effect, though others have shown an improvement in surrogate markers such as cholesterol, triglycerides and weight. Testosterone has a positive effect on vascular endothelial function and tone with observational studies suggesting that women with lower testosterone may be at greater risk for heart disease. Available studies are limited by small sample size and study design. Low sex hormone-binding globulin, which occurs with menopause, is associated with increased body mass index and risk for type 2 diabetes. === Blood clots === Effects of hormone replacement therapy on venous blood clot formation and potential for pulmonary embolism may vary with different estrogen and progestogen therapies, and with different doses or method of use. Comparisons between routes of administration suggest that when estrogens are applied to the skin or vagina, there is a lower risk of blood clots, whereas when used orally, the risk of blood clots and pulmonary embolism is increased. Skin and vaginal routes of hormone therapy are not subject to first pass metabolism, and so lack the anabolic effects that oral therapy has on liver synthesis of vitamin K-dependent clotting factors, possibly explaining why oral therapy may increase blood clot formation. While a 2018 review found that taking progesterone and estrogen together can decrease this risk, other reviews reported an increased risk of blood clots and pulmonary embolism when estrogen and progestogen were combined, particularly when treatment was started 10 years or more after menopause and when the women were older than 60 years. The risk of venous thromboembolism may be reduced with bioidentical preparations, though research on this is only preliminary. === Stroke === Multiple studies suggest that the possibility of HRT related stroke is absent if therapy is started within five years of menopause, and that the association is absent or even preventive when given by non-oral routes. Ischemic stroke risk was increased during the time of intervention in the WHI, with no significant effect after the cessation of therapy and no difference in mortality at long term follow up. When oral synthetic estrogen or combined estrogen-progestogen treatment is delayed until five years from menopause, cohort studies in Swedish women have suggested an association with hemorrhagic and ischemic stroke. Another large cohort of Danish women suggested that the specific route of administration was important, finding that although oral estrogen increased risk of stroke, absorption through the skin had no impact, and vaginal estrogen actually had a decreased risk. === Endometrial cancer === In postmenopausal women, continuous combined estrogen plus progestin decreases endometrial cancer incidence. The duration of progestogen therapy should be at least 14 days per cycle to prevent endometrial disease. Endometrial cancer has been grouped into two forms in the context of hormone replacement. Type 1 is the most common, can be associated with estrogen therapy, and is usually low grade. Type 2 is not related to estrogen stimulation and usually higher grade and poorer in prognosis. The endometrial hyperplasia that leads to endometrial cancer with estrogen therapy can be prevented by concomitant administration of progestogen. The extensive use of high-dose estrogens for birth control in the 1970s is thought to have resulted in a significant increase in the incidence of type 1 endometrial cancer. Paradoxically, progestogens do promote the growth of uterine fibroids, and a pelvic ultrasound can be performed before beginning HRT to make sure there are no underlying uterine or endometrial lesions. Androgens do not stimulate endometrial proliferation in post menopausal women, and appear to inhibit the proliferation induced by estrogen to a certain extent. There is insufficient high‐quality evidence to inform women considering hormone replacement therapy after treatment for endometrial cancer. === Breast cancer === In general, hormone replacement therapy to treat menopause is associated with only a small increased risk of breast cancer. The level of risk also depends on the type of HRT, the duration of the treatment and the age of the person. Oestrogen-only HRT, taken by people who had a hysterectomy, comes with an extremely low level of breast cancer risk. The most commonly taken combined HRT (oestrogen and progestogen) is linked to a small risk of breast cancer. This risk is lower for women in their 50s and higher for older women. The risk increases with the duration of HRT. When HRT is taken for a year or less, there is no increased risk of breast cancer. HRT taken for more than 5 years comes with an increased risk but the risk reduces after the therapy is stopped. There is a non-statistically significant increased rate of breast cancer for hormone replacement therapy with synthetic progestogens. The risk may be reduced with bioidentical progesterone, though the only prospective study that suggested this was underpowered due to the rarity of breast cancer in the control population. There have been no randomized controlled trials as of 2018. The relative risk of breast cancer also varies depending on the interval between menopause and HRT and route of synthetic progestin administration. The most recent follow up of the Women's Health Initiative participants demonstrated a lower incidence of breast cancer in post-hysterectomy participants taking equine estrogen alone, though the relative risk was increased if estrogen was taken with medroxyprogesterone. Estrogen is usually only given alone in the setting of a hysterectomy due to the increased risk of vaginal bleeding and uterine cancer with unopposed estrogen. HRT has been more strongly associated with risk of breast cancer in women with lower body mass indices (BMIs). No breast cancer association has been found with BMIs of over 25. It has been suggested by some that the absence of significant effect in some of these studies could be due to selective prescription to overweight women who have higher baseline estrone, or to the very low progesterone serum levels after oral administration leading to a high tumor inactivation rate. Evaluating the response of breast tissue density to HRT using mammography appears to help assessing the degree of breast cancer risk associated with therapy; women with dense or mixed-dense breast tissue have a higher risk of developing breast cancer than those with low density tissue. Micronized progesterone does not appear to be associated with breast cancer risk when used for less than five years with limited data suggesting an increased risk when used for longer duration. For women who previously have had breast cancer, it is recommended to first consider other options for menopausal effects, such as bisphosphonates or selective estrogen receptor modulators (SERMs) for osteoporosis, cholesterol-lowering agents and aspirin for cardiovascular disease, and vaginal estrogen for local symptoms. Observational studies of systemic HRT after breast cancer are generally reassuring. If HRT is necessary after breast cancer, estrogen-only therapy or estrogen therapy with a progestogen may be safer options than combined systemic therapy. In women who are BRCA1 or BRCA2 mutation carriers, HRT does not appear to impact breast cancer risk. The relative number of women using HRT who also obtain regular screening mammograms is higher than that in women who do not use HRT, a factor which has been suggested as contributing to different breast cancer detection rates in the two groups. With androgen therapy, pre-clinical studies have suggested an inhibitory effect on breast tissue though the majority of epidemiological studies suggest a positive association. === Ovarian cancer === HRT is associated with an increased risk of ovarian cancer, with women using HRT having about one additional case of ovarian cancer per 1,000 users. This risk is decreased when progestogen therapy is given concomitantly, as opposed to estrogen alone, and also decreases with increasing time since stopping HRT. Regarding the specific subtype, there may be a higher risk of serous cancer, but no association with clear cell, endometrioid, or mucinous ovarian cancer. Hormonal therapy in ovarian cancer survivors after surgical removal of the ovaries is generally thought to improval survival rates. === Other cancers === ==== Colorectal cancer ==== In the WHI, women who took combined estrogen-progesterone therapy had a lower risk of getting colorectal cancer. However, the cancers they did have were more likely to have spread to lymph nodes or distant sites than colorectal cancer in women not taking hormones. In colorectal cancer survivors, usage of HRT is thought to lead to lower recurrence risk and overall mortality. ==== Cervical cancer ==== There appears to be a significantly decreased risk of cervical squamous cell cancer in post menopausal women treated with HRT and a weak increase in adenocarcinoma. No studies have reported an increased risk of recurrence when HRT is used with cervical cancer survivors. === Neurodegenerative disorders === As of 2024 there has been conflicting evidence from clinical studies regarding the beneficial effects of estrogens at reducing the risk of Alzheimer's Disease. For prevention, the WHI suggested in 2013, that HRT may increase risk of dementia if initiated after 65 years of age, but have a neutral outcome or be neuroprotective for those between 50 and 55 years. However, the prospective ELITE trial showed negligible effects on verbal memory and other mental skills regardless of how soon after menopause a woman began HRT. A 2012 review of clinical and epidemiological studies of HRT and AD, PD, FTD and HIV related dementia concluded results were inconclusive at this time. The majority of clinical and epidemiological studies show either no association with the risk of developing Parkinson's disease or inconclusive results. One Danish study suggested an increased risk of Parkinson's with HRT in cyclical dosing schedules. Other randomized trials have shown HRT to improve executive and attention processes outside of the context of dementia in postmenopausal women, both in asymptomatic and those with mild cognitive impairment. As of 2011, estrogen replacement in post menopausal women with Parkinson's disease appeared to improve motor symptoms and activities of daily living , with significant improvement of UPDRS scores. Testosterone replacement has also shown to be associated with small statistically significant improvements in verbal learning and memory in postmenopausal women but DHEA has not been found to improve cognitive performance after menopause. Pre-clinical studies have indicated that endogenous estrogen and testosterone are neuroprotective and can prevent brain amyloid deposition. == Contraindications == The following are absolute and relative contraindications to HRT: === Absolute contraindications === Undiagnosed vaginal bleeding Severe liver disease Pregnancy Severe coronary artery disease Aggressive breast, uterine or ovarian cancer === Relative contraindications === Migraine headaches History of breast cancer History of ovarian cancer Venous thrombosis History of uterine fibroids Atypical ductal hyperplasia of the breast Active gallbladder disease (cholangitis, cholecystitis) Well-differentiated and early endometrial cancer – once treatment for the malignancy is complete, is no longer an absolute contraindication. == History and research == The extraction of CEEs from the urine of pregnant mares led to the marketing in 1942 of Premarin, one of the earlier forms of estrogen to be introduced. From that time until the mid-1970s, estrogen was administered without a supplemental progestogen. Beginning in 1975, studies began to show that without a progestogen, unopposed estrogen therapy with Premarin resulted in an eight-fold increased risk of endometrial cancer, eventually causing sales of Premarin to plummet. It was recognized in the early 1980s that the addition of a progestogen to estrogen reduced this risk to the endometrium. This led to the development of combined estrogen–progestogen therapy, most commonly with a combination of conjugated equine estrogen (Premarin) and medroxyprogesterone (Provera). === Trials === The Women's Health Initiative trials were conducted between 1991 and 2006 and were the first large, double-blind, placebo-controlled clinical trials of HRT in healthy women. Their results were both positive and negative, suggesting that during the time of hormone therapy itself, there are increases in invasive breast cancer, stroke and lung clots. Other risks include increased endometrial cancer, gallbladder disease, and urinary incontinence, while benefits include decreased hip fractures, decreased incidence of diabetes, and improvement of vasomotor symptoms. There is also an increased risk of dementia with HRT in women over 65, though at younger ages it appears to be neuroprotective. After the cessation of HRT, the WHI continued to observe its participants, and found that most of these risks and benefits dissipated, though some elevation in breast cancer risk did persist. Other studies have also suggested an increased risk of ovarian cancer. The arm of the WHI receiving combined estrogen and progestin therapy was closed prematurely in 2002 by its Data Monitoring Committee (DMC) due to perceived health risks, though this occurred a full year after the data suggesting increased risk became manifest. In 2004, the arm of the WHI in which post-hysterectomy patients were being treated with estrogen alone was also closed by the DMC. Clinical medical practice changed based upon two parallel Women's Health Initiative (WHI) studies of HRT. Prior studies were smaller, and many were of women who electively took hormonal therapy. One portion of the parallel studies followed over 16,000 women for an average of 5.2 years, half of whom took placebo, while the other half took a combination of CEEs and MPA (Prempro). This WHI estrogen-plus-progestin trial was stopped prematurely in 2002 because preliminary results suggested risks of combined CEEs and progestins exceeded their benefits. The first report on the halted WHI estrogen-plus-progestin study came out in July 2002. Initial data from the WHI in 2002 suggested mortality to be lower when HRT was begun earlier, between age 50 to 59, but higher when begun after age 60. In older patients, there was an apparent increased incidence of breast cancer, heart attacks, venous thrombosis, and stroke, although a reduced incidence of colorectal cancer and bone fracture. At the time, The WHI recommended that women with non-surgical menopause take the lowest feasible dose of HRT for the shortest possible time to minimize associated risks. Some of the WHI findings were again found in a larger national study done in the United Kingdom, known as the Million Women Study (MWS). As a result of these findings, the number of women taking HRT dropped precipitously. In 2012, the United States Preventive Task Force (USPSTF) concluded that the harmful effects of combined estrogen and progestin therapy likely exceeded their chronic disease prevention benefits. In 2002 when the first WHI follow up study was published, with HRT in post menopausal women, both older and younger age groups had a slightly higher incidence of breast cancer, and both heart attack and stroke were increased in older patients, although not in younger participants. Breast cancer was increased in women treated with estrogen and a progestin, but not with estrogen and progesterone or estrogen alone. Treatment with unopposed estrogen (i.e., an estrogen alone without a progestogen) is contraindicated if the uterus is still present, due to its proliferative effect on the endometrium. The WHI also found a reduced incidence of colorectal cancer when estrogen and a progestogen were used together, and most importantly, a reduced incidence of bone fractures. Ultimately, the study found disparate results for all cause mortality with HRT, finding it to be lower when HRT was begun during ages 50–59, but higher when begun after age 60. The authors of the study recommended that women with non-surgical menopause take the lowest feasible dose of hormones for the shortest time to minimize risk. The data published by the WHI suggested supplemental estrogen increased risk of venous thromboembolism and breast cancer but was protective against osteoporosis and colorectal cancer, while the impact on cardiovascular disease was mixed. These results were later supported in trials from the United Kingdom, but not in more recent studies from France and China. Genetic polymorphism appears to be associated with inter-individual variability in metabolic response to HRT in postmenopausal women. The WHI reported statistically significant increases in rates of breast cancer, coronary heart disease, strokes and pulmonary emboli. The study also found statistically significant decreases in rates of hip fracture and colorectal cancer. "A year after the study was stopped in 2002, an article was published indicating that estrogen plus progestin also increases the risks of dementia." The conclusion of the study was that the HRT combination presented risks that outweighed its measured benefits. The results were almost universally reported as risks and problems associated with HRT in general, rather than with Prempro, the specific proprietary combination of CEEs and MPA studied. After the increased clotting found in the first WHI results was reported in 2002, the number of Prempro prescriptions filled reduced by almost half. Following the WHI results, a large percentage of HRT users opted out of them, which was quickly followed by a sharp drop in breast cancer rates. The decrease in breast cancer rates has continued in subsequent years. An unknown number of women started taking alternatives to Prempro, such as compounded bioidentical hormones, though researchers have asserted that compounded hormones are not significantly different from conventional hormone therapy. The other portion of the parallel studies featured women who were post hysterectomy and so received either placebo progestogen or CEEs alone. This group did not show the risks demonstrated in the combination hormone study, and the estrogen-only study was not halted in 2002. However, in February 2004 it, too, was halted. While there was a 23% decreased incidence of breast cancer in the estrogen-only study participants, risks of stroke and pulmonary embolism were increased slightly, predominantly in patients who began HRT over the age of 60. Several other large studies and meta-analyses have reported reduced mortality for HRT in women younger than age 60 or within 10 years of menopause, and a debatable or absent effect on mortality in women over 60. Though research thus far has been substantial, further investigation is needed to fully understand differences in effect for different types of HRT and lengths of time since menopause. As of 2023, for example, no trial has studied women who begin taking HRT around age 50 and continue taking it for longer than 10 years. == Available forms == There are five major human steroid hormones: estrogens, progestogens, androgens, mineralocorticoids, and glucocorticoids. Estrogens and progestogens are the two most often used in menopause. They are available in a wide variety of FDA approved and non–FDA-approved formulations. In women with intact uteruses, estrogens are almost always given in combination with progestogens, as long-term unopposed estrogen therapy is associated with a markedly increased risk of endometrial hyperplasia and endometrial cancer. Conversely, in women who have undergone a hysterectomy or do not have a uterus, a progestogen is not required, and estrogen can be used alone. There are many combined formulations which include both estrogen and progestogen. Specific types of hormone replacement include: Estrogens – bioidentical estrogens like estradiol and estriol, animal-derived estrogens like conjugated estrogens (CEEs), and synthetic estrogens like ethinylestradiol Progestogens – bioidentical progesterone, and progestins (synthetic progestogens) like medroxyprogesterone acetate (MPA), norethisterone, and dydrogesterone Androgens – bioidentical testosterone and dehydroepiandrosterone (DHEA), and synthetic anabolic steroids like methyltestosterone and nandrolone decanoate Tibolone – a synthetic medication available in Europe but not the United States– is more effective than placebo but less effective than combination hormone therapy in postmenopausal women. It may have a decreased risk of breast and colorectal cancer, though conversely it can be associated with vaginal bleeding, endometrial cancer, and increase the risk of stroke in women over age 60 years. Vaginal estrogen can improve local atrophy and dryness, with fewer systemic effects than estrogens delivered by other routes. Sometimes an androgen, generally testosterone, can be added to treat diminished libido. === Continuous versus cyclic === Dosage is often varied cyclically to more closely mimic the ovarian hormone cycle, with estrogens taken daily and progestogens taken for about two weeks every month or every other month, a schedule referred to as 'cyclic' or 'sequentially combined'. Alternatively, 'continuous combined' HRT can be given with a constant daily hormonal dosage. Continuous combined HRT is associated with less complex endometrial hyerplasia than cyclic. Impact on breast density appears to be similar in both regimen timings. === Route of administration === The medications used in menopausal HRT are available in numerous different formulations for use by a variety of different routes of administration: Oral administration – tablets, capsules Transdermal administration – patches, gels, creams Vaginal administration – tablets, creams, suppositories, rings Intramuscular or subcutaneous injection – solutions in vials or ampoules Subcutaneous implant – surgically-inserted pellets placed into fat tissue Less commonly sublingual, buccal, intranasal, and rectal administration, as well as intrauterine devices More recently developed forms of drug delivery are alleged to have increased local effect lower dosing, fewer side effects, and constant rather than cyclical serum hormone levels. Transdermal and vaginal estrogen, in particular, avoid first pass metabolism through the liver. This in turn prevents an increase in clotting factors and accumulation of anti-estrogenic metabolites, resulting in fewer adverse side effects, particularly with regard to cardiovascular disease and stroke. Injectable forms of estradiol exist and have been used occasionally in the past. However, they are rarely used in menopausal hormone therapy in modern times and are no longer recommended. Instead, other non-oral forms of estradiol such as transdermal estradiol are recommended and may be used. Estradiol injectables are generally well-tolerated and convenient, requiring infrequent administration. However, this form of estradiol does not release estradiol at a constant rate and there are very high circulating estradiol levels soon after injection followed by a rapid decline in levels. Injections may also be painful. Examples of estradiol injectables that may be used in menopausal hormone therapy include estradiol valerate and estradiol cypionate. In terms of injectable progestogens, injectable progesterone is associated with pain and injection site reactions as well as a short duration of action requiring very frequent injections, and is similarly not recommended in menopausal hormone therapy. === Bioidentical hormone therapy === Bioidentical hormone therapy (BHT) is the usage of hormones that are chemically identical to those produced in the body. Although proponents of BHT claim advantages over non-bioidentical or conventional hormone therapy, the FDA does not recognize the term 'bioidentical hormone', stating there is no scientific evidence that these hormones are identical to their naturally occurring counterparts. There are, however, FDA approved products containing hormones classified as 'bioidentical'. Bioidentical hormones can be used in either pharmaceutical or compounded preparations, with the latter generally not recommended by regulatory bodies due to their lack of standardization and regulatory oversight. Most classifications of bioidentical hormones do not take into account manufacturing, source, or delivery method of the products, and so describe both non-FDA approved compounded products and FDA approved pharmaceuticals as 'bioidentical'. The British Menopause Society has issued a consensus statement endorsing the distinction between "compounded" forms (cBHRT), described as unregulated, custom made by specialty pharmacies and subject to heavy marketing and "regulated" pharmaceutical grade forms (rBHRT), which undergo formal oversight by entities such as the FDA and form the basis of most clinical trials. Some practitioners recommending compounded bioidentical HRT also use salivary or serum hormonal testing to monitor response to therapy, a practice not endorsed by current clinical guidelines in the United States and Europe. Bioidentical hormones in pharmaceuticals may have very limited clinical data, with no randomized controlled prospective trials to date comparing them to their animal derived counterparts. Some pre-clinical data has suggested a decreased risk of venous thromboembolism, cardiovascular disease, and breast cancer. As of 2012, guidelines from the North American Menopause Society, the Endocrine Society, the International Menopause Society, and the European Menopause and Andropause Society endorsed the reduced risk of bioidentical pharmaceuticals for those with increased clotting risk. ==== Compounding ==== Compounding for HRT is generally discouraged by the FDA and medical industry in the United States due to a lack of regulation and standardized dosing. The U.S. Congress did grant the FDA explicit but limited oversight of compounded drugs in a 1997 amendment to the Federal Food, Drug, and Cosmetic Act (FDCA), but they have encountered obstacles in this role since that time. After 64 patient deaths and 750 harmed patients from a 2012 meningitis outbreak due to contaminated steroid injections, Congress passed the 2013 Drug Quality and Security Act, authorizing creation by the FDA of a voluntary registration for facilities that manufactured compounded drugs, and reinforcing FDCA regulations for traditional compounding. The DQSA and its reinforcement of provision §503A of the FDCA solidifies FDA authority to enforce FDCA regulation of against compounders of bioidentical hormone therapy. In the United Kingdom, on the other hand, compounding is a regulated activity. The Medicines and Healthcare products Regulatory Agency regulates compounding performed under a Manufacturing Specials license and the General Pharmaceutical Council regulates compounding performed within a pharmacy. All testosterone prescribed in the United Kingdom is bioidentical, with its use supported by the National Health Service. There is also marketing authorisation for male testosterone products. National Institute for Health and Care Excellence guideline 1.4.8 states: "consider testosterone supplementation for menopausal women with low sexual desire if HRT alone is not effective". The footnote adds: "at the time of publication (November 2015), testosterone did not have a United Kingdom marketing authorisation for this indication in women. Bioidentical progesterone is used in IVF treatment and for pregnant women who are at risk of premature labour." == Society and culture == === Wyeth controversy === Wyeth, now a subsidiary of Pfizer, was a pharmaceutical company that marketed the HRT products Premarin (CEEs) and Prempro (CEEs + MPA). In 2009, litigation involving Wyeth resulted in the release of 1,500 documents that revealed practices concerning its promotion of these medications. The documents showed that Wyeth commissioned dozens of ghostwritten reviews and commentaries that were published in medical journals to promote unproven benefits of its HRT products, downplay their harms and risks, and cast competing therapies in a negative light. Starting in the mid-1990s and continuing for over a decade, Wyeth pursued an aggressive "publication plan" strategy to promote its HRT products through the use of ghostwritten publications. It worked mainly with DesignWrite, a medical writing firm. Between 1998 and 2005, Wyeth had 26 papers promoting its HRT products published in scientific journals. These favorable publications emphasized the benefits and downplayed the risks of its HRT products, especially the "misconception" of the association of its products with breast cancer. The publications defended unsupported cardiovascular "benefits" of its products, downplayed risks such as breast cancer, and promoted off-label and unproven uses like prevention of dementia, Parkinson's disease, vision problems, and wrinkles. In addition, Wyeth emphasized negative messages against the SERM raloxifene for osteoporosis, instructed writers to stress the fact that "alternative therapies have increased in usage since the WHI even though there is little evidence that they are effective or safe...", called into question the quality and therapeutic equivalence of approved generic CEE products, and made efforts to spread the notion that the unique risks of CEEs and MPA were a class effect of all forms of menopausal HRT: "Overall, these data indicate that the benefit/risk analysis that was reported in the Women's Health Initiative can be generalized to all postmenopausal hormone replacement therapy products." Following the publication of the WHI data in 2002, the stock prices for the pharmaceutical industry plummeted, and huge numbers of women stopped using HRT. The stocks of Wyeth, which supplied the Premarin and Prempro that were used in the WHI trials, decreased by more than 50%, and never fully recovered. Some of their articles in response promoted themes such as the following: "the WHI was flawed; the WHI was a controversial trial; the population studied in the WHI was inappropriate or was not representative of the general population of menopausal women; results of clinical trials should not guide treatment for individuals; observational studies are as good as or better than randomized clinical trials; animal studies can guide clinical decision-making; the risks associated with hormone therapy have been exaggerated; the benefits of hormone therapy have been or will be proven, and the recent studies are an aberration." Similar findings were observed in a 2010 analysis of 114 editorials, reviews, guidelines, and letters by five industry-paid authors. These publications promoted positive themes and challenged and criticized unfavorable trials such as the WHI and MWS. In 2009, Wyeth was acquired by Pfizer in a deal valued at US$68 billion. Pfizer, a company that produces Provera and Depo-Provera (MPA) and has also engaged in medical ghostwriting, continues to market Premarin and Prempro, which remain best-selling medications. According to Fugh-Berman (2010), "Today, despite definitive scientific data to the contrary, many gynecologists still believe that the benefits of [HRT] outweigh the risks in asymptomatic women. This non-evidence–based perception may be the result of decades of carefully orchestrated corporate influence on medical literature." As many as 50% of physicians have expressed skepticism about large trials like the WHI and HERS in a 2011 survey. The positive perceptions of many physicians of HRT in spite of large trials showing risks that potentially outweigh any benefits may be due to the efforts of pharmaceutical companies like Wyeth, according to May and May (2012) and Fugh-Berman (2015). === Popularity === The 1990s showed a dramatic decline in prescription rates, though more recently they have begun to rise again. Transdermal therapy, in part due to its lack of increase in venous thromboembolism, is now often the first choice for HRT in the United Kingdom. Conjugate equine estrogen, in distinction, has a potentially higher thrombosis risk and is now not commonly used in the UK, replaced by estradiol based compounds with lower thrombosis risk. Oral progestogen combinations such as medroxyprogesterone acetate have changed to dyhydrogesterone, due to a lack of association of the latter with venous clot. == See also == Androgen replacement therapy Androgen deficiency Hormone therapy Gender-affirming hormone therapy Feminizing hormone therapy == References == == External links == Menopause treatment, Hormone Health Network, The Endocrine Society Sexual Health and Menopause Online, The North American Menopause Society Menopause, US Food and Drug Administration British Menopause Society	Wikipedia/Estrogen_replacement_therapy
Upper-limb surgery in tetraplegia includes a number of surgical interventions that can help improve the quality of life of a patient with tetraplegia. Loss of upper-limb function in patients with following a spinal cord injury is a major barrier to regain autonomy. The functional abilities of a tetraplegic patient increase substantially for instance if the patient can extend the elbow. This can increase the workspace and give a better use of a manual wheelchair. To be able to hold objects a patient needs to have a functional pinch grip, this can be useful for performing daily living activities. A large survey in patients with tetraplegia demonstrated that these patients give preference to improving upper extremity function above other lost functions like being able to walk or sexual function. Surgical procedures do exist to improve the function of the tetraplegic patient's arms, but these procedures are performed in fewer than 10% of the tetraplegic patients. Each tetraplegic patient is unique, and therefore surgical indication should be based on the remaining physical abilities, wishes and expectations of the patient. In 2007 a resolution was presented and accepted at the world congress in reconstructive hand surgery and rehabilitation in tetraplegia, that stated that every patient with tetraplegia should be examined and informed about the options for reconstructive surgery of the tetraplegic arms and hands. This resolution demonstrates mostly the necessity to increase the awareness on this subject amongst physicians. == History == Reconstructive surgery of the upper limb in tetraplegic patients began during the mid-20th century. The first attempts at regaining gripping function of the hand probably took place in Europe at the end of the 1920s with the construction of flexor-hinge splints. In the early 1940s, a surgeon called Sterling Bunnell (1882–1957) was probably one of the first to refer to the reconstruction of gripping function for the tetraplegic hand. He described surgeries of combining tenodeses and tendon transfers to restore hand function. He also advocated transferring the m. brachioradialis to the wrist extensors when these muscles are paralyzed. In the 1950s, understanding of the tenodesis effect (See Tenodesis grasp) influenced the development of surgical techniques such as the static flexor tenodesis. These procedures provided the basic functions of grasp and pinch. Tendon transfers were developed to accomplish both digital release and gripping functions in two surgical stages. The originators of these procedures were Lipscomb et al. [20], Zancolli, House et al. House et al. contributed important clinical investigations while showing the value of different surgical procedures. According to Zancolli, transfer of the m. brachioradialis to the m. extensor carpi radialis tendons was proposed by Vulpius and Stoffel in 1920. In tetraplegia, this was first proposed by Wilson. and first described fully by Freehafer. In 1967, Alvin Freehafer of Cleveland, Ohio, contributed valuable ideas towards achieving independence in the arms of tetraplegic patients. He and his team published the results of six patients who underwent transfer of the m. brachioradialis to restore active wrist extension. In 1974, Freehafer et al. recommended opposition transfers and finger-flexion transfers. In 1971, surgery of the tetraplegic upper limb experienced a revival after Moberg's clinical investigations. His main contributions were (1) to restore elbow extension through transfer of the posterior deltoid to triceps (the initial procedure); and (2) to reconstruct a key pinch. Moberg's idea of posterior deltoid transfer to restore elbow extension has been used extensively by many surgeons, such as Bryan and DeBenedetti. In 1983, Douglas Lamb of Edinburgh, Scotland, gave great headway to surgery of the tetraplegic upper extremity when Lamb and Chan recommended reconstruction of elbow extension by transferring the posterior deltoid to the triceps according to Moberg's technique, which was published in 1975. A publication by Friedenberg was the starting point for future indications of biceps-to-triceps transfers, including those of Zancolli, Hentz et al., Kuts et al., Allieu et al. and Revol et al. Another major change was the change to one-step procedures, reconstructiong opening and closing phases at the same time. Especially Jan Friden, from Gothenburg, with major experience in this area championed this thought, partially driven by the transport problems in Sweden during winter, it saved the patients an operation and minimized hospital stay. The development of hand surgery for tetraplegia has received important contributions through published reports and by the international conferences initiated with the influence of Erik Moberg from Goteborg, Sweden. Conferences have been of great interest because of the convergences of hand surgeons interested in the field, promoting discussion and comparison of different surgical methods and experiences. == Goals for surgery == A common goal of surgical reconstruction of the arms in patients with tetraplegia is to restore elbow extension, key pinch and palmar grip. Restoration of these functions, results in increasing a patient's independence. Elbow extension is an important part of upper limb surgical reconstruction in patients with tetraplegia. Although gravity can extend the arm, active elbow extension is needed to maintain a stable arm while extended in space. This is needed to reach for something or replace an object. Other functional gains include: increasing available workspace, performing pressure relief maneuvers, propelling a manual wheelchair, enhancing self-care and leisure activities, and promoting independent transfer. Elbow extension against gravity further enhances these activities above the shoulder level and reachable workspace. The key pinch is a simple grasp in which the thumb applies force to an object to hold it against the lateral side of the index finger. Restoring this function allows a patient to hold objects such as a fork or pen that are necessary for activities of daily living such as eating, self-grooming and self-catheterization. Palmar grip allows the patient to grasp objects in the palm of the hand and secure the object by flexing the fingers at the metacarpal joint. This gives the patient the possibility to hold objects such as a cup and also permits use of the hand for wheelchair propulsion. A social aspect of regaining the palmar grip is that the patient is able to give a handshake. == Classification of the injury == Spinal cord injuries are classified as complete and incomplete by the American Spinal Injury Association (ASIA) classification. The ASIA scale grades patients based on their functional impairment as a result of the injury, grading a patient from A to D. This has considerable consequences for surgical planning and therapy. More information on classification of tetraplegia can be found on the tetraplegia page. == Pre-operative assessment == A group of hand surgeons realized in the 1970s that the level of injury did not predict the number of available muscles in the upper limb very well. Therefore, the international classification was established in 1979, at the Edinburgh meeting. It was called "The international classification (IC) of hand surgery in tetraplegic patients" (table 2) and it describes the number of possible transferable muscles. To measure and evaluate hand strength each muscle is tested and all muscles with a BMRC grade of M4 or more are recorded. Table 2: International Classification of Hand surgery in Tetraplegic Patients A muscle not included in the International Classification, but of great importance, is the triceps muscle. When assessing a patient pre-operatively the triceps strength must also be recorded. An active triceps means a patient can reach in space, and the elbow can be stabilized against gravity and against other muscles to be transferred. (see further) Furthermore, to classify patients it is essential to record sensation in at least the thumb and index pulpa. Patients with a two point discrimination of less than 10mm are classified as cutaneous sensation (OCu) and patients with a two-point discrimination of more than 10mm are classified as ocular sensation (O) (meaning that control of the to be operated limb cannot be performed by normal sensation, but is controlled visually). Therefore, patients are classified as: O or OCu, IC gr(0-X), Triceps + or – For example: a patient has sensation of 8 mm in thumb and index pulpa, and has a good brachioradialis, extensor carpi radialis longus and brevis and a pronator teres (all of M4) but no Triceps. This patient is classified as OCu 4, Tr -. == Patient oriented goals == The pre-operative assessment of patients has turned more patient-goal oriented. This means that the patients are asked to define their goals before surgery. In order to evaluate this the Canadian Occupational Performance Measure (COPM) was developed. This test is based on the World Health Organisation's framework of measuring health and disability: The International Classification of Function (ICF): This framework measures health and disability by means of two lists: a list of body functions and structure, and a list of domains of activity and participation. Functional deficits can be measured according to the level of loss of structure and function, the level of activity limitations, and the level of restriction in social participation. Reaching or gripping represents the integration of strength, sensation and range of motion, and therefore occur at the individual level rather than at the organ system level. For this reason, reaching and gripping are on the ICF level of activities. However, this level includes a broad range of activities, from basic activities (for example grasping and moving objects) to complex activities (such as dressing, grooming). It is useful to make a distinction between basic activities and complex activities. === COPM === As mentioned above, The Canadian Occupational Performance Measure (COPM) is used to measure a tetraplegic patient's performance and satisfaction before and after upper limb surgery. This is done by identifying important goals of hand surgery and evaluating patient-perceived performance and satisfaction of hand surgery for these goals. Goals are identified through an interview between the therapist and the patient based on past experience. Published reports are provided about the expected outcomes of elbow extension transfers on strength and function of patients with a spinal cord injury. For each goal, the subject rated performance and satisfaction using a 10-point Likert scale, in which 1 was negative ("cannot perform", "not satisfied") and 10 was positive ("performs very well", "very satisfied"). After surgery, performance and satisfaction are rated again for each goal. A positive change is seen in patient-perceived performance and satisfaction with self-identified goals after tendon transfers. A good example of the use of the COPM can be found in a report published by Scott Kozin, thirty-three goals for surgery were established. Following the biceps-to-triceps transfer, improvement in at least one goal was seen in all patients. Performance and satisfaction were greatly improved (an improvement of at least 4 points) in certain activities of daily living, including reaching for objects, recreational activities, wheelchair propulsion, and transfers. Although improvement was seen in most goals, a reduction was reported in 2 goals (one pertaining to dressing and the other to transfer). After tendon transfers, the total mean score statistically increased from 2.6 to 5.6 for performance (p .001) and from 1.8 to 5.7 for satisfaction (p .001). == Criteria for surgery == General indications for functional surgery of the hand and arm in tetraplegic patients: There are different views on optimal timing of surgery after a spinal cord injury. The general consensus is to operate the patient when he or she is neurologically stable. Some surgeons try to operate a patient as early as possible. The advantages of this are that the patient can take advantage of the new functional possibilities before new adjustments and adaptations develop. Other surgeons operate when it becomes feasible. This is usually 12–18 months after injury (can be shortened to 6–7 months) and only after stabilization of motor function. Important spasticity (see further) and neurovegetative complications (i.e. bladder function, bowel function, pulmonary function and pressure sores) must have been treated already. The patient must be able to sit in a wheelchair so that he/she can move the arm against gravity. Usually a compromise is found between the patient's wishes and the surgeon when timing the surgery. An indication for biceps-to-triceps surgery is when the patient plateaud for more than 3 months in their motor recovery. It is usually the choice of procedure for patients who have a flexion contractures greater than 45 degrees. The procedure will release the contracture and allows for active flexion by transferring the biceps. It is important that the psychological condition of the patient is evaluated before surgery. The dramatic change in the patient's life requires a psychological adjustment. This should be evaluated and addressed before surgery. Follow-up by a psychologist is necessary. Patient must be psychologically ready to understand the surgical planning, aims and possible outcomes. The patient must be motivated, well-informed, in sound psychological condition and must have a precise and realistic need for rehabilitation. Individual factors must be taken into account. (age, profession, hobbies, education, family support and social background). This is especially important in associated brain injury. === Contraindications === Contraindications for surgery are severe pressure sores, severe spasticity, inability to stabilize the trunk. Spasticity, if present, can be very important. It is not a contraindication per se, but severe spasticity must be treated first depending in which muscle groups it is present. Spascticity can be treated with botox or myotomies. In some cases spastic tone can be useful to facilitate hand grasp and grip. Harmful spasticity that does not respond to medication or surgical treatment is a contraindication. The shoulder muscles, pectoralis major and latissimus dorsi, must be evaluated. The shoulder must not only have good motor condition but also good proprioceptive control. The trophicity and articular condition of the upper limb must also be considered. A poor condition requires a preoperative rehabilitation program. Before any hand surgery is performed, the patient should be able to actively extend the elbow. Therefore, if there is no active elbow extension, elbow extension reconstruction surgery should precede any hand surgery. A contraindication specifically for posterior deltoid to triceps transfer is a flexion contracture of the elbow, biceps to triceps transfer might then be a possible transfer for elbow extension reconstruction. The contraindications for biceps-to-triceps transfer relate to the muscle balance surrounding the elbow. The m. supinator and m. brachialis function is a prerequisite for this surgery. If one of these muscles is nonfunctional the patient will lose forearm supination and elbow flexion if the tendon is transferred. == Surgical procedures – active and passive tendon transfers == In general, reconstruction of the upper limb can only be performed if active elbow extension is present. This stabilizes the elbow and gives the patient a reach. It will also allow the transfer of the other muscles crossing the elbow joint (like the m. brachioradialis and m. extensor carpi radialis longus). It is also an operation whose results allow the patient to gain confidence in the rest of the treatment. Wrist-related tenodesis effect (Tenodesis grasp) means that wrist flexion passively opens the hand and wrist extension passively closes the hand. (see pictures below) Wrist-related tenodesis effect is the key point of any functional surgery in a paralyzed hand, therefore active wrist extension is required and reconstruction of this active wrist extension is of utmost importance for the tetraplegic hand. If no active wrist extension is available (IC group 0 and 1), the brachioradialis (only IC group 1) can be transferred to achieve wrist extension. Active tendon transfers are possible if m. extensor carpi radialis longus and m. extensor carpi radialis brevis are present. The use of the m. extensor carpi radialis longus and the m. brachioradialis are possible to restore hand function. === Techniques === ==== Elbow ==== There are two major techniques used to gain elbow extension. Deltoid-to-triceps transfer: For this transfer, the posterior part of the deltoid muscle is released from its origin and attached to the triceps muscle (usually by means of a tendon graft or a synthetic graft) leaving the rest of the deltoid muscle intact. This transfer is usually very successful because the line of pull of the posterior deltoid muscle is in the same direction as the triceps muscle. Also, there is hardly any loss of function. The deltoid muscle is usually innervated by the fifth and sixth cervical nerve roots and is therefore often functional in patients with tetraplegia, though the triceps muscle, which is innervated by the seventh cervical root, is paralysed. Because of the location at the back of the arm, the posterior part of the deltoid muscle can give strength in the same direction as the triceps muscle and is therefore theoretically a good donor to regain elbow extension. Not only the direction of the strength provided by the donormuscle is important, Smith et al. showed that the matching between the original functional properties of the donor and recipient muscles affects the outcome of the transfer. Therefore, Fridén studied the architectural properties of the deltoid and triceps muscle in cadavers and concluded that the posterior deltoid would be a very suitable transfer to provide elbow extension. Since the tendon of the triceps is not long enough to reach the posterior deltoid muscle, an interposition graft is needed. Different procedures have been described to achieve the transfer. Moberg used free tendon grafts from the long toe extensors to connect the posterior deltoid to the triceps, other interposition grafts have been described, including fascia lata and a triceps tendon turnup. One should keep in mind that many patients hold out a hope for a cure and are therefore concerned about incurring a significant donor defect that could cause impairment if they recovered a lowerextremity function. The first part of the surgery should be to make an incision along the posterior border of the deltoid. The muscle is exposed to its insertion on the humerus. Next the part of the muscles that originates from the spina scapulae, the posterior one third to one half, is isolated from the anterior portion of the muscle. The insertion of the posterior deltoid is then elevated of the muscle and the distance between the mobilized deltoid tendon to the olecranon is measured to determine the length of the interposition graft needed. The interposition graft must now be harvested from its donor site. It should be 5 to 10 cm longer than the gap. After this a longitudinal incision should be made over the triceps tendon in which two transverse slits are made. One end of the graft should be wrapped around the posterior deltoid and sutured securely to it, after which the grafted is passed through an intercutaneous tunnel towards the triceps tendon, woven through the transverse slits and sutured securely to the triceps tendon and itself. Once the graft is securely in place, the wound is closed and a long armcast is applied with the elbow at 10 degrees of flexion. This tendon transfer has a high risk of being stretched, during the postsurgical period. It is extremely important that a challenging and precise post-surgical rehabilitation program is implemented, in order to maximize the results and prevent the tendon from becoming stretched. Biceps-to-triceps transfer: The biceps muscle can only be used for this transfer if the other elbow flexors are intact (m. brachialis and m. brachioradialis). This procedure is typically performed under general anesthesia but can be performed under supraclavicular brachial plexus blockade. The incision depends on whether there is a contracture that needs to be released. If this is the case a wide exposure of the anterior side of the elbow joint is needed. The distal side of the incision should allow complete dissection of the tendon of the biceps. The primary tendon of the biceps is released from its insertion on the radius and then rerouted medial or lateral. If the ulnar nerve is functional a lateral route is favored to prevent compression, however, the lateral route can cause compression of the radial nerve. A second incision is made to expose the triceps insertion and the triceps is dissected from its insertion on the olecranon. A hole is then drilled in the olecranon and a gauge wire is then looped in the hole. The biceps is routed through a skin tunnel to the posterior side and woven into the triceps tendon to create more length. Then the tendon is inserted to the olecranon. ==== Hand ==== Restoration of key pinch: In general for key pinch the thumb has to be activated. In the lower groups according to the International Classification (IC groups 0–1) this can be done onyby means of tenodesis. In IC groups 2 and higher the m. brachioradialis is used to strengthen the thumb flexor. Usually the thumb extensor is fixed to the extensor retinaculum and the carpometacarpal joint is fused in the right position. Restoration of palmar grip: When active wrist extension is present, it must not be weakened. Therefore, the extensor carpi radialis longus can only be used on patients in IC 3 and higher where active extension is supplied by both the extensor carpi radialis longus and the extensor carpi radialis brevis. In IC 2 patients active extension of the wrist depends only on the m. extensor carpi radialis longus, therefore this muscle must not be used for a transfer in this group of patients. The brachioradialis muscle is a versatile motor muscle and is used for different transfers in tetraplegic patients. In IC 1 it is used to restore wrist extension, while in IC 2–8 it is used to restore finger extension (m.extensor digitorum communis) and finger (m.flexor digitorum profundus) or thumb flexion (m.flexor pollicis longus). Surgical techniques in this type of hand surgery are mainly the same for the different transfers. Technique for transferring the m. extensor carpi radialis longus: the m. extensor carpi radialis longus tendon is divided at its insertion on the second metacarpal. The muscle is separated, and freed entirely from the surrounding tissues. The m. extensor carpi radialis longus tendon is strongly attached to the planned tendon under maximum tension. The m. extensor carpi radialis longus can be transferred to the flexor digitorum profundus or flexor pollicis longus. Technique for transferring the m. brachioradialis: The brachioradialis is freed entirely from the surrounding tissues up to the elbow to get extra excursion. The brachioradialis tendon is strongly attached to the planned tendon. == Rehabilitation == The post-operative regimens depend on the surgical procedures used. However, they tend to constrain the tetraplegic patient considerably. During most regimens they are not allowed to drive hand-driven wheelchairs, or to make transfers alone, because of the risk of rupturing a tendon suture. In general the elbow extension reconstructions are immobilised for a few weeks and then slowly allowed to flex the elbow in the following weeks, at a rate of 10 degrees per week. After 10 weeks the patient is allowed to move freely again. After the posterior deltoid-triceps transfer, a cast is applied with the elbow at 10 degrees of flexion. The cast should be worn for 4 to 6 weeks and then exchanged for an elbow brace with an adjustable range of motion. After the biceps-to-triceps surgery the patient's arm is immobilized for 3–5 weeks in slight flexion, this only counts for patient who could fully extend their arm before the operation. Otherwise the patient is immobilized in maximum extension and casted. This stays on for 10–14 days and a second cast is applied in further extension. After the immobilization the patient is given a protective polyaxial brace, which allows the patient to begin active limited flexion and still keep the full extension. This brace is worn by day and at night the patient wears a semi-firm splint that keeps the arm in maximal extension. With the emergence of the one step procedures for the hand, the post-operative rehabilitation programmes became even more important, since early movement is essential. Patients are mobilised 24 hrs post-operatively, with protective splints. The regimen takes approximately 12 weeks, before the hand is allowed to be fully loaded. Patients are not required to stay as an in-patient for the entire regimen, but can be treated as an outpatient after 1–4 weeks, depending on the centre where the procedures are performed. == References ==	Wikipedia/Tetraplegic_upper_limb_surgery
Microsurgery is a general term for surgery requiring an operating microscope. The most obvious developments have been procedures developed to allow anastomosis of successively smaller blood vessels and nerves (typically 1 mm in diameter) which have allowed transfer of tissue from one part of the body to another and re-attachment of severed parts. Microsurgical techniques are utilized by several specialties today, such as general surgery, ophthalmology, orthopedic surgery, gynecological surgery, otolaryngology, neurosurgery, oral and maxillofacial surgery, endodontic microsurgery, plastic surgery, podiatric surgery and pediatric surgery. == History == Otolaryngologists were the first physicians to use microsurgical techniques. A Swedish otolaryngologist, Carl-Olof Siggesson Nylén (1892–1978), was the father of microsurgery. In 1921, in the University of Stockholm, he built the first surgical microscope, a modified monocular Brinell-Leitz microscope. At first he used it for operations in animals. In November of the same year he used it to operate on a patient with chronic otitis who had a labyrinthine fistula. Nylen's microscope was soon replaced by a binocular microscope, developed in 1922 by his colleague Gunnar Holmgren (1875–1954). Gradually the operating microscope began to be used for ear operations. In the 1950s many otologists began to use it in the fenestration operation, usually to perfect the opening of the fenestra in the lateral semicircular canal. The revival of the stapes mobilization operation by Rosen, in 1953, made the use of the microscope mandatory, although it was not used by the originators of the technique, Kessel (1878), Boucheron (1888) and Miot (1890). Mastoidectomies began to be performed with the surgical microscope and so were the tympanoplasty techniques that became known in the early 1950s. The stapes mobilization operation had varying results and was soon replaced by stapedectomy, first described by John Shea, Jr.; this was an operation that was always performed with the microscope. Today neurosurgeons are very proud to use microscopes in their procedures. But it was not always so: many prestigious centers did not accept that idea and it had to be developed in relative isolation. In the late 1950s William House began to explore new techniques for temporal bone surgery. He developed the middle fossa approach and perfected the translabyrinthine approach and began to use these techniques to remove acoustic nerve tumors. The first neurosurgeon to make use of the surgical microscope was a Turkish emigrant, Gazi Yasargil. In 1953 he studied neurovascular surgery during work with Prof. Hugo Krayenbühl in Switzerland. His ideas interested Dr. Pete Donaghy, who invited Yasargil to his microvascular laboratory in Burlington, Vermont. After his return to Zürich in 1967 Yasargil concentrated on discovering clinical applications to their novel inventions. Publications on that topic: Micro-Vascular Surgery and Microsurgery Applied to Neurosurgery won him international recognition. His lifelong experiences with microsurgery were recapitulated in the four-volume textbook entitled simply Microneurosurgery. Advances in the techniques and technology that popularized microsurgery began in the early 1960s to involve other medical areas. The first microvascular surgery, using a microscope to aid in the repair of blood vessels, was described by vascular surgeon, Julius H. Jacobson II of the University of Vermont in 1960. Using an operating microscope, he performed coupling of vessels as small as 1.4 mm and coined the term microsurgery. Hand surgeons at the University of Louisville, Drs. Harold Kleinert and Mort Kasdan, performed the first revascularization of a partial digital amputation in 1963. Nakayama, a Japanese cardiothoracic surgeon, reported the first true series of microsurgical free-tissue transfers using vascularized intestinal segments to the neck for esophageal reconstruction after cancer resections using 3–4 mm vessels. Contemporary reconstructive microsurgery was introduced by an American plastic surgeon, Dr. Harry J. Buncke. In 1964, Buncke reported a rabbit ear replantation, famously using a garage as a lab/operating theatre and home-made instruments This was the first report of successfully using blood vessels 1 millimeter in size. In 1966, Buncke used microsurgery to transplant a primate's great toe to its hand. During the late sixties and early 1970s, plastic surgeons ushered in many new microsurgical innovations that were previously unimaginable. The first human microsurgical transplantation of the second toe to thumb was performed in February 1966 by Dr. Dong-yue Yang and Yu-dong Gu, in Shanghai, China. Great toe (big toe) to thumb was performed in April 1968 by Dr. John Cobbett, in England. In Australia work by Dr. Ian Taylor saw new techniques developed to reconstruct head and neck cancer defects with living bone from the hip or the fibula. A number of surgical specialties use microsurgical techniques. Otolaryngologists (ear, nose, throat and head and neck surgeons) perform microsurgery on structures of the inner ear and the vocal cords. Otolaryngologists and maxillofacial surgeons use microsurgical techniques when reconstructing defects from resection of head and neck cancers. Cataract surgery, corneal transplants, and treatment of conditions like glaucoma are performed by ophthalmologists. Urologists and gynecologists frequently now reverse vasectomies and tubal ligations to restore fertility. == Free tissue transfer == Free tissue transfer is a surgical reconstructive procedure using microsurgery. A region of "donor" tissue is selected that can be isolated on a feeding artery and vein; this tissue is usually a composite of several tissue types (e.g., skin, muscle, fat, bone). Common donor regions include the rectus abdominis muscle, latissimus dorsi muscle, fibula, radial forearm bone and skin, and lateral arm skin. The composite tissue is transferred (moved as a free flap of tissue) to the region on the patient requiring reconstruction (e.g., mandible after oral cancer resection, breast after cancer resection, traumatic tissue loss, congenital tissue absence). The vessels that supply the free flap are anastomosed with microsurgery to matching vessels (artery and vein) in the reconstructive site. The procedure was first done in the early 1970s and has become a popular "one-stage" (single operation) procedure for many surgical reconstructive applications. == Replantation == Replantation is the reattachment of a completely detached body part. Fingers and thumbs are the most common but the ear, scalp, nose, face, arm and penis have all been replanted. Generally replantation involves restoring blood flow through arteries and veins, restoring the bony skeleton and connecting tendons and nerves as required. Robert Malt and Charles Mckhann reported the first replantation of two human upper extremities by microvascular means in 1964, with the first arm replanted in a child after a train injury in 1962 in Boston. Initially, when the techniques were developed to make replantation possible, success was defined in terms of a survival of the amputated part alone. However, as more experience was gained in this field, surgeons specializing in replantation began to understand that survival of the amputated piece was not enough to ensure success of the replant. In this way, functional demands of the amputated specimen became paramount in guiding which amputated pieces should and should not be replanted. Additional concerns about the patient's ability to tolerate the long rehabilitation process that is necessary after replantation both on physical and psychological levels also became important. So, when fingers are amputated, for instance, a replantation surgeon must seriously consider the contribution of the finger to the overall function of the hand. In this way, every attempt will be made to salvage an amputated thumb, since a great deal of hand function is dependent on the thumb, while an index finger or small finger might not be replanted, depending on the individual needs of the patient and the ability of the patient to tolerate a long surgery and a long course of rehabilitation. However, if an amputated specimen is not able to be replanted to its original location entirely, this does not mean that the specimen is unreplantable. In fact, replantation surgeons have learned that only a piece or a portion may be necessary to obtain a functional result, or especially in the case of multiple amputated fingers, a finger or fingers may be transposed to a more useful location to obtain a more functional result. This concept is called "spare parts" surgery. == Transplantation == Microsurgical techniques have played a crucial role in the development of transplantation immunological research because it allowed the use of rodent models, which are more appropriate for transplantation research (there are more reagents, monoclonal antibodies, knockout animals, and other immunological tools for mice and rats than other species). Before it was introduced, transplant immunology was studied in rodents using the skin transplantation model, which is limited by the fact that it is not vascularized. Thus, microsurgery represents the link between surgery and transplant immunological research. The first microsurgical experiments (porto-caval anastomosis in the rat) were performed by Dr. Sun Lee (pioneer of microsurgery) at the University of Pittsburgh in 1958. After a short time, many models of organ transplants in rat and mice have been established. Today, virtually every rat or mouse organ can be transplanted with relative high success rate. Microsurgery was also important to develop new techniques for transplantation, that would be later performed in humans. In addition, it allows reconstruction of small arteries in clinical organ transplantation (e.g. accessory arteries in cadaver liver transplantation, polar arteries in renal transplantation and in living liver donor transplantation). == Treatment of infertility == Microsurgery has been used to treat several pathologic conditions leading to infertility such as tubal obstructions, vas deferens obstructions, and varicocele, which is one of the most frequent cause of male infertility. Microsurgical drainages by placing microvascular bypasses between spermatic and inferior epigastric veins as proposed by Flati et al. have been successfully performed in treating male infertility due to varicocele. Microsurgical treatment has been shown to significantly improve fertility rate also in patients with recurrent varicocele who had previously undergone non-microsurgical treatments. == References == == External links == E-Medicine Microsurgery Principles Video recorded through Microscope of Ulnar Artery Repaired using Microsurgical Techniques	Wikipedia/Microvascular_surgery
Transforming growth factor beta (TGF-β) is a multifunctional cytokine belonging to the transforming growth factor superfamily that includes three different mammalian isoforms (TGF-β 1 to 3, HGNC symbols TGFB1, TGFB2, TGFB3) and many other signaling proteins. TGFB proteins are produced by all white blood cell lineages. Activated TGF-β complexes with other factors to form a serine/threonine kinase complex that binds to TGF-β receptors. TGF-β receptors are composed of both type 1 and type 2 receptor subunits. After the binding of TGF-β, the type 2 receptor kinase phosphorylates and activates the type 1 receptor kinase that activates a signaling cascade. This leads to the activation of different downstream substrates and regulatory proteins, inducing transcription of different target genes that function in differentiation, chemotaxis, proliferation, and activation of many immune cells. TGF-β is secreted by many cell types, including macrophages, in a latent form in which it is complexed with two other polypeptides, latent TGF-beta binding protein (LTBP) and latency-associated peptide (LAP). Serum proteinases such as plasmin catalyze the release of active TGF-β from the complex. This often occurs on the surface of macrophages where the latent TGF-β complex is bound to CD36 via its ligand, thrombospondin-1 (TSP-1). Inflammatory stimuli that activate macrophages enhance the release of active TGF-β by promoting the activation of plasmin. Macrophages can also endocytose IgG-bound latent TGF-β complexes that are secreted by plasma cells and then release active TGF-β into the extracellular fluid. Among its key functions is regulation of inflammatory processes, particularly in the gut. TGF-β also plays a crucial role in stem cell differentiation as well as T-cell regulation and differentiation. Because of its role in immune and stem cell regulation and differentiation, it is a highly researched cytokine in the fields of cancer, auto-immune diseases, and infectious disease. The TGF-β superfamily includes endogenous growth inhibiting proteins; an increase in expression of TGF-β often correlates with the malignancy of many cancers and a defect in the cellular growth inhibition response to TGF-β. Its immunosuppressive functions then come to dominate, contributing to oncogenesis. The dysregulation of its immunosuppressive functions is also implicated in the pathogenesis of autoimmune diseases, although their effect is mediated by the environment of other cytokines present. == Structure == The primary 3 mammalian types are: TGF beta 1 – TGFB1 TGF beta 2 – TGFB2 TGF beta 3 – TGFB3 A fourth member of the subfamily, TGFB4, has been identified in birds and a fifth, TGFB5, only in frogs. The peptide structures of the TGF-β isoforms are highly similar (homologies on the order of 70–80%). They are all encoded as large protein precursors; TGF-β1 contains 390 amino acids and TGF-β2 and TGF-β3 each contain 412 amino acids. They each have an N-terminal signal peptide of 20–30 amino acids that they require for secretion from a cell, a pro-region called latency-associated peptide (LAP - Alias: Pro-TGF beta 1, LAP/TGF beta 1), and a 112-114 amino acid C-terminal region that becomes the mature TGF-β molecule following its release from the pro-region by proteolytic cleavage. The mature TGF-β protein dimerizes to produce a 25 KDa active protein with many conserved structural motifs. TGF-β has nine cysteine residues that are conserved among its family. Eight form disulfide bonds within the protein to create a cysteine knot structure characteristic of the TGF-β superfamily. The ninth cysteine forms a disulfide bond with the ninth cysteine of another TGF-β protein to produce a dimer. Many other conserved residues in TGF-β are thought to form secondary structure through hydrophobic interactions. The region between the fifth and sixth conserved cysteines houses the most divergent area of TGF-β proteins that is exposed at the surface of the protein and is implicated in receptor binding and specificity of TGF-β. == Latent TGF-β complex == All three TGF-βs are synthesized as precursor molecules containing a propeptide region in addition to the TGF-β homodimer. After it is synthesized, the TGF-β homodimer interacts with a Latency-Associated Peptide (LAP), a protein derived from the N-terminal region of the TGF-β gene product, forming a complex called Small Latent Complex (SLC). This complex remains in the cell until it is bound by another protein called Latent TGF-β-Binding Protein (LTBP), forming a larger complex called Large Latent Complex (LLC). It is this LLC that gets secreted to the extracellular matrix (ECM). In most cases, before the LLC is secreted, the TGF-β precursor is cleaved from the propeptide but remains attached to it by noncovalent bonds. After its secretion, it remains in the extracellular matrix as an in activated complex containing both the LTBP and the LAP which need to be further processed in order to release active TGF-β. The attachment of TGF-β to the LTBP is by disulfide bond which allows it to remain inactive by preventing it from binding to its receptors . Because different cellular mechanisms require distinct levels of TGF-β signaling, the inactive complex of this cytokine gives opportunity for a proper mediation of TGF-β signaling. There are four different LTBP isoforms known, LTBP-1, LTBP-2, LTBP-3 and LTBP-4. Mutation or alteration of LAP or LTBP can result in improper TGF-β signaling. Mice lacking LTBP-3 or LTBP-4 demonstrate phenotypes consistent to phenotypes seen in mice with altered TGF-β signaling. Furthermore, specific LTBP isoforms have a propensity to associate with specific LAP•TGF-β isoforms. For example, LTBP-4 is reported to bind only to TGF-β1, thus, mutation in LTBP-4 can lead to TGF-β associated complications which are specific to tissues that predominantly involves TGF-β1. Moreover, the structural differences within the LAP's provide different latent TGF-β complexes which are selective but to specific stimuli generated by specific activators. == Activation == Although TGF-β is important in regulating crucial cellular activities, only a few TGF-β activating pathways are currently known, and the full mechanism behind the suggested activation pathways is not yet well understood. Some of the known activating pathways are cell or tissue specific, while some are seen in multiple cell types and tissues. Proteases, integrins, pH, and reactive oxygen species are just few of the currently known factors that can activate TGF-β, as discussed below. It is well known that perturbations of these activating factors can lead to unregulated TGF-β signaling levels that may cause several complications including inflammation, autoimmune disorders, fibrosis, cancer and cataracts. In most cases, an activated TGF-β ligand will initiate the TGF-β signaling cascade as long as TGF-β receptors I and II are available for binding. This is due to a high affinity between TGF-β and its receptors, suggesting why the TGF-β signaling recruits a latency system to mediate its signaling. == Integrin-independent activation == === Activation by protease and metalloprotease === Plasmin and a number of matrix metalloproteinases (MMP) play a key role in promoting tumor invasion and tissue remodeling by inducing proteolysis of several ECM components. The TGF-β activation process involves the release of the LLC from the matrix, followed by further proteolysis of the LAP to release TGF-β to its receptors. MMP-9 and MMP-2 are known to cleave latent TGF-β. The LAP complex contains a protease-sensitive hinge region which can be the potential target for this liberation of TGF-β. Despite the fact that MMPs have been proven to play a key role in activating TGF-β, mice with mutations in MMP-9 and MMP-2 genes can still activate TGF-β and do not show any TGF-β deficiency phenotypes, this may reflect redundancy among the activating enzymes suggesting that other unknown proteases might be involved. === Activation by pH === Acidic conditions can denature the LAP. Treatment of the medium with extremes of pH (1.5 or 12) resulted in significant activation of TGF-β as shown by radio-receptor assays, while mild acid treatment (pH 4.5) yielded only 20-30% of the activation achieved by pH 1.5. === Activation by reactive oxygen species (ROS) === The structure of LAP is important in maintaining its function. Structure modification of LAP can lead to disturb the interaction between LAP and TGF-β and thus activating it. Factors that may cause such modification may include hydroxyl radicals from reactive oxygen species (ROS). TGF-β was rapidly activated after in vivo radiation exposure ROS. === Activation by thrombospondin-1 === Thrombospondin-1 (TSP-1) is a matricellular glycoprotein found in plasma of healthy patients with levels in the range of 50–250 ng/ml. TSP-1 levels are known to increase in response to injury and during development. TSP-1 activates latent TGF-beta by forming direct interactions with the latent TGF-β complex and induces a conformational rearrangement preventing it from binding to the matured TGF-β. == Activation by Alpha(V) containing integrins == The general theme of integrins participating in latent TGF-β1 activation arose from studies that examined mutations/knockouts of β6 integrin, αV integrin, β8 integrin and in LAP. These mutations produced phenotypes that were similar to phenotypes seen in TGF-β1 knockout mice. Currently there are two proposed models of how αV containing integrins can activate latent TGF-β1; the first proposed model is by inducing conformational change to the latent TGF-β1 complex and hence releasing the active TGF-β1 and the second model is by a protease-dependent mechanism. === Conformation change mechanism pathway (without proteolysis) === αVβ6 integrin was the first integrin to be identified as TGF-β1 activator. LAPs contain an RGD motif which is recognized by vast majority of αV containing integrins, and αVβ6 integrin can activate TGF-β1 by binding to the RGD motif present in LAP-β1 and LAP-β3. Upon binding, it induces adhesion-mediated cell forces that are translated into biochemical signals which can lead to liberation/activation of TGFb from its latent complex. This pathway has been demonstrated for activation of TGF-β in epithelial cells and does not associate MMPs. === Integrin protease-dependent activation mechanism === Because MMP-2 and MMP-9 can activate TGF-β through proteolytic degradation of the latent TGF beta complex, αV containing integrins activate TGF-β1 by creating a close connection between the latent TGF-β complex and MMPs. Integrins αVβ6 and αVβ3 are suggested to simultaneously bind the latent TGF-β1 complex and proteinases, simultaneous inducing conformational changes of the LAP and sequestering proteases to close proximity. Regardless of involving MMPs, this mechanism still necessitates the association of integrins and that makes it a non proteolytic pathway. == Signaling pathways == === Canonical signaling: The SMAD pathway === Smads are a class of intracellular signalling proteins and transcription factors for the TGF-β family of signalling molecules. This pathway conceptually resembles the Jak-STAT signal transduction pathway characterized in the activation of cytokine receptors implicated, for example, in the B cell isotype switching pathway. As previously stated, the binding of the TGF-β ligand to the TGF-β receptor, the type 2 receptor kinase phosphorylates and activates the type 1 receptor kinase that activates a signaling cascade. In the case of Smad, receptor-activated Smads are phosphorylated by the type 1 TGF-β receptor kinase, and these go on to complex with other Smads, which is able to translocate into the cell nucleus to induce transcription of different effectors. More specifically, activated TGF-β complexes bind to the type 2 domain of the TGF-β receptor which then recruits and phosphorylates a type 1 receptor. The type 1 receptor then recruits and phosphorylates a receptor regulated SMAD (R-SMAD). The R-SMAD then binds to the common SMAD (coSMAD) SMAD4 and forms a heterodimeric complex. This complex then enters the cell nucleus where it acts as a transcription factor for various genes, including those to activate the mitogen-activated protein kinase 8 pathway, which triggers apoptosis. The SMAD pathway is regulated by feedback inhibition. SMAD6 and SMAD7 may block type I receptors. There is also substantial evidence that TGF-β-dependent signaling via the SMAD-3 pathway is responsible for many of the inhibitory functions of TGF-β discussed in later sections and thus it is implicated in oncogenesis. The Smads are not the only TGF-β-regulated signaling pathways. Non-Smad signaling proteins can initiate parallel signaling that eventually cooperate with the Smads or crosstalk with other major signaling pathways. Among them, the mitogen-activated protein kinase (MAPK) family that include the extracellular-regulated kinases (ERK1 and 2), Jun N-terminal kinases (JNKs) and p38 MAPK play an important role in the TGF-β signaling. ERK 1 and 2 are activated via the Raf-Ras-MEK1/2 pathway induced by mitogenic stimuli such as epidermal growth factor, whereas the JNK and p38 MAPK are activated by the MAPK kinase, activated themselves by the TGF-β-activated kinase-1 (TAK1) upon stress stimuli. === Apoptosis via the DAXX pathway === TGF-β induces apoptosis, or programmed cell death, in human lymphocytes and hepatocytes. The importance of this function is clear in TGF-β deficient mice which experience hyperproliferation and unregulated autoimmunity. In a separate apoptotic pathway from the association of death-associated protein 6 (DAXX) with the death receptor Fas, there is evidence of association and binding between DAXX and type 2 TGF-β receptor kinase, wherein DAXX binds to the C-terminal region of the type 2 TGF-β receptor. The exact molecular mechanism is unknown, but as a general overview, DAXX is then phosphorylated by homeodomain-interacting protein kinase 2 (HIPK2), which then activates apoptosis signal-inducing kinase 1 (ASK1), which goes on to activate the Jun amino-terminal kinase (JNK) pathway and thus apoptosis as seen in the left panel of the adjacent image. == TGFβ receptor inhibitors == Galunisertib is the selective and potent TGFβRI kinase inhibitor. == TGF-β mimic == The parasitic roundworm Heligmosomoides polygyrus secretes a molecule that mimics the ability of mammalian TGF-β to bind to the TGFβR complex and trigger downstream signalling pathways. This molecule, termed Hp-TGM, shares no sequence homology to TGF-β and is secreted by H. polygyrus in a biologically active form. Hp-TGM consists of 5 domains, with the first three shown to crucial for interaction with the TGFβR complex, with functions for domains 4 and 5 not yet known. Importantly, Hp-TGM shows promise as a novel therapeutic as it induces less fibrosis than TGF-β in vivo in mice and can be used to induce populations of human FOXP3+ regulatory T cells that had much greater stability than those induced by TGF-β. == Effects on immune cells == === T lymphocytes === TGF-β1 plays a role in the induction from CD4+ T cells of both induced Treg cells (iTreg cells), which have a regulatory function, and Th17 cells, which secrete pro-inflammatory cytokines. TGF-β1 alone precipitates the expression of FOXP3 and Treg differentiation from activated T helper cells, and the mechanism for this differentiation is unknown for both induced T regulatory cells as well as natural T regulatory cells. In mouse models, the effect of TGF-β1 appears to be age-dependent. Studies show that neutralization of TGF-β1 in vitro inhibits the differentiation of helper T cells into Th17 cells. The role of TGF-β1 in the generation of Th17 cells goes against its dominant conceptualization as an anti-inflammatory cytokine; however, the shared requirement between inflammatory and anti-inflammatory immune cells suggests that an imbalance between these two cell types can be an important link to autoimmunity. Co-activation by IL-6 from activated dendritic cells, which serves to activate the transcription factor STAT3, is required in addition to TGF-β1 for the differentiation of Th17 cells. However, the molecular mechanism of Th17 differentiation is not well understood. Because Th17 cells are distinct from Th1 and Th2 lineages in that they have been shown to be capable of regulatory functions, this is further evidence of TGF-β1's regulatory function in the immune system. === B lymphocytes === TGF-β has mainly inhibitory effects on B lymphocytes. TGF-β inhibits B cell proliferation. The exact mechanism is unknown, but there is evidence that TGF-β inhibits B cell proliferation by inducing the transcription factor Id3, inducing expression of cyclin-dependent kinase inhibitor 21 (a regulator of cell cycle progression through the G1 and S phase), and repressing other key regulatory genes such as c-myc and ATM. CD40, a key surface molecule in the activation of the innate immune response, can induce Smad7 expression to reverse the growth inhibition of B cells induced by TGF-β. TGF-β also blocks B cell activation and promotes class switching IgA in both human and mouse B cells and has an otherwise inhibitory function for antibody production. TGF-β also induces apoptosis of immature or resting B cells; the mechanism is unknown, but may overlap with its anti-proliferation pathway. TGF-β has been shown to downregulate c-myc as it does in the inhibition of B cell proliferation. It is also known to induce NF-κB inhibitor IKBa, inhibiting NF-κB activation. NF-κB is a transcription factor that regulates the production of cytokines like IL-1, TNF-a, and defensins, although its function in apoptosis may be separate from this function. === Macrophages === The general consensus in the literature is that TGF-β stimulates resting monocytes and inhibits activated macrophages. For monocytes, TGF-β has been shown to function as a chemoattractant as well as an upregulator of anti-inflammatory response. However, TGF-β has also been shown to downregulate inflammatory cytokine production in monocytes and macrophages, likely by the aforementioned inhibition of NF-κB. This contradiction may be due to the fact that the effect of TGF-β has been shown to be highly context-dependent. TGF-β is thought to play a role in alternative macrophage activation seen in lean mice, and these macrophages maintain an anti-inflammatory phenotype. This phenotype is lost in obese mice, who have not only more macrophages than lean mice but also classically activated macrophages which release TNF-α and other pro-inflammatory cytokines that contribute to a chronically pro-inflammatory milieu. === Cell cycle === TGF-β plays a crucial role in the regulation of the cell cycle by blocking progress through G1 phase. TGF-β causes synthesis of p15 and p21 proteins, which block the cyclin:CDK complex responsible for retinoblastoma protein (Rb) phosphorylation. Thus, TGF-β blocks advancement through the G1 phase of the cycle. In doing so, TGF-β suppresses expression of c-myc, a gene which is involved in G1 cell cycle progression. == Clinical significance == === Cancer === In normal cells, TGF-β, acting through its signaling pathway, stops the cell cycle at the G1 stage to stop proliferation, induce differentiation, or promote apoptosis. In many cancer cells, parts of the TGF-β signaling pathway are mutated, and TGF-β no longer controls the cell. These cancer cells proliferate. The surrounding stromal cells (fibroblasts) also proliferate. Both cells increase their production of TGF-β. This TGF-β acts on the surrounding stromal cells, immune cells, endothelial and smooth-muscle cells. It causes immunosuppression and angiogenesis, which makes the cancer more invasive. TGF-β1 has been implicated in the process of activating Hepatic Stellate Cells (HSCs) with the magnitude of hepatic fibrosis being in proportion to increase in TGF-β levels. Studies have shown that ACTA2 is associated with TGF-β pathway that enhances contractile properties of HSCs leading to Liver fibrosis. TGF-β also converts effector T-cells, which normally attack cancer with an inflammatory (immune) reaction, into regulatory (suppressor) T-cells, which turn off the inflammatory reaction. Normal tissue integrity is preserved by feedback interactions between different cell types that express adhesion molecules and secrete cytokines. Disruption of these feedback mechanisms in cancer damages a tissue. When TGF-β signaling fails to control NF-κB activity in cancer cells, this has at least two potential effects: first, it enables the malignant tumor to persist in the presence of activated immune cells, and second, the cancer cell outlasts immune cells because it survives in the presence of apoptotic, and anti-inflammatory mediators. Furthermore, forkhead box protein 3 (FOXP3) as a transcription factor is an essential molecular marker of regulatory T (Treg) cells. FOXP3 polymorphism (rs3761548) might be involved in cancer progression like gastric cancer through influencing Tregs function and the secretion of immunomodulatory cytokines such as IL-10, IL-35, and TGF-β. === Tuberculosis === Mycobacterium tuberculosis infection, or tuberculosis, has been shown to result in increased levels of active TGF-β within the lung. Due to the broad range of suppressive effects of TGF-β on immune cells, computer modeling has predicted that TGF-β blockade may improve immune responses and infection outcome. Research in animal models has further shown that TGF-β impairs immune responses and elimination of TGF-β signaling results in an enhanced T cell response and lower bacterial burdens. Thus, therapies which block TGF-β may have the potential to improve therapy for tuberculosis. === Heart disease === One animal study suggests that cholesterol suppresses the responsiveness of cardiovascular cells to TGF-β and its protective qualities, thus allowing atherosclerosis and heart disease to develop, while statins, drugs that lower cholesterol levels, may enhance the responsiveness of cardiovascular cells to the protective actions of TGF-β. TGF-β is involved in regeneration of zebrafish heart. === Marfan syndrome === TGF-β signaling also likely plays a major role in the pathogenesis of Marfan syndrome, a disease characterized by disproportionate height, arachnodactyly, ectopia lentis and heart complications such as mitral valve prolapse and aortic enlargement increasing the likelihood of aortic dissection. While the underlying defect in Marfan syndrome is faulty synthesis of the glycoprotein fibrillin I, normally an important component of elastic fibers, it has been shown that the Marfan syndrome phenotype can be relieved by addition of a TGF-β antagonist in affected mice. This suggests that while the symptoms of Marfan syndrome may seem consistent with a connective tissue disorder, the mechanism is more likely related to reduced sequestration of TGF-β by fibrillin. === Loeys–Dietz syndrome === TGF-β signaling is also disturbed in Loeys–Dietz syndrome which is caused by mutations in the TGF-β receptor. === Obesity and diabetes === TGF-β/SMAD3 signaling pathway is important in regulating glucose and energy homeostasis and might play a role in diabetic nephropathy. As noted above in the section about macrophages, loss of TGF-β signaling in obesity is one contributor to the inflammatory milieu generated in the case of obesity. === Multiple Sclerosis === Induced T regulatory cells (iTreg), stimulated by TGF-β in the presence of IL-2, suppressed the development of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS) via a FOXP3 and IL-10 mediated response. This suggests a possible role for TGF-β and iTreg in the regulation and treatment of MS. Decreased levels of TGF-β have been observed in patients diagnosed with multiple sclerosis. Its role in multiple sclerosis can be explained due to TGF-β role in regulating apoptosis of Th17 cells. When TGF-β levels decrease, they are unable to induce Th17 cells apoptosis. Th17 cells secretes TNF-α, which induces demyelination of the oligodendroglial via TNF receptor 1. The decreased TGF-β levels lead to increased Th17 cells and subsequently increased TNFα levels. As a result, demyelination of neurons occurs. TGF-β have also been observed to induce oligodendrocyte (myelin sheath producing cells) growth. Hence, the decreased TGF-β levels during MS may also prevent remyelination of neurons. === Neurological === Higher concentrations of TGF-β are found in the blood and cerebrospinal fluid of patients with Alzheimer's disease as compared to control subjects, suggesting a possible role in the neurodegenerative cascade leading to Alzheimer's disease symptoms and pathology. The role of TGF-β in neuronal dysfunction remains an active area of research. === Other === Overactive TGF-β pathway, with an increase of TGF-β2, was reported in the studies of patients with keratoconus. There is substantial evidence in animal and some human studies that TGF-β in breast milk may be a key immunoregulatory factor in the development of infant immune response, moderating the risk of atopic disease or autoimmunity. Skin aging is caused in part by TGF-β, which reduces the subcutaneous fat that gives skin a pleasant appearance and texture. TGF-β does this by blocking the conversion of dermal fibroblasts into fat cells; with fewer fat cells underneath to provide support, the skin becomes saggy and wrinkled. Subcutaneous fat also produces cathelicidin, which is a peptide that fights bacterial infections. == See also == Anita Roberts, a molecular biologist who made pioneering observations of TGF-β Ziad Mallat, identified a major atheroprotective role of regulatory T cells and associated anti-inflammatory cytokines, IL-10 and TGF-β == References == == Further reading == Moses HL, Roberts AB, Derynck R (July 2016). "The Discovery and Early Days of TGF-β: A Historical Perspective". Cold Spring Harbor Perspectives in Biology. 8 (7): a021865. doi:10.1101/cshperspect.a021865. PMC 4930926. PMID 27328871. == External links == Description of the TGF beta producing genes at ncbi.nlm.nih.gov Diagram of the TGF beta signaling pathway at genome.ad.jp The TGF-beta system—Nature Reviews Molecular Cell Biology SMART:TGFB domain annotation—European Molecular Biology Laboratory Heidelberg TGF-beta at the U.S. National Library of Medicine Medical Subject Headings (MeSH) Biochemists Solve Structure Of TGF-Beta And Its Receptor. 2008 – shows TGF-β3 dimer in TGFB-receptor Measurement of Human Latent TGF-β1 TGF beta pathway diagram IntroPro Entry - IPR016319	Wikipedia/Transforming_growth_factor_beta
Autologous Endometrial Coculture is a technique of assisted reproductive technology. It involves placing a patient’s fertilized eggs on top of a layer of cells from her own uterine lining, creating a more natural environment for embryo development and maximizing the chance for an in vitro fertilization (IVF) pregnancy. == How Coculture is performed == A typical Coculture cycle consists of the following steps: 1. Once a patient has been deemed an appropriate candidate for the procedure, she undergoes an endometrial biopsy during which a small piece of her uterine lining is removed. 2. The uterine lining sample is sent to a research lab, where it is treated, purified and frozen. 3. The patient then undergoes a typical IVF cycle and is given medication to stimulate egg growth in her ovaries. 4. The patient’s eggs are retrieved and mixed with the sperm. At this time, the lab begins thawing and growing her endometrial cells. 5. Once fertilization is confirmed, the patient’s embryos are placed on top of her own (and now thawed) endometrial cells. 6. Over the next two days, the embryos are closely monitored for growth and development. 7. The patient’s embryos are transferred into her uterus for implantation and pregnancy. == The potential candidate == Coculture can be an effective treatment for patients who have failed previous IVF cycles or who have poor embryo quality. == Advantages == A study of 12,377 embryo cultures showed that endometrial coculture is significantly better than sequential culture media; the rates (fraction) reaching blastocyst stage were 56% versus 46% in the coculture versus the sequential system, respectively, with own oocytes. With eggs from ovum donations, the rates were 71% versus 56%, respectively. Pregnancy rates were 39% vs. 28% and implantation rates were 33% vs. 21%. In addition to being noninvasive and relatively pain free, Coculture can be performed during a short office visit. The procedure also can improve embryo quality and stimulate embryo growth. == Risks == The risks of Coculture are minimal. The procedure has been performed in over 1000 patients with no reported detrimental effects on embryo growth. Complications involving uterine infection or damage caused by endometrial biopsy are extremely rare. == References ==	Wikipedia/Autologous_endometrial_coculture
Controlled ovarian hyperstimulation is a technique used in assisted reproduction involving the use of fertility medications to induce ovulation by multiple ovarian follicles. These multiple follicles can be taken out by oocyte retrieval (egg collection) for use in in vitro fertilisation (IVF), or be given time to ovulate, resulting in superovulation which is the ovulation of a larger-than-normal number of eggs, generally in the sense of at least two. When ovulated follicles are fertilised in vivo, whether by natural or artificial insemination, there is a very high risk of a multiple pregnancy. In this article, unless otherwise specified, hyperstimulation will refer to hyperstimulation as part of IVF. In contrast, ovulation induction is ovarian stimulation without subsequent IVF, with the aim of developing one or two ovulatory follicles. == Procedure == === Response prediction === Response predictors determine the protocol for ovulation suppression as well as dosage of medication used for hyperstimulation. Response prediction based on ovarian reserve confers substantially higher live birth rates, lower total costs and more safety. It is commonly agreed not to exclude anyone from their first IVF attempt only on the basis of poor results on response predictors, as the accuracy of these tests can be poor for the prediction of pregnancy. ==== Antral follicle count ==== The response to gonadotropins may be roughly approximated by antral follicle count (AFC), estimated by vaginal ultrasound, which in turn reflects how many primordial follicles there are in reserve in the ovary. The definition of "poor ovarian response" is the retrieval of less than 4 oocytes following a standard hyperstimulation protocol, that is, following maximal stimulation. On the other hand, the term "hyper response" refers to the retrieval of more than 15 or 20 oocytes following a standard hyperstimulation protocol. The cut-offs used to predict poor responders versus normal versus hyper-responders upon vaginal ultrasonography vary in the literature, with that of likely poor response varying between an AFC under 3 and under 12, largely resulting from various definitions of the size follicles to be called antral ones. The following table defines antral follicles as those about 2–8 mm in diameter: The incidence of poor ovarian response in IVF ranges from 10 to 20%. Older poor responders have a lower range of pregnancy rates compared with younger ones (1.5–12.7 versus 13.0–35%, respectively). Also, the other way around, there is a lower prevalence of poor responders among young women compared to those of advancing age, with 50% of women aged 43–44 years being poor responders. ==== Other response predictors ==== Circulating anti-Müllerian hormone (AMH) can predict excessive and poor response to ovarian stimulation. According to NICE guidelines of in vitro fertilization, an anti-Müllerian hormone level of less than or equal to 5.4 pmol/L (0.8 ng/mL) predicts a low response to ovarian hyperstimulation, while a level greater than or equal to 25.0 pmol/L (3.6 ng/mL) predicts a high response. For predicting an excessive response, AMH has a sensitivity and specificity of 82% and 76%, respectively. Overall it may be superior to AFC and basal FSH. Tailoring the dosage of gonadotrophin administration to AMH level has been shown to reduce the incidence of excessive response and cancelled cycles. Elevated basal follicle stimulating hormone (FSH) levels imply a need of more ampoules of gonadotropins for stimulation, and have a higher cancellation rate because of poor response. However, one study came to the result that this method by itself is worse than only AMH by itself, with live birth rate with AMH being 24%, compared with 18% with FSH. Advanced maternal age causes decreased success rates in ovarian hyperstimulation. In ovarian hyperstimulation combined with IUI, women aged 38–39 years appear to have reasonable success during the first two cycles, with an overall live birth rate of 6.1% per cycle. However, for women aged ≥40 years, the overall live birth rate is 2.0% per cycle, and there appears to be no benefit after a single cycle of COH/IUI. It is therefore recommended to consider in vitro fertilization after one failed COH/IUI cycle for women aged ≥40 years. Body mass index Previous hyperstimulation experiences Length of menstrual cycles, with shorter cycles being associated with poorer response. Previous ovarian surgery. === Hyperstimulation medications === ==== FSH preparations ==== In most patients, injectable gonadotropin preparations are used, usually FSH preparations. The clinical choice of gonadotrophin should depend on availability, convenience and costs. The optimal dosage is mainly a trade-off between the pregnancy rate and risk of ovarian hyperstimulation syndrome. A meta-analysis came to the result that the optimal daily recombinant FSH stimulation dose is 150 IU/day in presumed normal responders younger than 39 years undergoing IVF. Compared with higher doses, this dose is associated with a slightly lower oocyte yield, but similar pregnancy rates and embryo cryopreservation rates. For women predicted to have a poor response, there may not be any benefit to start at a higher FSH dosage than 150 IU per day. When used in medium dosage, a long-acting FSH preparation has the same outcome in regard to live birth rate and risk of ovarian hyperstimulation syndrome as compared to daily FSH. A long-acting FSH preparation may cause decreased live birth rates compared to daily FSH when using low dosages (60 to 120 μg of corifollitropin alfa). Recombinant FSH (rFSH) appears to be equally effective in terms of live birth rate compared to any of the other types of gonadotropin preparations irrespective of the protocol used for ovulation suppression. Typically, approximately 8–12 days of injections are necessary. ==== Alternatives and complements to FSH ==== Administering recombinant hCG in addition to an FSH-preparation has no significant beneficial effect. The hCG is the FSH extracted from the urine in menopausical women. Clomifene, in addition to gonadotropins, may make little or no difference to the live birth rate but may lower the probability of ovarian hyperstimulation syndrome. A systematic review showed that using clomifene citrate in addition to low dose gonadotropin (in a GnRH antagonist protocol as described in the following section) resulted in a trend towards better pregnancy rates and a greater number of oocytes retrieved when compared with a standard high-dose FSH regime. Such a protocol avails for using lower dosages of FSH-preparations, conferring lower costs per cycle, being particularly useful in cases where cost is a major limiting factor. Recombinant luteinizing hormone (rLH) in addition to FSH probably increases pregnancy rates, but it is not certain if the live birth rate is also increased. Using low dose human chorionic gonadotropin (hCG) to replace FSH during the late follicular phase in women undergoing hyperstimulation as part of IVF may make little or no difference to pregnancy rates, and possibly leads to in an equivalent number of oocytes retrieved, but with less expenditure of FSH. Before ovarian stimulation with antagonist protocols, pretreatment with combined oral contraceptive pills probably reduces the rate of live birth or ongoing pregnancy, while it is uncertain whether pretreatment with progesterone only has any effect on live birth or ongoing pregnancy rates. For other stimulation protocols, the evidence around pretreatment with combined oral contraceptives and progesterone only is uncertain. Findings are conflicting, but metformin treatment as a complement in IVF cycles may reduce the risk of ovarian hyperstimulation syndrome and increase live birth rates. === Suppression of spontaneous ovulation === When used in conjunction with in vitro fertilization (IVF), controlled ovarian hyperstimulation confers a need to avoid spontaneous ovulation, since oocyte retrieval of the mature egg from the fallopian tube or uterus is much harder than from the ovarian follicle. The main regimens to achieve ovulation suppression are: GnRH agonist administration given continuously before starting the gonadotropin hyperstimulation regimen. Physiologically, GnRH agonists are normally released in a cyclical fashion in the body to increase normal gonadotropin release, including luteinizing hormone that triggers ovulation, but continuous exogenous administration of GnRH agonists has the opposite effect of causing cessation of physiological gonadotropin production in the body. GnRH antagonist administration, which is typically administered in the mid-follicular phase in stimulated cycles after administration of gonadotropins and prior to triggering final maturation of oocytes. The GnRH antagonists that are currently licensed for use in fertility treatment are cetrorelix and ganirelix. In GnRH antagonist cycles, hyperstimulation medication is typically started on the second or third day of a previous natural menstruation. ==== Agonist vs antagonist ==== Regarding pregnancy rate, choosing GnRH agonist protocol for a cycle is approximately as efficient as choosing GnRH antagonist protocol. Still, the two protocols differ on a number of aspects: Practically, the timing of the hyperstimulation and the day of oocyte retrieval in a GnRH antagonist protocol needs to be timed after the spontaneous initiation of the previous menstrual cycle, while the schedule can be started at a time to meet practical needs in a GnRH agonist protocol. The start of GnRH agonist administration can range from a long protocol of 14 to 18 days prior to gonadotropin administration, to a short protocol where it is started by the time of gonadotropin administration. Its duration can then be from 3 days to final maturation induction. A long GnRH agonist protocol has been associated with a higher pregnancy rate, but there is insufficient evidence for any higher live birth rate, compared to a short GnRH agonist protocol.For GnRH antagonists, administration from the day after the onset of menstruation has been associated with a higher number of mature oocytes compared to starting when follicle diameter reaches 12 mm. Regarding time per cycle, on the other hand, the cycle duration using GnRH antagonist protocol is typically substantially shorter than one using a standard long GnRH agonist protocol, potentially resulting in a higher number of cycles in any given time period, which is beneficial for women with more limited time to become pregnant. Regarding antral follicle count, with the GnRH antagonist protocol initial follicular recruitment and selection is undertaken by endogenous endocrine factors prior to starting the exogenous hyperstimulation. This results in a smaller number of growing follicles when compared with the standard long GnRH agonist protocol. This is an advantage in women expected to be high responders, thereby decreasing the risk of ovarian hyperstimulation syndrome. Regarding subsequent final maturation induction, usage of GnRH agonist protocol necessitates subsequent usage of human chorionic gonadotropin (HCG or hCG) for this purpose, while usage of GnRH antagonist protocol also avails for subsequently using a GnRH agonist for final oocyte maturation. Using a GnRH agonist for final oocyte maturation rather than hCG results in an elimination of the risk of ovarian hyperstimulation syndrome, while having a delivery rate after IVF of approximately 6% less. Unlike the agonist protocol, the antagonist protocol is rapidly reversible because the GnRH receptors are merely blocked but functional. Administration of enough GnRH agonist to compete with the antagonist will result in release of FSH and LH which subsequently increases the release of Estrogen. In GnRH agonist protocol, there is a risk of estrogen deprivation symptoms, e.g. hot flushes, vagina dryness. This is because the pituitary gonadotropic cells are desensitized , i.e. the number of receptors have reduced. Whereas in the antagonist protocol there are no deprivation symptoms because its administration occurs after FSH stimulation has been done therefore there is increased level of estrogen. Thus, in short, a GnRH antagonist protocol may be harder to schedule timewise but has shorter cycle lengths and less (or even eliminated) risk of ovarian hyperstimulation syndrome. GnRH antagonist protocol has overall better results for expected poor and hyper-responders; A study of these protocols in women undergoing their first IVF and having a poor predicted response (by an AMH level below 5 pmol/L by DSL assay), using the GnRH antagonist protocol was associated with a substantial drop in cycle cancellation (odds ratio 0.20) and required fewer days of gonadotrophin stimulation (10 days versus 14 days) compared to GnRH agonist protocol. Using GnRH antagonist protocol in high responders has been associated with significantly higher clinical pregnancy rates (62 versus 32%). The pregnancy rate is probably higher with long-course GnRH protocols compared to short or ultra-short GnRH agonist protocols. There is no evidence that stopping or reducing GnRH agonist administration at the start of gonadotropin administration results in a decrease in pregnancy rate. === Monitoring === There is a concomitant monitoring, including frequently checking the estradiol level and, by means of gynecologic ultrasonography, follicular growth. A Cochrane review (updated in 2021) found no difference between cycle monitoring by ultrasound (TVUS) plus serum estradiol compared to monitoring by ultrasound only relative to pregnancy rates and the incidence of ovarian hyperstimulation syndrome (OHSS). Tracking or supervising the maturation of follicles is performed in order to timely schedule oocyte retrieval. Two-dimensional ultrasound is conventionally used. Automated follicle tracking does not appear to improve the clinical outcome of assisted reproduction treatment. === Retrieval === When used in conjunction with IVF, ovarian hyperstimulation may be followed by final maturation of oocytes, using human chorionic gonadotropin (hCG), or a GnRH agonist if a GnRH antagonist protocol is used for ovulation suppression. A transvaginal oocyte retrieval is then performed just prior to when the follicles would rupture. It is uncertain if coasting, which is ovarian hyperstimulation without induction of final maturation, reduces the risk of OHSS. == Risks == Perhaps the greatest risk associated with controlled ovarian hyperstimulation is ovarian hyperstimulation syndrome (OHSS). OHSS occurs when, following a "trigger" injection for final oocyte maturation, excessive VEGF production by numerous follicles acts systemically. This can result in a shift of fluid from the bloodstream to "third spaces", including the belly and the space around the lungs. This can make it difficult and painful to breathe or move, and in extremely rare cases can be fatal. Severe cases often require hospitalization, removal of fluid from the abdomen, and replacement of fluid in the blood. OHSS is most prevalent in very high responders, almost always those with more than 20 developing ovarian follicles, who are triggered with hCG. One means of greatly reducing OHSS risk is to trigger with GnRH agonist instead of hCG. This results in a surge of LH from the pituitary, the same hormone that matures the eggs in natural cycles. LH has a much shorter half-life than hCG, so that nearly all of the LH is cleared by the time of egg collection, or about 36 hours after trigger. Any developing signs of OHSS will typically vanish at that point. However, in rare cases, severe OHSS can continue to develop. Reduced success rates have been reported in fresh embryo transfers when the agonist trigger is used without hCG, so that most centers will freeze all embryos in cycles triggered only with the agonist. Ovarian hyperstimulation does not seem to be associated with an elevated risk of cervical cancer, nor with ovarian cancer or endometrial cancer when neutralizing the confounder of infertility itself. Also, it does not seem to impact increased risk for breast cancer. == Alternatives == Ovulation induction is ovarian stimulation without subsequent IVF, with the aim of developing one or two ovulatory follicles (the maximum number before recommending sexual abstinence in such treatments). It is cheaper and easier to perform than controlled ovarian hyperstimulation, and is therefore the preferred initial stimulation protocol in menstrual disorders including anovulation and oligoovulation. In vitro maturation is letting ovarian follicles mature in vitro, and with this technique ovarian hyperstimulation is not essential. Rather, oocytes can mature outside the body prior to fertilisation by IVF. Hence, gonadotropins does not need to be injected in the body, or at least a lower dose may be injected. However, there is still not enough evidence to prove the effectiveness and safety of the technique. == Notes == == References == == External links == Antral Follicle Counts, Resting Follicles, Ovarian Volume and Ovarian Reserve Advanced Fertility Center of Chicago.	Wikipedia/Controlled_ovarian_hyperstimulation
Intersex people are born with natural variations in physical and sex characteristics including those of the chromosomes, gonads, sex hormones, or genitals that, according to the UN Office of the High Commissioner for Human Rights, "do not fit the typical definitions for male or female bodies". Such variations may involve genital ambiguity, and combinations of chromosomal genotype and sexual phenotype other than XY-male and XX-female. Preimplantation genetic diagnosis allows the elimination of embryos and fetuses with intersex traits and thus has an impact on discrimination against intersex people. == Preimplantation genetic diagnosis == Preimplantation genetic diagnosis (PGD or PIGD) refers to genetic evaluation of embryos and oocytes prior to implantation. When used to screen for a specific genetic condition, the method also makes it possible to select embryos with intersex conditions for termination. Some national authorities, such as the UK Human Fertilization and Embryology Authority, maintain lists of conditions for which PGD is permissible, including intersex conditions such as 5 alpha reductase deficiency, androgen insensitivity syndrome, congenital adrenal hyperplasia and others. Surgical interventions on children with intersex conditions are contentious and may lead to selection for other traits like same sex attraction. Robert Sparrow states that intersex conditions are comparable to sexual orientation in that harms may be associated with a "hostile social environment". He concluded that the acceptability of elimination of intersex conditions has "uncomfortable" implications for "other nonpathological human variations" that do not affect physical health. Organisation Intersex International Australia has quoted research showing pregnancy termination rates of up to 88% in 47,XXY even while the World Health Organization describes the trait as "compatible with normal life expectancy", and "often undiagnosed". In 2014, it called for the Australian National Health and Medical Research Council to prohibit such interventions, noting a "close entanglement of intersex status, gender identity and sexual orientation in social understandings of sex and gender norms, and in medical and medical sociology literature". In 2016, the organization wrote about the sponsorship of lesbian, gay, bisexual, transgender and intersex (LGBTI) events by IVF clinics in Australia, stating that, in addition to ethical issues raised by the elimination of intersex traits, "sponsorship of "LGBTI" events by such businesses raises more ethical issues still, including the nature of community and comprehension of issues relating to intersex bodily diversity". In response to Sparrow, Georgiann Davis argues that such discrimination fails to recognize that many people with intersex traits led full and happy lives, and that the "intersex community is only "invisible" to those who choose to ignore it", while "the medical profession, not the intersex trait itself, is a major source of the social and psychological harm that perpetuates intersex stigmatization and the "hostile social environment" that individuals with intersex traits encounter". Jeff Nisker links the elimination of intersex conditions to their pathologization, describing how "[o]nce a difference becomes a medical disorder to which the medical profession is dedicating time and resources to prevent, procedures to this end become endowed with appropriateness". Jason Behrmann and Vardit Ravitsky state: "Parental choice against intersex may ... conceal biases against same-sex attractedness and gender nonconformity." In 2014, Morgan Carpenter expressed concern about intersex variations appeared in a list by the Human Fertilisation and Embryology Authority of "serious" "genetic conditions" that may be de-selected in the United Kingdom. These include 5-alpha-reductase deficiency and androgen insensitivity syndrome, traits evident in elite Olympic-level women athletes and "the world's first openly intersex mayor". In 2015, the Council of Europe published an Issue Paper on Human rights and intersex people, remarking on a right to life: Intersex people's right to life can be violated in discriminatory "sex selection" and "preimplantation genetic diagnosis, other forms of testing, and selection for particular characteristics". Such de-selection or selective abortions are incompatible with ethics and human rights standards due to the discrimination perpetrated against intersex people on the basis of their sex characteristics. == Prenatal hormone treatment == Currently, prenatal testing and hormone treatment to prevent the physical and behavioral expression of intersex traits is available. In 1990, a paper by Heino Meyer-Bahlburg titled Will Prenatal Hormone Treatment Prevent Homosexuality? was published in the Journal of Child and Adolescent Psychopharmacology. It examined the use of "prenatal hormone screening or treatment for the prevention of homosexuality" using research conducted on foetuses with congenital adrenal hyperplasia and other traits. Alice Dreger, Ellen Feder, and Anne Tamar-Mattis describe how research published by Saroj Nimkarn and Maria New in 2010 constructs "low interest in babies and men – and even interest in what they consider to be men's occupations and games – as "abnormal", and potentially preventable with prenatal dexamethasone". The authors state that "weak and unsupported conclusions" of investigations into the attempted "prevention of benign behavioral sex variations" indicates gaps in the ethical management of clinical research. In 2012, Hirvikoski and others described a lack of long-term follow-up studies of individuals exposed to prenatal treatment, and the results of a 10-year Swedish study of 43 mothers and children. The authors found evidence of unacceptable side-effects in their study, including neurological consequences. Treatment with dexamethasone was discontinued in Sweden. == See also == Intersex medical interventions Preimplantation genetic diagnosis Sex selection Vaginal anomalies == Notes == == Bibliography == Behrmann, Jason; Ravitsky, Vardit (October 2013). "Queer Liberation, Not Elimination: Why Selecting Against Intersex is Not "Straight" Forward". The American Journal of Bioethics. 13 (10): 39–41. doi:10.1080/15265161.2013.828131. ISSN 1526-5161. PMID 24024805. S2CID 27065247. Council of Europe; Commissioner for Human Rights (April 2015), Human rights and intersex people, Issue Paper Davis, Georgiann (October 2013). "The Social Costs of Preempting Intersex Traits". The American Journal of Bioethics. 13 (10): 51–53. doi:10.1080/15265161.2013.828119. ISSN 1526-5161. PMID 24024811. S2CID 7331095. Nisker, Jeff (October 2013). "Informed Choice and PGD to Prevent "Intersex Conditions"". The American Journal of Bioethics. 13 (10): 47–49. doi:10.1080/15265161.2013.828125. ISSN 1526-5161. PMID 24024809. S2CID 6085229. Organisation Intersex International Australia; Carpenter, Morgan (April 2014). "Submission on the Review of Part B of the Ethical Guidelines for the Use of Assisted Reproductive Technology in Clinical Practice and Research, 2007". Sydney. Sparrow, Robert (October 2013). "Gender Eugenics? The Ethics of PGD for Intersex Conditions". The American Journal of Bioethics. 13 (10): 29–38. doi:10.1080/15265161.2013.828115. ISSN 1526-5161. PMID 24024804. S2CID 41857961.	Wikipedia/Genetic_diagnosis_of_intersex
Pathology is the study of disease. The word pathology also refers to the study of disease in general, incorporating a wide range of biology research fields and medical practices. However, when used in the context of modern medical treatment, the term is often used in a narrower fashion to refer to processes and tests that fall within the contemporary medical field of "general pathology", an area that includes a number of distinct but inter-related medical specialties that diagnose disease, mostly through analysis of tissue and human cell samples. Idiomatically, "a pathology" may also refer to the predicted or actual progression of particular diseases (as in the statement "the many different forms of cancer have diverse pathologies", in which case a more proper choice of word would be "pathophysiologies"). The suffix pathy is sometimes used to indicate a state of disease in cases of both physical ailment (as in cardiomyopathy) and psychological conditions (such as psychopathy). A physician practicing pathology is called a pathologist. As a field of general inquiry and research, pathology addresses components of disease: cause, mechanisms of development (pathogenesis), structural alterations of cells (morphologic changes), and the consequences of changes (clinical manifestations). In common medical practice, general pathology is mostly concerned with analyzing known clinical abnormalities that are markers or precursors for both infectious and non-infectious disease, and is conducted by experts in one of two major specialties, anatomical pathology and clinical pathology. Further divisions in specialty exist on the basis of the involved sample types (comparing, for example, cytopathology, hematopathology, and histopathology), organs (as in renal pathology), and physiological systems (oral pathology), as well as on the basis of the focus of the examination (as with forensic pathology). Pathology is a significant field in modern medical diagnosis and medical research. == Etymology == The Latin term pathology derives from the Ancient Greek roots pathos (πάθος), meaning "experience" or "suffering", and -logia (-λογία), meaning "study of". The term is of early 16th-century origin, and became increasingly popularized after the 1530s. == History == The study of pathology, including the detailed examination of the body, including dissection and inquiry into specific maladies, dates back to antiquity. Rudimentary understanding of many conditions was present in most early societies and is attested to in the records of the earliest historical societies, including those of the Middle East, India, and China. By the Hellenic period of ancient Greece, a concerted causal study of disease was underway (see Medicine in ancient Greece), with many notable early physicians (such as Hippocrates, for whom the modern Hippocratic Oath is named) having developed methods of diagnosis and prognosis for a number of diseases. The medical practices of the Romans and those of the Byzantines continued from these Greek roots, but, as with many areas of scientific inquiry, growth in understanding of medicine stagnated somewhat after the Classical Era, but continued to slowly develop throughout numerous cultures. Notably, many advances were made in the medieval era of Islam (see Medicine in medieval Islam), during which numerous texts of complex pathologies were developed, also based on the Greek tradition. Even so, growth in complex understanding of disease mostly languished until knowledge and experimentation again began to proliferate in the Renaissance, Enlightenment, and Baroque eras, following the resurgence of the empirical method at new centers of scholarship. By the 17th century, the study of rudimentary microscopy was underway and examination of tissues had led British Royal Society member Robert Hooke to coin the word "cell", setting the stage for later germ theory. Modern pathology began to develop as a distinct field of inquiry during the 19th Century through natural philosophers and physicians that studied disease and the informal study of what they termed "pathological anatomy" or "morbid anatomy". However, pathology as a formal area of specialty was not fully developed until the late 19th and early 20th centuries, with the advent of detailed study of microbiology. In the 19th century, physicians had begun to understand that disease-causing pathogens, or "germs" (a catch-all for disease-causing, or pathogenic, microbes, such as bacteria, viruses, fungi, amoebae, molds, protists, and prions) existed and were capable of reproduction and multiplication, replacing earlier beliefs in humors or even spiritual agents, that had dominated for much of the previous 1,500 years in European medicine. With the new understanding of causative agents, physicians began to compare the characteristics of one germ's symptoms as they developed within an affected individual to another germ's characteristics and symptoms. This approach led to the foundational understanding that diseases are able to replicate themselves, and that they can have many profound and varied effects on the human host. To determine causes of diseases, medical experts used the most common and widely accepted assumptions or symptoms of their times, a general principle of approach that persists in modern medicine. Modern medicine was particularly advanced by further developments of the microscope to analyze tissues, to which Rudolf Virchow gave a significant contribution, leading to a slew of research developments. By the late 1920s to early 1930s pathology was deemed a medical specialty. Combined with developments in the understanding of general physiology, by the beginning of the 20th century, the study of pathology had begun to split into a number of distinct fields, resulting in the development of a large number of modern specialties within pathology and related disciplines of diagnostic medicine. == General pathology == The modern practice of pathology is divided into a number of subdisciplines within the distinct but deeply interconnected aims of biological research and medical practice. Biomedical research into disease incorporates the work of a vast variety of life science specialists, whereas, in most parts of the world, to be licensed to practice pathology as a medical specialty, one has to complete medical school and secure a license to practice medicine. Structurally, the study of disease is divided into many different fields that study or diagnose markers for disease using methods and technologies particular to specific scales, organs, and tissue types. === Anatomical pathology === Anatomical pathology (Commonwealth) or anatomic pathology (United States) is a medical specialty that is concerned with the diagnosis of disease based on the gross, microscopic, chemical, immunologic and molecular examination of organs, tissues, and whole bodies (as in a general examination or an autopsy). Anatomical pathology is itself divided into subfields, the main divisions being surgical pathology, cytopathology, and forensic pathology. Anatomical pathology is one of two main divisions of the medical practice of pathology, the other being clinical pathology, the diagnosis of disease through the laboratory analysis of bodily fluids and tissues. Sometimes, pathologists practice both anatomical and clinical pathology, a combination known as general pathology. ==== Cytopathology ==== Cytopathology (sometimes referred to as "cytology") is a branch of pathology that studies and diagnoses diseases on the cellular level. It is usually used to aid in the diagnosis of cancer, but also helps in the diagnosis of certain infectious diseases and other inflammatory conditions as well as thyroid lesions, diseases involving sterile body cavities (peritoneal, pleural, and cerebrospinal), and a wide range of other body sites. Cytopathology is generally used on samples of free cells or tissue fragments (in contrast to histopathology, which studies whole tissues) and cytopathologic tests are sometimes called smear tests because the samples may be smeared across a glass microscope slide for subsequent staining and microscopic examination. However, cytology samples may be prepared in other ways, including cytocentrifugation. ==== Dermatopathology ==== Dermatopathology is a subspecialty of anatomic pathology that focuses on the skin and the rest of the integumentary system as an organ. It is unique, in that there are two paths a physician can take to obtain the specialization. All general pathologists and general dermatologists train in the pathology of the skin, so the term dermatopathologist denotes either of these who has reached a certain level of accreditation and experience; in the US, either a general pathologist or a dermatologist can undergo a 1 to 2 year fellowship in the field of dermatopathology. The completion of this fellowship allows one to take a subspecialty board examination, and becomes a board certified dermatopathologist. Dermatologists are able to recognize most skin diseases based on their appearances, anatomic distributions, and behavior. Sometimes, however, those criteria do not lead to a conclusive diagnosis, and a skin biopsy is taken to be examined under the microscope using usual histological tests. In some cases, additional specialized testing needs to be performed on biopsies, including immunofluorescence, immunohistochemistry, electron microscopy, flow cytometry, and molecular-pathologic analysis. One of the greatest challenges of dermatopathology is its scope. More than 1500 different disorders of the skin exist, including cutaneous eruptions ("rashes") and neoplasms. Therefore, dermatopathologists must maintain a broad base of knowledge in clinical dermatology, and be familiar with several other specialty areas in Medicine. ==== Forensic pathology ==== Forensic pathology focuses on determining the cause of death by post-mortem examination of a corpse or partial remains. An autopsy is typically performed by a coroner or medical examiner, often during criminal investigations; in this role, coroners and medical examiners are also frequently asked to confirm the identity of a corpse. The requirements for becoming a licensed practitioner of forensic pathology varies from country to country (and even within a given nation) but typically a minimal requirement is a medical doctorate with a specialty in general or anatomical pathology with subsequent study in forensic medicine. The methods forensic scientists use to determine death include examination of tissue specimens to identify the presence or absence of natural disease and other microscopic findings, interpretations of toxicology on body tissues and fluids to determine the chemical cause of overdoses, poisonings or other cases involving toxic agents, and examinations of physical trauma. Forensic pathology is a major component in the trans-disciplinary field of forensic science. ==== Histopathology ==== Histopathology refers to the microscopic examination of various forms of human tissue. Specifically, in clinical medicine, histopathology refers to the examination of a biopsy or surgical specimen by a pathologist, after the specimen has been processed and histological sections have been placed onto glass slides. This contrasts with the methods of cytopathology, which uses free cells or tissue fragments. Histopathological examination of tissues starts with surgery, biopsy, or autopsy. The tissue is removed from the body of an organism and then placed in a fixative that stabilizes the tissues to prevent decay. The most common fixative is formalin, although frozen section fixing is also common. To see the tissue under a microscope, the sections are stained with one or more pigments. The aim of staining is to reveal cellular components; counterstains are used to provide contrast. Histochemistry refers to the science of using chemical reactions between laboratory chemicals and components within tissue. The histological slides are then interpreted diagnostically and the resulting pathology report describes the histological findings and the opinion of the pathologist. In the case of cancer, this represents the tissue diagnosis required for most treatment protocols. ==== Neuropathology ==== Neuropathology is the study of disease of nervous system tissue, usually in the form of either surgical biopsies or sometimes whole brains in the case of autopsy. Neuropathology is a subspecialty of anatomic pathology, neurology, and neurosurgery. In many English-speaking countries, neuropathology is considered a subfield of anatomical pathology. A physician who specializes in neuropathology, usually by completing a fellowship after a residency in anatomical or general pathology, is called a neuropathologist. In day-to-day clinical practice, a neuropathologist generates diagnoses for patients. If a disease of the nervous system is suspected, and the diagnosis cannot be made by less invasive methods, a biopsy of nervous tissue is taken from the brain or spinal cord to aid in diagnosis. Biopsy is usually requested after a mass is detected by medical imaging. With autopsies, the principal work of the neuropathologist is to help in the post-mortem diagnosis of various conditions that affect the central nervous system. Biopsies can also consist of the skin. Epidermal nerve fiber density testing (ENFD) is a more recently developed neuropathology test in which a punch skin biopsy is taken to identify small fiber neuropathies by analyzing the nerve fibers of the skin. This test is becoming available in select labs as well as many universities; it replaces the traditional nerve biopsy test as less invasive. ==== Pulmonary pathology ==== Pulmonary pathology is a subspecialty of anatomic (and especially surgical) pathology that deals with diagnosis and characterization of neoplastic and non-neoplastic diseases of the lungs and thoracic pleura. Diagnostic specimens are often obtained via bronchoscopic transbronchial biopsy, CT-guided percutaneous biopsy, or video-assisted thoracic surgery. These tests can be necessary to diagnose between infection, inflammation, or fibrotic conditions. ==== Renal pathology ==== Renal pathology is a subspecialty of anatomic pathology that deals with the diagnosis and characterization of disease of the kidneys. In a medical setting, renal pathologists work closely with nephrologists and transplant surgeons, who typically obtain diagnostic specimens via percutaneous renal biopsy. The renal pathologist must synthesize findings from traditional microscope histology, electron microscopy, and immunofluorescence to obtain a definitive diagnosis. Medical renal diseases may affect the glomerulus, the tubules and interstitium, the vessels, or a combination of these compartments. ==== Surgical pathology ==== Surgical pathology is one of the primary areas of practice for most anatomical pathologists. Surgical pathology involves the gross and microscopic examination of surgical specimens, as well as biopsies submitted by surgeons and non-surgeons such as general internists, medical subspecialists, dermatologists, and interventional radiologists. Often an excised tissue sample is the best and most definitive evidence of disease (or lack thereof) in cases where tissue is surgically removed from a patient. These determinations are usually accomplished by a combination of gross (i.e., macroscopic) and histologic (i.e., microscopic) examination of the tissue, and may involve evaluations of molecular properties of the tissue by immunohistochemistry or other laboratory tests. There are two major types of specimens submitted for surgical pathology analysis: biopsies and surgical resections. A biopsy is a small piece of tissue removed primarily for surgical pathology analysis, most often in order to render a definitive diagnosis. Types of biopsies include core biopsies, which are obtained through the use of large-bore needles, sometimes under the guidance of radiological techniques such as ultrasound, CT scan, or magnetic resonance imaging. Incisional biopsies are obtained through diagnostic surgical procedures that remove part of a suspicious lesion, whereas excisional biopsies remove the entire lesion, and are similar to therapeutic surgical resections. Excisional biopsies of skin lesions and gastrointestinal polyps are very common. The pathologist's interpretation of a biopsy is critical to establishing the diagnosis of a benign or malignant tumor, and can differentiate between different types and grades of cancer, as well as determining the activity of specific molecular pathways in the tumor. Surgical resection specimens are obtained by the therapeutic surgical removal of an entire diseased area or organ (and occasionally multiple organs). These procedures are often intended as definitive surgical treatment of a disease in which the diagnosis is already known or strongly suspected, but pathological analysis of these specimens remains important in confirming the previous diagnosis. === Clinical pathology === Clinical pathology is a medical specialty that is concerned with the diagnosis of disease based on the laboratory analysis of bodily fluids such as blood and urine, as well as tissues, using the tools of chemistry, clinical microbiology, hematology and molecular pathology. Clinical pathologists work in close collaboration with medical technologists, hospital administrations, and referring physicians. Clinical pathologists learn to administer a number of visual and microscopic tests and an especially large variety of tests of the biophysical properties of tissue samples involving automated analysers and cultures. Sometimes the general term "laboratory medicine specialist" is used to refer to those working in clinical pathology, including medical doctors, Ph.D.s and doctors of pharmacology. Immunopathology, the study of an organism's immune response to infection, is sometimes considered to fall within the domain of clinical pathology. ==== Hematopathology ==== Hematopathology is the study of diseases of blood cells (including constituents such as white blood cells, red blood cells, and platelets) and the tissues, and organs comprising the hematopoietic system. The term hematopoietic system refers to tissues and organs that produce and/or primarily host hematopoietic cells and includes bone marrow, the lymph nodes, thymus, spleen, and other lymphoid tissues. In the United States, hematopathology is a board certified subspecialty (licensed under the American Board of Pathology) practiced by those physicians who have completed a general pathology residency (anatomic, clinical, or combined) and an additional year of fellowship training in hematology. The hematopathologist reviews biopsies of lymph nodes, bone marrows and other tissues involved by an infiltrate of cells of the hematopoietic system. In addition, the hematopathologist may be in charge of flow cytometric and/or molecular hematopathology studies. === Molecular pathology === Molecular pathology is focused upon the study and diagnosis of disease through the examination of molecules within organs, tissues or bodily fluids. Molecular pathology is multidisciplinary by nature and shares some aspects of practice with both anatomic pathology and clinical pathology, molecular biology, biochemistry, proteomics and genetics. It is often applied in a context that is as much scientific as directly medical and encompasses the development of molecular and genetic approaches to the diagnosis and classification of human diseases, the design and validation of predictive biomarkers for treatment response and disease progression, and the susceptibility of individuals of different genetic constitution to particular disorders. The crossover between molecular pathology and epidemiology is represented by a related field "molecular pathological epidemiology". Molecular pathology is commonly used in diagnosis of cancer and infectious diseases. Molecular Pathology is primarily used to detect cancers such as melanoma, brainstem glioma, brain tumors as well as many other types of cancer and infectious diseases. Techniques are numerous but include quantitative polymerase chain reaction (qPCR), multiplex PCR, DNA microarray, in situ hybridization, DNA sequencing, antibody-based immunofluorescence tissue assays, molecular profiling of pathogens, and analysis of bacterial genes for antimicrobial resistance. Techniques used are based on analyzing samples of DNA and RNA. Pathology is widely used for gene therapy and disease diagnosis. === Oral and maxillofacial pathology === Oral and Maxillofacial Pathology is one of nine dental specialties recognized by the American Dental Association, and is sometimes considered a specialty of both dentistry and pathology. Oral Pathologists must complete three years of post doctoral training in an accredited program and subsequently obtain diplomate status from the American Board of Oral and Maxillofacial Pathology. The specialty focuses on the diagnosis, clinical management and investigation of diseases that affect the oral cavity and surrounding maxillofacial structures including but not limited to odontogenic, infectious, epithelial, salivary gland, bone and soft tissue pathologies. It also significantly intersects with the field of dental pathology. Although concerned with a broad variety of diseases of the oral cavity, they have roles distinct from otorhinolaryngologists ("ear, nose, and throat" specialists), and speech pathologists, the latter of which helps diagnose many neurological or neuromuscular conditions relevant to speech phonology or swallowing. Owing to the availability of the oral cavity to non-invasive examination, many conditions in the study of oral disease can be diagnosed, or at least suspected, from gross examination, but biopsies, cell smears, and other tissue analysis remain important diagnostic tools in oral pathology. == Medical training and accreditation == Becoming a pathologist generally requires specialty-training after medical school, but individual nations vary some in the medical licensing required of pathologists. In the United States, pathologists are physicians (D.O. or M.D.) who have completed a four-year undergraduate program, four years of medical school training, and three to four years of postgraduate training in the form of a pathology residency. Training may be within two primary specialties, as recognized by the American Board of Pathology: [anatomical pathology and clinical pathology, each of which requires separate board certification. The American Osteopathic Board of Pathology also recognizes four primary specialties: anatomic pathology, dermatopathology, forensic pathology, and laboratory medicine. Pathologists may pursue specialised fellowship training within one or more subspecialties of either anatomical or clinical pathology. Some of these subspecialties permit additional board certification, while others do not. In the United Kingdom, pathologists are physicians licensed by the UK General Medical Council. The training to become a pathologist is under the oversight of the Royal College of Pathologists. After four to six years of undergraduate medical study, trainees proceed to a two-year foundation program. Full-time training in histopathology currently lasts between five and five and a half years and includes specialist training in surgical pathology, cytopathology, and autopsy pathology. It is also possible to take a Royal College of Pathologists diploma in forensic pathology, dermatopathology, or cytopathology, recognising additional specialist training and expertise and to get specialist accreditation in forensic pathology, pediatric pathology, and neuropathology. All postgraduate medical training and education in the UK is overseen by the General Medical Council. In France, pathology is separated into two distinct specialties, anatomical pathology, and clinical pathology. Residencies for both lasts four years. Residency in anatomical pathology is open to physicians only, while clinical pathology is open to both physicians and pharmacists. At the end of the second year of clinical pathology residency, residents can choose between general clinical pathology and a specialization in one of the disciplines, but they can not practice anatomical pathology, nor can anatomical pathology residents practice clinical pathology. == Overlap with other diagnostic medicine == Though separate fields in terms of medical practice, a number of areas of inquiry in medicine and medical science either overlap greatly with general pathology, work in tandem with it, or contribute significantly to the understanding of the pathology of a given disease or its course in an individual. As a significant portion of all general pathology practice is concerned with cancer, the practice of oncology makes extensive use of both anatomical and clinical pathology in diagnosis and treatment. In particular, biopsy, resection, and blood tests are all examples of pathology work that is essential for the diagnoses of many kinds of cancer and for the staging of cancerous masses. In a similar fashion, the tissue and blood analysis techniques of general pathology are of central significance to the investigation of serious infectious disease and as such inform significantly upon the fields of epidemiology, etiology, immunology, and parasitology. General pathology methods are of great importance to biomedical research into disease, wherein they are sometimes referred to as "experimental" or "investigative" pathology. Medical imaging is the generating of visual representations of the interior of a body for clinical analysis and medical intervention. Medical imaging reveals details of internal physiology that help medical professionals plan appropriate treatments for tissue infection and trauma. Medical imaging is also central in supplying the biometric data necessary to establish baseline features of anatomy and physiology so as to increase the accuracy with which early or fine-detail abnormalities are detected. These diagnostic techniques are often performed in combination with general pathology procedures and are themselves often essential to developing new understanding of the pathogenesis of a given disease and tracking the progress of disease in specific medical cases. Examples of important subdivisions in medical imaging include radiology (which uses the imaging technologies of X-ray radiography) magnetic resonance imaging, medical ultrasonography (or ultrasound), endoscopy, elastography, tactile imaging, thermography, medical photography, nuclear medicine and functional imaging techniques such as positron emission tomography. Though they do not strictly relay images, readings from diagnostics tests involving electroencephalography, magnetoencephalography, and electrocardiography often give hints as to the state and function of certain tissues in the brain and heart respectively. == Pathology informatics == Pathology informatics is a subfield of health informatics. It is the use of information technology in pathology. It encompasses pathology laboratory operations, data analysis, and the interpretation of pathology-related information. Key aspects of pathology informatics include: Laboratory information management systems (LIMS): Implementing and managing computer systems specifically designed for pathology departments. These systems help in tracking and managing patient specimens, results, and other pathology data. Digital pathology: Involves the use of digital technology to create, manage, and analyze pathology images. This includes side scanning and automated image analysis. Telepathology: Using technology to enable remote pathology consultation and collaboration. Quality assurance and reporting: Implementing informatics solutions to ensure the quality and accuracy of pathology processes. == Psychopathology == Psychopathology is the study of mental illness, particularly of severe disorders. Informed heavily by both psychology and neurology, its purpose is to classify mental illness, elucidate its underlying causes, and guide clinical psychiatric treatment accordingly. Although diagnosis and classification of mental norms and disorders is largely the purview of psychiatry—the results of which are guidelines such as the Diagnostic and Statistical Manual of Mental Disorders, which attempt to classify mental disease mostly on behavioural evidence, though not without controversy—the field is also heavily, and increasingly, informed upon by neuroscience and other of the biological cognitive sciences. Mental or social disorders or behaviours seen as generally unhealthy or excessive in a given individual, to the point where they cause harm or severe disruption to the person's lifestyle, are often called "pathological" (e.g., pathological gambling or pathological liar). == Non-humans == Although the vast majority of lab work and research in pathology concerns the development of disease in humans, pathology is of significance throughout the biological sciences. Two main catch-all fields exist to represent most complex organisms capable of serving as host to a pathogen or other form of disease: veterinary pathology (concerned with all non-human species of kingdom of Animalia) and phytopathology, which studies disease in plants. === Veterinary pathology === Veterinary pathology covers a vast array of species, but with a significantly smaller number of practitioners, so understanding of disease in non-human animals, especially as regards veterinary practice, varies considerably by species. Nevertheless, significant amounts of pathology research are conducted on animals, for two primary reasons: 1) The origins of diseases are typically zoonotic in nature, and many infectious pathogens have animal vectors and, as such, understanding the mechanisms of action for these pathogens in non-human hosts is essential to the understanding and application of epidemiology and 2) those animals that share physiological and genetic traits with humans can be used as surrogates for the study of the disease and potential treatments as well as the effects of various synthetic products. For this reason, as well as their roles as livestock and companion animals, mammals generally have the largest body of research in veterinary pathology. Animal testing remains a controversial practice, even in cases where it is used to research treatment for human disease. As in human medical pathology, the practice of veterinary pathology is customarily divided into the two main fields of anatomical and clinical pathology. === Plant pathology === Although the pathogens and their mechanics differ greatly from those of animals, plants are subject to a wide variety of diseases, including those caused by fungi, oomycetes, bacteria, viruses, viroids, virus-like organisms, phytoplasmas, protozoa, nematodes and parasitic plants. Damage caused by insects, mites, vertebrate, and other small herbivores is not considered a part of the domain of plant pathology. The field is connected to plant disease epidemiology and especially concerned with the horticulture of species that are of high importance to the human diet or other human utility. == See also == == References == == External links ==	Wikipedia/pathology
A disease is a particular abnormal condition that adversely affects the structure or function of all or part of an organism and is not immediately due to any external injury. Diseases are often known to be medical conditions that are associated with specific signs and symptoms. A disease may be caused by external factors such as pathogens or by internal dysfunctions. For example, internal dysfunctions of the immune system can produce a variety of different diseases, including various forms of immunodeficiency, hypersensitivity, allergies, and autoimmune disorders. In humans, disease is often used more broadly to refer to any condition that causes pain, dysfunction, distress, social problems, or death to the person affected, or similar problems for those in contact with the person. In this broader sense, it sometimes includes injuries, disabilities, disorders, syndromes, infections, isolated symptoms, deviant behaviors, and atypical variations of structure and function, while in other contexts and for other purposes these may be considered distinguishable categories. Diseases can affect people not only physically but also mentally, as contracting and living with a disease can alter the affected person's perspective on life. Death due to disease is called death by natural causes. There are four main types of disease: infectious diseases, deficiency diseases, hereditary diseases (including both genetic and non-genetic hereditary diseases), and physiological diseases. Diseases can also be classified in other ways, such as communicable versus non-communicable diseases. The deadliest diseases in humans are coronary artery disease (blood flow obstruction), followed by cerebrovascular disease and lower respiratory infections. In developed countries, the diseases that cause the most sickness overall are neuropsychiatric conditions, such as depression and anxiety. Pathology, the study of disease, includes etiology, or the study of cause. == Terminology == === Concepts === In many cases, terms such as disease, disorder, morbidity, sickness and illness are used interchangeably; however, there are situations when specific terms are considered preferable. Disease The term disease broadly refers to any condition that impairs the normal functioning of the body. For this reason, diseases are associated with the dysfunction of the body's normal homeostatic processes. Commonly, the term is used to refer specifically to infectious diseases, which are clinically evident diseases that result from the presence of pathogenic microbial agents, including viruses, bacteria, fungi, protozoa, multicellular organisms, and aberrant proteins known as prions. An infection or colonization that does not and will not produce clinically evident impairment of normal functioning, such as the presence of the normal bacteria and yeasts in the gut, or of a passenger virus, is not considered a disease. By contrast, an infection that is asymptomatic during its incubation period, but expected to produce symptoms later, is usually considered a disease. Non-infectious diseases are all other diseases, including most forms of cancer, heart disease, and genetic disease. Acquired disease An acquired disease is one that began at some point during one's lifetime, as opposed to disease that was already present at birth, which is congenital disease. Acquired sounds like it could mean "caught via contagion", but it simply means acquired sometime after birth. It also sounds like it could imply secondary disease, but acquired disease can be primary disease. Acute disease An acute disease is one of a short-term nature (acute); the term sometimes also connotes a fulminant nature Chronic condition or chronic disease A chronic disease is one that persists over time, often for at least six months, but may also include illnesses that are expected to last for the entirety of one's natural life. Congenital disorder or congenital disease A congenital disorder is one that is present at birth. It is often a genetic disease or disorder and can be inherited. It can also be the result of a vertically transmitted infection from the mother, such as HIV/AIDS. Genetic disease A genetic disorder or disease is caused by one or more genetic mutations. It is often inherited, but some mutations are random and de novo. Hereditary or inherited disease A hereditary disease is a type of genetic disease caused by genetic mutations that are hereditary (and can run in families) Iatrogenic disease An iatrogenic disease or condition is one that is caused by medical intervention, whether as a side effect of a treatment or as an inadvertent outcome. Idiopathic disease An idiopathic disease has an unknown cause or source. As medical science has advanced, many diseases with entirely unknown causes have had some aspects of their sources explained and therefore shed their idiopathic status. For example, when germs were discovered, it became known that they were a cause of infection, but particular germs and diseases had not been linked. In another example, it is known that autoimmunity is the cause of some forms of diabetes mellitus type 1, even though the particular molecular pathways by which it works are not yet understood. It is also common to know certain factors are associated with certain diseases; however, association does not necessarily imply causality. For example, a third factor might be causing both the disease, and the associated phenomenon. Incurable disease A disease that cannot be cured. Incurable diseases are not necessarily terminal diseases, and sometimes a disease's symptoms can be treated sufficiently for the disease to have little or no impact on quality of life. Primary disease A primary disease is a disease that is due to a root cause of illness, as opposed to secondary disease, which is a sequela, or complication that is caused by the primary disease. For example, a common cold is a primary disease, where rhinitis is a possible secondary disease, or sequela. A doctor must determine what primary disease, a cold or bacterial infection, is causing a patient's secondary rhinitis when deciding whether or not to prescribe antibiotics. Secondary disease A secondary disease is a disease that is a sequela or complication of a prior, causal disease, which is referred to as the primary disease or simply the underlying cause (root cause). For example, a bacterial infection can be primary, wherein a healthy person is exposed to bacteria and becomes infected, or it can be secondary to a primary cause, that predisposes the body to infection. For example, a primary viral infection that weakens the immune system could lead to a secondary bacterial infection. Similarly, a primary burn that creates an open wound could provide an entry point for bacteria, and lead to a secondary bacterial infection. Terminal disease A terminal disease is one that is expected to have the inevitable result of death. Previously, AIDS was a terminal disease; it is now incurable, but can be managed indefinitely using medications. Illness The terms illness and sickness are both generally used as synonyms for disease; however, the term illness is occasionally used to refer specifically to the patient's personal experience of their disease. In this model, it is possible for a person to have a disease without being ill (to have an objectively definable, but asymptomatic, medical condition, such as a subclinical infection, or to have a clinically apparent physical impairment but not feel sick or distressed by it), and to be ill without being diseased (such as when a person perceives a normal experience as a medical condition, or medicalizes a non-disease situation in their life – for example, a person who feels unwell as a result of embarrassment, and who interprets those feelings as sickness rather than normal emotions). Symptoms of illness are often not directly the result of infection, but a collection of evolved responses – sickness behavior by the body – that helps clear infection and promote recovery. Such aspects of illness can include lethargy, depression, loss of appetite, sleepiness, hyperalgesia, and inability to concentrate. Disorder A disorder is a functional abnormality or disturbance that may or may not show specific signs and symptoms. Medical disorders can be categorized into mental disorders, physical disorders, genetic disorders, emotional and behavioral disorders, and functional disorders. The term disorder is often considered more value-neutral and less stigmatizing than the terms disease or illness, and therefore is preferred terminology in some circumstances. In mental health, the term mental disorder is used as a way of acknowledging the complex interaction of biological, social, and psychological factors in psychiatric conditions; however, the term disorder is also used in many other areas of medicine, primarily to identify physical disorders that are not caused by infectious organisms, such as metabolic disorders. Medical condition or health condition A medical condition or health condition is a broad concept that includes all diseases, lesions, disorders, or nonpathologic condition that normally receives medical treatment, such as pregnancy or childbirth. While the term medical condition generally includes mental illnesses, in some contexts the term is used specifically to denote any illness, injury, or disease except for mental illnesses. The Diagnostic and Statistical Manual of Mental Disorders (DSM), the widely used psychiatric manual that defines all mental disorders, uses the term general medical condition to refer to all diseases, illnesses, and injuries except for mental disorders. This usage is also commonly seen in the psychiatric literature. Some health insurance policies also define a medical condition as any illness, injury, or disease except for psychiatric illnesses. As it is more value-neutral than terms like disease, the term medical condition is sometimes preferred by people with health issues that they do not consider deleterious. However, by emphasizing the medical nature of the condition, this term is sometimes rejected, such as by proponents of the autism rights movement. The term medical condition is also a synonym for medical state, in which case it describes an individual patient's current state from a medical standpoint. This usage appears in statements that describe a patient as being in critical condition, for example. Morbidity Morbidity (from Latin morbidus 'sick, unhealthy') is a diseased state, disability, or poor health due to any cause. The term may refer to the existence of any form of disease, or to the degree that the health condition affects the patient. Among severely ill patients, the level of morbidity is often measured by ICU scoring systems. Comorbidity, or co-existing disease, is the simultaneous presence of two or more medical conditions, such as schizophrenia and substance abuse. In epidemiology and actuarial science, the term morbidity (also morbidity rate or morbidity frequency) can refer to either the incidence rate, the prevalence of a disease or medical condition, or the percentage of people who experience a given condition within a given timeframe (e.g., 20% of people will get influenza in a year). This measure of sickness is contrasted with the mortality rate of a condition, which is the proportion of people dying during a given time interval. Morbidity rates are used in actuarial professions, such as health insurance, life insurance, and long-term care insurance, to determine the premiums charged to customers. Morbidity rates help insurers predict the likelihood that an insured will contract or develop any number of specified diseases. Pathosis or pathology Pathosis (plural pathoses) is synonymous with disease. The word pathology also has this sense, in which it is commonly used by physicians in the medical literature, although some editors prefer to reserve pathology to its other senses. Sometimes a slight connotative shade causes preference for pathology or pathosis implying "some [as yet poorly analyzed] pathophysiologic process" rather than disease implying "a specific disease entity as defined by diagnostic criteria being already met". This is hard to quantify denotatively, but it explains why cognitive synonymy is not invariable. Syndrome A syndrome is the association of several signs and symptoms, or other characteristics that often occur together, regardless of whether the cause is known. Some syndromes such as Down syndrome are known to have only one cause (an extra chromosome at birth). Others such as Parkinsonian syndrome are known to have multiple possible causes. Acute coronary syndrome, for example, is not a single disease itself but is rather the manifestation of any of several diseases including myocardial infarction secondary to coronary artery disease. In yet other syndromes, however, the cause is unknown. A familiar syndrome name often remains in use even after an underlying cause has been found or when there are a number of different possible primary causes. Examples of the first-mentioned type are that Turner syndrome and DiGeorge syndrome are still often called by the "syndrome" name despite that they can also be viewed as disease entities and not solely as sets of signs and symptoms. Predisease Predisease is a subclinical or prodromal vanguard of a disease. Prediabetes and prehypertension are common examples. The nosology or epistemology of predisease is contentious, though, because there is seldom a bright line differentiating a legitimate concern for subclinical or premonitory status and the conflict of interest–driven over-medicalization (e.g., by pharmaceutical manufacturers) or de-medicalization (e.g., by medical and disability insurers). Identifying legitimate predisease can result in useful preventive measures, such as motivating the person to get a healthy amount of physical exercise, but labeling a healthy person with an unfounded notion of predisease can result in overtreatment, such as taking drugs that only help people with severe disease or paying for treatments with a poor benefit–cost ratio. One review proposed three criteria for predisease: a high risk for progression to disease making one "far more likely to develop" it than others are- for example, a pre-cancer will almost certainly turn into cancer over time actionability for risk reduction – for example, removal of the precancerous tissue prevents it from turning into a potentially deadly cancer benefit that outweighs the harm of any interventions taken – removing the precancerous tissue prevents cancer, and thus prevents a potential death from cancer. === Types by body system === Mental Mental illness is a broad, generic label for a category of illnesses that may include affective or emotional instability, behavioral dysregulation, cognitive dysfunction or impairment. Specific illnesses known as mental illnesses include major depression, generalized anxiety disorders, schizophrenia, and attention deficit hyperactivity disorder, to name a few. Mental illness can be of biological (e.g., anatomical, chemical, or genetic) or psychological (e.g., trauma or conflict) origin. It can impair the affected person's ability to work or study and can harm interpersonal relationship. Organic An organic disease is one caused by a physical or physiological change to some tissue or organ of the body. The term sometimes excludes infections. It is commonly used in contrast with mental disorders. It includes emotional and behavioral disorders if they are due to changes to the physical structures or functioning of the body, such as after a stroke or a traumatic brain injury, but not if they are due to psychosocial issues. === Stages === In an infectious disease, the incubation period is the time between infection and the appearance of symptoms. The latency period is the time between infection and the ability of the disease to spread to another person, which may precede, follow, or be simultaneous with the appearance of symptoms. Some viruses also exhibit a dormant phase, called viral latency, in which the virus hides in the body in an inactive state. For example, varicella zoster virus causes chickenpox in the acute phase; after recovery from chickenpox, the virus may remain dormant in nerve cells for many years, and later cause herpes zoster (shingles). Acute disease An acute disease is a short-lived disease, like the common cold. Chronic disease A chronic disease is one that lasts for a long time, usually at least six months. During that time, it may be constantly present, or it may go into remission and periodically relapse. A chronic disease may be stable (does not get any worse) or it may be progressive (gets worse over time). Some chronic diseases can be permanently cured. Most chronic diseases can be beneficially treated, even if they cannot be permanently cured. Clinical disease One that has clinical consequences; in other words, the stage of the disease that produces the characteristic signs and symptoms of that disease. AIDS is the clinical disease stage of HIV infection. Cure A cure is the end of a medical condition or a treatment that is very likely to end it, while remission refers to the disappearance, possibly temporarily, of symptoms. Complete remission is the best possible outcome for incurable diseases. Flare-up A flare-up can refer to either the recurrence of symptoms or an onset of more severe symptoms. Progressive disease Progressive disease is a disease whose typical natural course is the worsening of the disease until death, serious debility, or organ failure occurs. Slowly progressive diseases are also chronic diseases; many are also degenerative diseases. The opposite of progressive disease is stable disease or static disease: a medical condition that exists, but does not get better or worse. Refractory disease A refractory disease is a disease that resists treatment, especially an individual case that resists treatment more than is normal for the specific disease in question. Subclinical disease Also called silent disease, silent stage, or asymptomatic disease. This is a stage in some diseases before the symptoms are first noted. Terminal phase If a person will die soon from a disease, regardless of whether that disease typically causes death, then the stage between the earlier disease process and active dying is the terminal phase. Recovery Recovery can refer to the repairing of physical processes (tissues, organs etc.) and the resumption of healthy functioning after damage causing processes have been cured. === Extent === Localized disease A localized disease is one that affects only one part of the body, such as athlete's foot or an eye infection. Disseminated disease A disseminated disease has spread to other parts; with cancer, this is usually called metastatic disease. Systemic disease A systemic disease is a disease that affects the entire body, such as influenza or high blood pressure. == Classification == Diseases may be classified by cause, pathogenesis (mechanism by which the disease is caused), or by symptoms. Alternatively, diseases may be classified according to the organ system involved, though this is often complicated since many diseases affect more than one organ. A chief difficulty in nosology is that diseases often cannot be defined and classified clearly, especially when cause or pathogenesis are unknown. Thus diagnostic terms often only reflect a symptom or set of symptoms (syndrome). Classical classification of human disease derives from the observational correlation between pathological analysis and clinical syndromes. Today it is preferred to classify them by their cause if it is known. The most known and used classification of diseases is the World Health Organization's ICD. This is periodically updated. Currently, the last publication is the ICD-11. == Causes == Diseases can be caused by any number of factors and may be acquired or congenital. Microorganisms, genetics, the environment or a combination of these can contribute to a diseased state. Only some diseases such as influenza are contagious and commonly believed infectious. The microorganisms that cause these diseases are known as pathogens and include varieties of bacteria, viruses, protozoa, and fungi. Infectious diseases can be transmitted, e.g. by hand-to-mouth contact with infectious material on surfaces, by bites of insects or other carriers of the disease, and from contaminated water or food (often via fecal contamination), etc. Also, there are sexually transmitted diseases. In some cases, microorganisms that are not readily spread from person to person play a role, while other diseases can be prevented or ameliorated with appropriate nutrition or other lifestyle changes. Some diseases, such as most (but not all) forms of cancer, heart disease, and mental disorders, are non-infectious diseases. Many non-infectious diseases have a partly or completely genetic basis (see genetic disorder) and may thus be transmitted from one generation to another. Social determinants of health are the social conditions in which people live that determine their health. Illnesses are generally related to social, economic, political, and environmental circumstances. Social determinants of health have been recognized by several health organizations such as the Public Health Agency of Canada and the World Health Organization to greatly influence collective and personal well-being. The World Health Organization's Social Determinants Council also recognizes Social determinants of health in poverty. When the cause of a disease is poorly understood, societies tend to mythologize the disease or use it as a metaphor or symbol of whatever that culture considers evil. For example, until the bacterial cause of tuberculosis was discovered in 1882, experts variously ascribed the disease to heredity, a sedentary lifestyle, depressed mood, and overindulgence in sex, rich food, or alcohol, all of which were social ills at the time. When a disease is caused by a pathogenic organism (e.g., when malaria is caused by Plasmodium), one should not confuse the pathogen (the cause of the disease) with disease itself. For example, West Nile virus (the pathogen) causes West Nile fever (the disease). The misuse of basic definitions in epidemiology is frequent in scientific publications. === Types of causes === Airborne An airborne disease is any disease that is caused by pathogens and transmitted through the air. Foodborne Foodborne illness or food poisoning is any illness resulting from the consumption of food contaminated with pathogenic bacteria, toxins, viruses, prions or parasites. Infectious Infectious diseases, also known as transmissible diseases or communicable diseases, comprise clinically evident illness (i.e., characteristic medical signs or symptoms of disease) resulting from the infection, presence and growth of pathogenic biological agents in an individual host organism. Included in this category are contagious diseases – an infection, such as influenza or the common cold, that commonly spreads from one person to another – and communicable diseases – a disease that can spread from one person to another, but does not necessarily spread through everyday contact. Lifestyle A lifestyle disease is any disease that appears to increase in frequency as countries become more industrialized and people live longer, especially if the risk factors include behavioral choices like a sedentary lifestyle or a diet high in unhealthful foods such as refined carbohydrates, trans fats, or alcoholic beverages. Non-communicable A non-communicable disease is a medical condition or disease that is non-transmissible. Non-communicable diseases cannot be spread directly from one person to another. Heart disease and cancer are examples of non-communicable diseases in humans. == Prevention == Many diseases and disorders can be prevented through a variety of means. These include sanitation, proper nutrition, adequate exercise, vaccinations and other self-care and public health measures, such as obligatory face mask mandates. == Treatments == Medical therapies or treatments are efforts to cure or improve a disease or other health problems. In the medical field, therapy is synonymous with the word treatment. Among psychologists, the term may refer specifically to psychotherapy or "talk therapy". Common treatments include medications, surgery, medical devices, and self-care. Treatments may be provided by an organized health care system, or informally, by the patient or family members. Preventive healthcare is a way to avoid an injury, sickness, or disease in the first place. A treatment or cure is applied after a medical problem has already started. A treatment attempts to improve or remove a problem, but treatments may not produce permanent cures, especially in chronic diseases. Cures are a subset of treatments that reverse diseases completely or end medical problems permanently. Many diseases that cannot be completely cured are still treatable. Pain management (also called pain medicine) is that branch of medicine employing an interdisciplinary approach to the relief of pain and improvement in the quality of life of those living with pain. Treatment for medical emergencies must be provided promptly, often through an emergency department or, in less critical situations, through an urgent care facility. == Epidemiology == Epidemiology is the study of the factors that cause or encourage diseases. Some diseases are more common in certain geographic areas, among people with certain genetic or socioeconomic characteristics, or at different times of the year. Epidemiology is considered a cornerstone methodology of public health research and is highly regarded in evidence-based medicine for identifying risk factors for diseases. In the study of communicable and non-communicable diseases, the work of epidemiologists ranges from outbreak investigation to study design, data collection, and analysis including the development of statistical models to test hypotheses and the documentation of results for submission to peer-reviewed journals. Epidemiologists also study the interaction of diseases in a population, a condition known as a syndemic. Epidemiologists rely on a number of other scientific disciplines such as biology (to better understand disease processes), biostatistics (the current raw information available), Geographic Information Science (to store data and map disease patterns) and social science disciplines (to better understand proximate and distal risk factors). Epidemiology can help identify causes as well as guide prevention efforts. In studying diseases, epidemiology faces the challenge of defining them. Especially for poorly understood diseases, different groups might use significantly different definitions. Without an agreed-on definition, different researchers may report different numbers of cases and characteristics of the disease. Some morbidity databases are compiled with data supplied by states and territories health authorities, at national levels or larger scale (such as European Hospital Morbidity Database (HMDB)) which may contain hospital discharge data by detailed diagnosis, age and sex. The European HMDB data was submitted by European countries to the World Health Organization Regional Office for Europe. === Burdens of disease === Disease burden is the impact of a health problem in an area measured by financial cost, mortality, morbidity, or other indicators. There are several measures used to quantify the burden imposed by diseases on people. The years of potential life lost (YPLL) is a simple estimate of the number of years that a person's life was shortened due to a disease. For example, if a person dies at the age of 65 from a disease, and would probably have lived until age 80 without that disease, then that disease has caused a loss of 15 years of potential life. YPLL measurements do not account for how disabled a person is before dying, so the measurement treats a person who dies suddenly and a person who died at the same age after decades of illness as equivalent. In 2004, the World Health Organization calculated that 932 million years of potential life were lost to premature death. The quality-adjusted life year (QALY) and disability-adjusted life year (DALY) metrics are similar but take into account whether the person was healthy after diagnosis. In addition to the number of years lost due to premature death, these measurements add part of the years lost to being sick. Unlike YPLL, these measurements show the burden imposed on people who are very sick, but who live a normal lifespan. A disease that has high morbidity, but low mortality, has a high DALY and a low YPLL. In 2004, the World Health Organization calculated that 1.5 billion disability-adjusted life years were lost to disease and injury. In the developed world, heart disease and stroke cause the most loss of life, but neuropsychiatric conditions like major depressive disorder cause the most years lost to being sick. == Society and culture == How a society responds to diseases is the subject of medical sociology. A condition may be considered a disease in some cultures or eras but not in others. For example, obesity was associated with prosperity and abundance, and this perception persists in many African regions, especially since the beginning of the HIV/AIDS. Epilepsy is considered a sign of spiritual gifts among the Hmong people. Sickness confers the social legitimization of certain benefits, such as illness benefits, work avoidance, and being looked after by others. The person who is sick takes on a social role called the sick role. A person who responds to a dreaded disease, such as cancer, in a culturally acceptable fashion may be publicly and privately honored with higher social status. In return for these benefits, the sick person is obligated to seek treatment and work to become well once more. As a comparison, consider pregnancy, which is not interpreted as a disease or sickness, even if the mother and baby may both benefit from medical care. Most religions grant exceptions from religious duties to people who are sick. For example, one whose life would be endangered by fasting on Yom Kippur or during the month of Ramadan is exempted from the requirement, or even forbidden from participating. People who are sick are also exempted from social duties. For example, ill health is the only socially acceptable reason for an American to refuse an invitation to the White House. The identification of a condition as a disease, rather than as simply a variation of human structure or function, can have significant social or economic implications. The controversial recognition of diseases such as repetitive stress injury (RSI) and post-traumatic stress disorder (PTSD) has had a number of positive and negative effects on the financial and other responsibilities of governments, corporations, and institutions towards individuals, as well as on the individuals themselves. The social implication of viewing aging as a disease could be profound, though this classification is not yet widespread. Lepers were people who were historically shunned because they had an infectious disease, and the term "leper" still evokes social stigma. Fear of disease can still be a widespread social phenomenon, though not all diseases evoke extreme social stigma. Social standing and economic status affect health. Diseases of poverty are diseases that are associated with poverty and low social status; diseases of affluence are diseases that are associated with high social and economic status. Which diseases are associated with which states vary according to time, place, and technology. Some diseases, such as diabetes mellitus, may be associated with both poverty (poor food choices) and affluence (long lifespans and sedentary lifestyles), through different mechanisms. The term lifestyle diseases describes diseases associated with longevity and that are more common among older people. For example, cancer is far more common in societies in which most members live until they reach the age of 80 than in societies in which most members die before they reach the age of 50. === Language of disease === An illness narrative is a way of organizing a medical experience into a coherent story that illustrates the sick individual's personal experience. People use metaphors to make sense of their experiences with disease. The metaphors move disease from an objective thing that exists to an affective experience. The most popular metaphors draw on military concepts: Disease is an enemy that must be feared, fought, battled, and routed. The patient or the healthcare provider is a warrior, rather than a passive victim or bystander. The agents of communicable diseases are invaders; non-communicable diseases constitute internal insurrection or civil war. Because the threat is urgent, perhaps a matter of life and death, unthinkably radical, even oppressive, measures are society's and the patient's moral duty as they courageously mobilize to struggle against destruction. The War on Cancer is an example of this metaphorical use of language. This language is empowering to some patients, but leaves others feeling like they are failures. Another class of metaphors describes the experience of illness as a journey: The person travels to or from a place of disease, and changes himself, discovers new information, or increases his experience along the way. He may travel "on the road to recovery" or make changes to "get on the right track" or choose "pathways". Some are explicitly immigration-themed: the patient has been exiled from the home territory of health to the land of the ill, changing identity and relationships in the process. This language is more common among British healthcare professionals than the language of physical aggression. Some metaphors are disease-specific. Slavery is a common metaphor for addictions: The alcoholic is enslaved by drink, and the smoker is captive to nicotine. Some cancer patients treat the loss of their hair from chemotherapy as a metonymy or metaphor for all the losses caused by the disease. Some diseases are used as metaphors for social ills: "Cancer" is a common description for anything that is endemic and destructive in society, such as poverty, injustice, or racism. AIDS was seen as a divine judgment for moral decadence, and only by purging itself from the "pollution" of the "invader" could society become healthy again. More recently, when AIDS seemed less threatening, this type of emotive language was applied to avian flu and type 2 diabetes mellitus. Authors in the 19th century commonly used tuberculosis as a symbol and a metaphor for transcendence. People with the disease were portrayed in literature as having risen above daily life to become ephemeral objects of spiritual or artistic achievement. In the 20th century, after its cause was better understood, the same disease became the emblem of poverty, squalor, and other social problems. == See also == == References == == External links == "Man and Disease", BBC Radio 4 discussion with Anne Hardy, David Bradley & Chris Dye (In Our Time, 15 December 2002) CTD The Comparative Toxicogenomics Database is a scientific resource connecting chemicals, genes, and human diseases. Free online health-risk assessment by Your Disease Risk at Washington University in St. Louis Health Topics A–Z, fact sheets about many common diseases at the Centers for Disease Control Health Topics, MedlinePlus descriptions of most diseases, with access to current research articles. NLM Comprehensive database from the US National Library of Medicine OMIM Comprehensive information on genes that cause disease at Online Mendelian Inheritance in Man Report: The global burden of disease from the World Health Organization (WHO), 2004 The Merck Manual containing detailed description of most diseases	Wikipedia/Organic_disease
Plant disease epidemiology is the study of disease in plant populations. Much like diseases of humans and other animals, plant diseases occur due to pathogens such as bacteria, viruses, fungi, oomycetes, nematodes, phytoplasmas, protozoa, and parasitic plants. Plant disease epidemiologists strive for an understanding of the cause and effects of disease and develop strategies to intervene in situations where crop losses may occur. Destructive and non-destructive methods are used to detect diseases in plants. Additionally, understanding the responses of the immune system in plants will further benefit and limit the loss of crops. Typically successful intervention will lead to a low enough level of disease to be acceptable, depending upon the value of the crop. Plant disease epidemiology is often looked at from a multi-disciplinary approach, requiring biological, statistical, agronomic and ecological perspectives. Biology is necessary for understanding the pathogen and its life cycle. It is also necessary for understanding the physiology of the crop and how the pathogen is adversely affecting it. Agronomic practices often influence disease incidence for better or for worse. Ecological influences are numerous. Native species of plants may serve as reservoirs for pathogens that cause disease in crops. Statistical models are often applied in order to summarize and describe the complexity of plant disease epidemiology, so that disease processes can be more readily understood. For example, comparisons between patterns of disease progress for different diseases, cultivars, management strategies, or environmental settings can help in determining how plant diseases may best be managed. Policy can be influential in the occurrence of diseases, through actions such as restrictions on imports from sources where a disease occurs. In 1963 J. E. van der Plank published "Plant Diseases: Epidemics and Control", providing a theoretical framework for the study of the epidemiology of plant diseases. This book provides a theoretical framework based on experiments in many different host pathogen systems and moved the study of plant disease epidemiology forward rapidly, especially for fungal foliar pathogens. Using this framework we can now model and determine thresholds for epidemics that take place in a homogeneous environment such as a mono-cultural crop field. == Elements of an epidemic == Disease epidemics in plants can cause huge losses in yield of crops as well threatening to wipe out an entire species such as was the case with Dutch Elm Disease and could occur with Sudden Oak Death. An epidemic of potato late blight, caused by Phytophthora infestans, led to the Great Irish Famine and the loss of many lives. Commonly the elements of an epidemic are referred to as the “disease triangle”: a susceptible host, pathogen, and conducive environment. For a disease to occur all three of these must be present. Below is an illustration of this point. Where all three items meet, there is a disease. The fourth element missing from this illustration for an epidemic to occur is time. As long as all three of these elements are present disease can initiate, an epidemic will only ensue if all three continue to be present. Anyone of the three might be removed from the equation though. The host might out-grow susceptibility as with high-temperature adult-plant resistance, the environment changes and is not conducive for the pathogen to cause disease, or the pathogen is controlled through a fungicide application. Sometimes a fourth factor of time is added as the time at which a particular infection occurs, and the length of time conditions remain viable for that infection, can also play an important role in epidemics. The age of the plant species can also play a role, as certain species change in their levels of disease resistance as they mature; in a process known as ontogenic resistance. If all of the criteria are not met, such as a susceptible host and pathogen are present, but the environment is not conducive to the pathogen infecting and causing disease, a disease cannot occur. For example, corn is planted into a field with corn residue that has the fungus Cercospora zea-maydis, the causal agent of Grey leaf spot of corn, but if the weather is too dry, and there is no leaf wetness the spores of the fungus in the residue cannot germinate and initiate infection. Likewise, if the host is susceptible and the environment favours the development of disease but the pathogen is not present there is no disease. Taking the example above, the corn is planted into a ploughed field where there is no corn residue with the fungus Cercospora zea-maydis, the causal agent of Grey leaf spot of corn, present but the weather means extended periods of leaf wetness, there is no infection initiated. When a pathogen requires a vector to be spread then for an epidemic to occur the vector must be plentiful and active. === Types of epidemics === Pathogens cause monocyclic epidemics with a low birth rate and death rate, meaning they only have one infection cycle per season. They are typical of soil-borne diseases such as Fusarium wilt of flax. Polycyclic epidemics are caused by pathogens capable of several infection cycles a season. They are most often caused by airborne diseases such as powdery mildew. Bimodal polycyclic epidemics can also occur. For example, in brown rot of stone fruits the blossoms and the fruits are infected at different times. For some diseases the disease occurrence needs to be evaluated over several growing seasons, especially if growing the crops in monoculture year after year or growing perennial plants. Such conditions can mean that the inoculum produced in one season can be carried over to the next leading to a build-up over the years, especially in the tropics where there are no clear-cut breaks between growing seasons. Epidemics under these conditions are called polyetic; they can be caused by both monocyclic and polycyclic pathogens. Apple powdery mildew is an example of a polyetic epidemic caused by a polycyclic pathogen; Dutch Elm disease a polyetic epidemic caused by a monocyclic pathogen. == Detecting diseases == There are many different ways to spot a disease both destructively and non-destructively. In order to understand the cause, affects, and cure for a disease, the non-destructive method is more favorable. They are techniques where sample preparation and/or repetitive processes are not necessary for measuring and observing the conditions of the plants’ health. Non-destructive approaches may include image processing, imaging-based, spectroscopy based, and remote sensing. Photography, digital imaging, and image analysis technology are useful tools to set up for image processing. Valuable data are extracted from these images and then are analyzed for diseases. But before any analysis happens, image acquisition is the first step. And within this step contains three stages. First, is energy which is the light source of illuminating from the object of interest. Second, is the optical system such as a camera to focus on the energy. Third, is the energy measured by the sensor. To continue with the image processing, there is a pre-process where one can make certain that there are no factors such as background, size, shape of leave, light, and camera effects the analysis.After the pre-process, image segmentation is used to split the image between regions of disease and non-disease. In these images, there features of color, texture, and shape that can be extracted and used for the analysis. Imaging-based approaches for the detection has two main methods, fluorescence imaging and hyper-spectral imaging. Fluorescence imaging helps identify the metabolic conditions of the plant. In order to do so, a tool is used to present light onto the chlorophyll complex of the plant. Hyper-spectral imaging is used to obtain reflected images. Such methods consist of the spectral information divergence (SID) where it can assess the spectral reflectance by looking at wavelength bands. Another non-destructive approach is spectroscopy. This is where the electromagnetic spectrum and matter becomes involved. There are visible and infrared spectroscopy, fluorescence spectroscopy, and electric impedance spectroscopy. Each spectroscopy gives information including the types of radiation energy, the types of material, the nature of interaction, and more. Finally, the last non-destructive approach is the application of remote sensing in plant diseases. This is where data is obtained without having to be with the plant while observing. There is hyper-spectral and multispectral in remote sensing. Hyper-spectral helps provide high spectral and spatial resolution. Multispectral remote sensing provides the severity of the disease. As of 2015 there is a need for further development of antibody- and molecular marker-tests for new pathogens and occurrence of known pathogens in new hosts, and also a need for further global integration of quarantine and surveillance. == Immune System == Plants can show many signs or physical evidence of fungal, viral or bacterial infections. This can range from rusts or molds to not showing anything at all when a pathogen invades the plant (occurs in some viral diseases in plants). Symptoms which are visible effects of diseases on the plant consist of changes in color, shape or function. These changes in the plant coordinates with their response to pathogens or foreign organisms that is negatively effecting their system. Even though plants do not have cells that can move and fight foreign organisms and they do not have a somatic adaptive immune system, they do have and depend on innate immunity of each cell and on systemic signals. In responses to infections, plants have a two-branched innate immune system. The first branch has to recognize and respond to molecules that are similar to classes of microbes, this includes non-pathogens. On the other hand, the second branch responds to pathogen virulence factors, either directly or indirectly to the host. Pattern recognition receptors (PRRs) are activated by recognition of pathogen or microbial-associated molecular patterns known as PAMPs or MAMPs. These leads to PAMP-Triggered Immunity or Pattern-Triggered Immunity (PTI) where PRRs causes intracellular signaling, transcriptional reprogramming, and biosynthesis of a complex output response that decreases colonization. In addition, R genes also known as Effector-Triggered Immunity is activated by specific pathogen “effectors” that can trigger a strong antimicrobial response. Both PTI and ETI assist in plant defense through activation of DAMP which is Damage-associated Compounds. Cellular changes or changes in gene expression are activated through ion channel gating, oxidative burst, cellular redox changes, or protein kinase cascades through PTI and ETI receptors. == Impact == Through 2013, invasive tree diseases had killed about 100 million elm trees combined in the United Kingdom and United States and 3.5 billion American chestnut trees. == See also == Distance Diagnostics Through Digital Imaging (DDDI) Landscape epidemiology Plant disease forecasting Robert Hartig Forest pathology Phytopathology with historical landmarks in plant pathology == References == == Further reading == === Crop disease epidemiology === Carvajal-Yepes, M.; Cardwell, K.; Nelson, A.; Garrett, K. A.; Giovani, B.; Saunders, D. G. O.; Kamoun, S.; Legg, J. P.; Verdier, V.; Lessel, J.; Neher, R. A.; Day, R.; Pardey, P.; Gullino, M. L.; Records, A. R.; Bextine, B.; Leach, J. E.; Staiger, S.; Tohme, J. (2019-06-27). "A global surveillance system for crop diseases". Science. 364 (6447). American Association for the Advancement of Science (AAAS): 1237–1239. Bibcode:2019Sci...364.1237C. doi:10.1126/science.aaw1572. ISSN 0036-8075. PMID 31249049. S2CID 195750384. "Global crop surveillance system, bulwark against disease". Emerging Pathogens Institute. University of Florida. 2019-07-11. Retrieved 2021-02-12. "Crop disease surveillance activities". Agriculture and Food. Western Australia Department of Primary Industries and Regional Development Agriculture and Food. 2020-05-07. Retrieved 2021-02-12. Fletcher, Jacqueline; Stack, James P. "Surveillance Strategies§Agricultural Biosecurity: Threats and Impacts for Plant Pathogens". NCBI Bookshelf (National Center for Biotechnology Information). National Academies Press (National Academy of Sciences). Retrieved 2021-02-12. == External links == Ecology and epidemiology in the R programming environment - Open access modules published in The Plant Health Instructor	Wikipedia/Plant_disease_epidemiology
A Doctor of Medicine (abbreviated MD, from the Latin Medicinae Doctor) is a medical degree, the meaning of which varies between different jurisdictions. In the United States, and some other countries, the MD denotes a professional degree of physician. This generally arose because many in 18th-century medical professions trained in Scotland, which used the MD degree nomenclature. In England, however, Bachelor of Medicine, Bachelor of Surgery (MBBS) was used: in the 19th century, it became the standard in Scotland too. Thus, in the United Kingdom, Ireland and other countries, the MD is a research doctorate, honorary doctorate or applied clinical degree restricted to those who already hold a professional degree (Bachelor's/Master's/Doctoral) in medicine. In those countries, the equivalent professional degree to the North American, and some others' usage of MD is still typically titled Bachelor of Medicine, Bachelor of Surgery. == History == The first medical degrees were awarded by the Schola Medica Salernitana around the year 1000, including to women such as Trota of Salerno. The degrees received legal sanction in 1137 by Roger II of Sicily and in 1231 by Emperor Federico II, in the Constitution of Melfi. In the titles XLIV-LXXXIX of the third book of the Constitutions of 1231, it was established that the activity of a physician (medicus) could only be carried out by physicians holding a medical degree, the Licentia Medendi (license to practice medicine), by the Schola Medica Salernitana (the only school in the kingdom authorized to award degrees in medicine). This degree was awarded after a curriculum composed of three years of study of logic, five years of medical studies, an examination of a commission composed of the professors of the university, a one-year apprenticeship with an expert doctor, and a final examination before the commissioners of the Royal Curia and the Provincial Curias. In 1703, the University of Glasgow's first medical graduate, Samuel Benion, was issued with the academic degree of Doctor of Medicine. University medical education in England culminated with the MB qualification, and in Scotland the MD, until in the mid-19th century the public bodies who regulated medical practice at the time required practitioners in Scotland as well as England to hold the dual Bachelor of Medicine and Bachelor of Surgery degrees (MB BS/MBChB/MB BChir/BM BCh etc.). North American medical schools switched to the tradition of the ancient universities of Scotland and began granting the MD title rather than the MB beginning in the late 18th century. The Columbia University College of Physicians and Surgeons in New York (which at the time was referred to as King's College of Medicine) was the first American university to grant the MD degree instead of the MB. Early medical schools in North America that granted the Doctor of Medicine degrees were Columbia, Penn, Harvard, Maryland, and McGill. These first few North American medical schools that were established were (for the most part) founded by physicians and surgeons who had been trained in England and Scotland. In most countries having a Doctor of Medicine degree does not mean that the individual will be allowed to practice medicine. Typically a physician must go through a year of general medical education in a hospital as an intern and then a residency for at least three years in a specific field of medicine and then take some form of licensing examination in their jurisdiction. A feminine form, "Doctress of Medicine" or Medicinae Doctrix, was also used by the New England Female Medical College in Boston in the 1860s. == By country == === Professional degrees === ==== Afghanistan ==== In Afghanistan, medical education begins after high school. No pre-medicine courses or bachelor's degree is required. Eligibility is determined through the rank applicants obtain in the public university entrance exam held every year throughout the country. Entry to medical school is competitive, and only students with the highest ranks are accepted into medical programs. The primary medical degree is completed in 7 years. According to the new medical curriculum (from 2016), during the 12th semester, medical students must complete research on a medical topic and provide a thesis as part of their training. Students have also a one-year compulsory internship which has to be completed in a teaching hospital. Medical graduates are awarded a certificate in general medicine, regarded as "MD" and validated by the "Ministry of Higher Education of Afghanistan". All physicians are to obtain licensing and a medical council registration number from the "Ministry of Public Health" before they officially begin to practice. They may subsequently specialize in a specific medical field at medical schools offering the necessary qualifications. After graduation, students may complete residency. The MD specification: Before the civil wars in Afghanistan, medical education used to be taught by foreign professors or Afghan professors who studied medical education abroad. The Kabul medical institute certified the students as "Master of Medicine". After the civil wars, medical education changed extensively, and the MD certification has been reduced to "Medicine Bachelor". ==== Argentina ==== In Argentina, the First Degree of Physician or Physician Diplomate (Spanish: Título de Médico) is equivalent to the North American MD Degree with six years of intensive studies followed by usually three or four years of residency as a major specialty in a particular empiric field, consisting of internships, social services and sporadic research. Only by holding a Medical Title can the postgraduate student apply for the Doctor degree through a doctorate in medicine program approved by the National Commission for University Evaluation and Accreditation. ==== Armenia ==== In Armenia, medical studies take six years. After completing high school, students can apply to one of the country's medical universities. The application process includes an admission examination testing the applicant in biology, chemistry, and physics. The six-year medical education course is a combined bachelor's and master's degree program. The first three years consist of lecture courses while the final three years consist of education in clinical settings alongside attending physicians. Medical students may also simultaneously study for a Master of Public Health if they wish, which takes one and a half years of study. After the six-year period of study, students must pass the state medical examination to graduate. They must then undergo a period of residency training in their chosen field of practice, the duration of which lasts from one to four years. ==== Australia ==== Historically, Australian medical schools have followed the British tradition by conferring the degrees of Bachelor of Medicine and Bachelor of Surgery (MBBS) to its graduates whilst reserving the title of Doctor of Medicine (MD) for their research training degree, analogous to the PhD, or for their higher or honorary doctorates. Although the majority of Australian MBBS degrees have been graduate programs since the 1990s, under the previous Australian Qualifications Framework (AQF) they remained categorized as Level 7 Bachelor's degrees together with other undergraduate programs. The latest version of the AQF includes the new category of Level 9 Master's (Extended) degrees which permits the use of the term 'Doctor' in the styling of the degree title of relevant professional programs. As a result, various Australian medical schools have replaced their MBBS degrees with the MD to resolve the previous anomalous nomenclature. With the introduction of the Master's level MD, universities have also renamed their previous medical research doctorates. The University of Melbourne was the first to introduce the MD in 2011 as a basic medical degree, and has renamed its research degree to Doctor of Medical Science (DMedSc). Australian National University offers a Doctor of Medicine and Surgery (MChD, abbreviated from Medicinae ac Chirurgiae Doctoranda) which is also a 4-year extended master's degree that qualifies graduates to be medical practitioners or work as surgeons. ==== Austria ==== In Austria, medical studies (medicine or dentistry) take six years full-time. In medicine, the first two years comprise basic fields of medicine such as anatomy, biology, chemistry, physics, physiology, etc., the next three years consist of all medical fields in the narrower sense with frequent bedside training and medical traineeships while the sixth and last year is dedicated solely to working in a clinic. After this, a specific six-year training (e.g. in internal medicine, paediatrics, ENT, pathology) or four year (GP) can be started; without this training, working with patients is forbidden. There is no central placement test for said specialist training, only a board-registered spot as a resident/registrar is needed. As with all other studies in Austria, there is no tuition but compulsory students' insurance (approx €38 per year). A specific entrance exam (MedAT, Medizin-Aufnahmetest, medicine acceptance test) has to be taken but is open only once a year in summer; a fee of €110 has to be paid. In 2019, 16443 persons registered for the MedAT and 12960 took the test. 1.680 university places for both medicine and dentistry are offered each year with 95% of all places for EU citizens and 75% for applicants with an Austrian higher education entrance qualification/GCE A-levels. Many Germans who are denied studying in their home country try to study medicine in Austria; hence this quota was introduced and approved by the EU as most of them leave upon graduation. The title of "Doktor" is granted to physicians (Dr. med. univ., Doctor medicinae universae, Dr. der gesamten Heilkunde = Dr. "of the entire art of healing") and dentists (Dr. med. dent., Doctor medicinae dentinae), who do not possess doctorate degrees, but Master's level 6 year-training, similar to the American MD or DDS. although they have to write a diploma thesis of approx. 50–100 pages. In former days the same title was connected to an official doctorate degree in connection with an older study regulation. The law has been changed in 2002. Some of which are published in peer-reviewed journals while others are not. A post-graduate research doctorate (Dr. scient. med., Dr. scientiae medicinae, or PhD) can be obtained after a three years post-graduate study at a medical university. All doctors may be addressed as "Doktor ______", and the title is usually contracted to "Dr. ______". In many everyday-day settings in Austria, also outside the clinic, it is common to address medical doctors solely as "Herr/Frau Doktor" (Mr./Ms./Mrs. doctor) without any specific family name (especially in rural areas and small villages, and by older people), and they are often viewed as the "real doctors". Among themselves, MDs do not use "doctor" as an appellation but just "Herr Kollege/Frau Kollegin" (Mr./Ms/Mrs. = "dear" colleague). Consistent use of "Doktor" when addressing another medical doctor is seen as confrontative and mockery. ==== Belgium ==== In Belgium, the medical degree awarded after six years of study is called "Docteur en Médecine" in the French-speaking part of the country and "Master in de geneeskunde" in Flanders. Physicians would then have to register with the Ordre des Médecins to practice medicine in the country. Physicians would then either have to do a three-year internship to become a general practitioner or up to 6 years to specialize. ==== Bosnia and Herzegovina ==== In Bosnia and Herzegovina, the title of "doktor medicine" (abbreviated "dr. med.") is awarded upon completion of six years of study at a Faculty of Medicine ("medicinski fakultet") immediately after high school. ==== Botswana ==== In Botswana, the seven-year medical studies only begin after the completion of senior secondary education and obtaining enough points to qualify for admittance to the University of Botswana. Students pursuing science based or STEM careers i.e. medicine are admitted to a two-year Bsc course where they'll be taught chemistry, Physics and Biology. Students who obtained extremely good grades at the end of this course are cherry picked to further their studies at the School of Medicine (A faculty of the university) if they wish to pursue a medical career. Standards are very high and admittance is strict with only about 50 students out of three to five thousand being able to qualify for medical studies. Here, the students specialise, and choose which medical careers they're going for. After doing so, students are placed in their respective classes; learning, studying and practicing their choice of medicine. Furthermore, it is in this school that they pursue an MBBS degree (Bachelor of Medicine Bachelor of Surgery) for five years. In these five years, the first two follow an integrated problem based learning approach. The last three years are clinically structured, providing an opportunity to practice in medical institutions and communities. An equivalent to residencies and internships in the medical western world. After completion of their internships. They graduate and are honoured with an MBBS degree and a medical practitioner license. Those that wish to further their studies can do so in order to pursue PhDs and master's degrees in medicine. ==== Bulgaria ==== At the end of the six-year medical programs from Bulgarian medical schools, medical students are awarded the academic degree Master/Magister in Medicine and the professional title Physician – Doctor of Medicine (MD / MA ). ==== Cambodia ==== After six years of general medical education (a foundation year plus five years), all students will graduate with a Bachelor of Medical Sciences (BMedSc, Khmer: បរិញ្ញាប័ត្រ វិទ្យាសាស្រ្តវេជ្ជសាស្ត្រ), equivalent to Bachelor of Science, Bachelor of Surgery (MBBS). This degree does not allow graduates to work independently as a physician, but it is possible for those who wish to continue to master's degrees in other fields relating to medical sciences such as public health, epidemiology, biomedical science, and nutrition. Medical graduates, who wish to be fully qualified as physicians or specialists must follow the process as below: General Practitioner's (GP) course of nine years (BMedSc plus a two-year internship). Clinical rotation during the internship is modulated within four main disciplines (general medicine, surgery, gynecology, and pediatrics). The medical certification awarded is Diploma of Doctor of Medicine (MD, Khmer: បណ្ឌិតវេជ្ជសាស្ត្រ ឬ វេជ្ជបណ្ឌិត) – equivalent to a master's degree [?]. After graduating with BMedSc; any students who wish to enter a 'Residency Training Program', are required to sit for an Residency Entrance Exam. The duration of the programs takes four years after either BMedSc or MD (BMedSc or MD plus four years of specialization). Once the graduates have successfully defended their practical thesis, they are awarded the Diploma of Specialized Doctor (MD with specialization, Khmer: សញ្ញាប័ត្រ៖ វេជ្ជបណ្ឌិតឯកទេស, lit. 'Professional Doctorate'). All medical graduates must complete a 'Thesis Defense' and pass the National Exit Exam (Khmer: ប្រឡងចេញថ្នាក់ជាតិក្នុងវិស័យសុខាភិបាល) to become either GPs or medical or surgical specialists. Last but importantly, those GPs or MDs have to register their name in the Cambodian Medical Committee (CMC) to receive the license to see patients, and pay for the registration every year. ==== Canada ==== In Canada, the MD is the degree required to practise medicine. Similar to the United States, students in Canada from English-speaking provinces must complete four years of a bachelor's degree, then write the MCAT at which point they move into the typical four year medical school curriculum. As a practical matter, nearly all successful applicants have completed one or more degrees before admission to a Canadian medical school, although despite this it is, along with other first professional degrees, the Canadian MD is considered to be a bachelor's degree-level qualification. The notable exception is the French-speaking province of Quebec, where their special CEGEP post-secondary institutions do not grant a bachelor's degree, but instead College Education Diplomas (DECs). Students typically enroll in a two-year Science Program such as Health Science, Pure & Applied, or Environmental (latter exclusive to CEGEP Dawson College) which lead into the Med-P qualifying year at Mcgill University or l'Université de Montréal, after which students complete the four-year curriculum similar to other provinces. Other Quebec universities such as the Université Laval and Université de Sherbrooke admit students possessing a DEC directly into the four-year program. This in total means the path to graduation from medical school is one to two years shorter for Quebec students (six or seven as opposed to eight). Another exception is the availability of a 3-year medical school curriculum, offered at two medical schools in Canada, the McMaster University Medical School and the University of Calgary. McGill University Faculty of Medicine is the only medical school in Canada that continues to award the MD, CM degrees (abbreviated MDCM). MDCM is from the Latin Medicinae Doctorem et Chirurgiae Magistrum meaning "Doctor of Medicine and Master of Surgery". Upon graduation, students enter into a residency phase of training. Prior to obtaining an independent practicing license from a provincial regulatory body, students must complete the Medical Council of Canada Qualifying Examination to obtain the Licentiate of the Medical Council of Canada (LMCC) qualification. and complete the specialty certifying exam from their respective college, the Royal College of Physicians and Surgeons of Canada for specialists and the College of Family Physicians of Canada for family physicians. ==== Chile ==== In Chile, medical education begins after graduating high-school, in public or private universities, which select candidates based on a national entrance exams (former University Selection Test, now in transition to a new selection test). Public universities and private universities cost around US$8,000–12,000 a year. In almost every university the career lasts for 7 years, the first two being basic sciences, then three years of preclinical studies, and ending with two years of supervised clinical practice (internship, or "internado") both at hospitals and ambulatory centers. Upon graduation, students obtain the professional title "Médico Cirujano", equivalent to Doctor of Medicine (MD). After graduation, in order to practise medicine in public establishments of primary or hospital care, every new physician must take the EUNACOM (National Exam of Medical Knowledge). The title enables the graduate to practice as a General Practitioner, and many of them may follow specialization studies in clinical or non-clinical fields. There is a national program of accreditation, mandatory to every Medicine School. In Chile, physicians receive the courtesy denomination of Doctor followed by their family name, even though in an academic environment the medical title is not accepted as an equivalent to PhDs; regardless, at community and family level, and in day-to-day activities, they are often viewed as "real doctors". ==== China ==== In China, research universities offer the eight-year Doctor of Medicine program. In the meantime, the majority of primary medical training comes in the form of a 5-year Bachelor of Medicine degree, which includes 4 years of basic science, biomedical science and clinical science training (with short-term clerkship) and 1 years of full-time clerkship training. Graduates from such programs are eligible to sit for Medical Doctor License Examination in China providing they are working as resident physicians or surgeons in a hospital. Many of the young doctors do seek further training by entering a three-year Master of Medicine (clinical track) program or five-year Doctor of Medicine (clinical track). Some take a job/promotion after the three-year program and work for a number of years and then take on another three years of training to get the ultimate Doctor of Medicine degree. ==== Croatia ==== In Croatia, the title of "doktor medicine" (abbreviated "dr. med.") is awarded to candidates who successfully completed six years of study in medicine and defended their graduate thesis (student's original research in clinical / preclinical medicine or life sciences). The title is legally awarded only upon the successful thesis exam (thesis defence) in the presence of a board of senior researchers and candidate's research mentor. It is not equivalent to "doktor znanosti" degree ("doctor scientiae", abbreviated "dr.sc."), which is equivalent to PhD. ==== Cuba ==== In Cuba, the title of "Doctor en Medicina" (Doctor of Medicine) is awarded upon completion of six years of study at a University of Medical Sciences after high school. Medicine was one of the four foundational careers of the first Cuban university named Real y Pontificia Universidad de San Jeronimo de La Habana (current University of Havana) founded in 1728. ==== Czech Republic ==== In the Czech Republic, students are awarded the title MUDr. (medicinae universae doctor in Latin) upon successfully passing set of State Examinations after six years of medical school composed of theoretical and clinical training. ==== Dominican Republic ==== In the Dominican Republic, it is known as "Doctor en Medicina" (Doctor in Medicine). In 1511 the Spanish Catholic church founded the first university of the Americas in Santo Domingo present capital of modern-day Dominican Republic and name it Universidad Santo Tomas de Aquino (today Universidad Autonoma de Santo Domingo). In 1630 this university graduated the first medical doctors of the Americas and amongst the graduates some Native Americans included. ==== Ecuador ==== In Ecuador, medical school begins after graduating high-school. There are two options; applying to public or private universities. Both private and public university select their candidates based on entrance exams. Public universities are free while private universities cost around US$6,000–12,000 a year. In most universities, the career lasts for six years. After graduating, students obtain a degree of "médico" or "médico cirujano", depending which one is offered by each university. Both degrees are equivalent to doctor of medicine (MD). ==== Egypt ==== In Egypt, the primary medical degree is Bachelor of Medicine and Surgery (MBBCh.), which is obtained after completion of six years of medical education and one year National Compulsory Internship Program. The Degree Doctor of Medicine (MD) is the highest academic medical degree in Egypt. It is a research degree obtained after the primary medical qualification (MBBCh.) and a master's degree in a certain specialty in medicine. It usually requires coursework, clinical training and a thesis. The degree Doctor of Medicine allows for promotion to the level of "Consultant Physician" in a specific medical specialty. ==== Estonia ==== In Estonia, there is only one university, The University of Tartu, with programs in medicine and dentistry. The program in medicine lasts for six years, including a one-year clinical internship, and students are awarded Doctor of Medicine (MD) upon graduation. The degree is academically equivalent to a master's degree. After that, one can work either as a general practitioner or enter a residency program to become a specialized doctor. Residency usually lasts, depending on the field, three to five years, with surgical residencies usually being the longest (5 years). ==== France ==== After graduating from high school with a Baccalaureat, any student can register at a university of medicine (there are about 30 of them throughout the country). Until 2018, at the end of the first year, an internal ranking examination took place at each of these universities in order to implement the numerus clausus. This ranking examination and the numerus clausus has since been abolished. First year consists primarily of theoretical classes such as biophysics and biochemistry, anatomy, ethics or histology. Passing first year is generally considered very challenging, requiring hard and continuous work. Each student can only try twice. For example, prior to its 2019 merger with Paris Diderot University, the Université René Descartes welcomed about 2,000 students in the first year and only 300 after numerus clausus. The second and third year are usually quite theoretical although the teachings are often accompanied by placements in the field (e.g., internships as nurses or in the emergency room, depending on the university). During their fourth, fifth and sixth years, medical students get a special status called "externe" (In some universities, such as Pierre et Marie Curie, the externe status is given beginning in the third year). They work as interns every morning at the hospital plus a few night shifts a month and study in the afternoon. Each internship lasts between three and four months and takes place in a different department. Med students get five weeks off a year. At the end of the sixth year, they need to pass a national ranking exam, which will determine their specialty. The first student gets to choose first, then the second, etcetera. Usually, students work hard during the fifth and sixth years in order to train properly for the national ranking exam. During these years, actual practice at the hospital and in conjunction with some theoretical courses are meant to balance the training. Such externs' average wage stands between 100 and 300 euros a month. After taking those ranking exams, students can start as residents in the specialty they have been able to pick. That is the point from which they also start getting paid. Towards the end of the medical program, French medical students are provided with more responsibilities and are required to defend a thesis; however, unlike a PhD thesis, no original research is actually necessary to write an MD thesis. At the conclusion of the thesis defense, French medical students receive a State Diploma of Doctor of Medicine (MD, French: diplôme d'Etat de docteur en médecine). Every new doctor must then proceed to a Diploma of Specialised Studies (DES, French: diplôme d'Etudes spécialisées) to mark their specialty. Some students may also receive a Diploma of Complementary Specialized Studies (DESC, French: diplôme d'Etudes spécialisées complémentaires). ==== Georgia ==== In Georgia, medical universities in Georgia offer a six-year curriculum leading to the award of Doctor of Medicine (MD) "Physician" "Medical Doctor (MD), a European medical degree which is valid throughout the world. Some of the reputed medical universities include Batumi State University, Tbilisi State Medical University, Akaki Tsereteli State University, Ilia State University and University of Georgia ==== Germany ==== After at least six years of medical school, the students graduate with a final federal medical exam (Dritter Abschnitt der ärztlichen Prüfung). Graduates receive their license to practice medicine and the professional title of physician (Arzt). About 60% of them additionally obtain the academic degree Doctor of Medicine (Dr. med.). The European Research Council ruled in 2010 that a medical doctorate alone is not considered equivalent to a PhD research degree for the purpose of selection for ERC Starting Grants, requiring additional evidence (e.g., proof of an appointment that requires doctoral equivalency, such as a post-doctoral fellowship) for the overall training to be considered equivalent to a PhD. ==== Guyana ==== In Guyana, Doctor of Medicine (MD) degree is awarded after the completion of four years or five years of study. Texila American University, Green Heart University, American International School of Medicine, Alexander American University, Lincoln American University provides medicine programs. ==== Hungary ==== In Hungary, after six years of medical school, which includes a sixth-year internship, students are awarded the degree of 'okleveles orvosdoktor' (Doctor of Medicine) degrees. ==== India ==== In India, students join medical school directly after high school, and after 5.5 years i.e. 4.5 years of medical school plus 1 year of compulsory rotatory internship, students are awarded the MBBS (Bachelor of Medicine and Bachelor of Surgery) degree. Admission to MBBS course is based on having a minimum qualifying score and the rank in the common entrance test NEET(UG) and reservation of seats for admission is based on caste, economically weaker section and other quotas. Admission to various specialties or Post-graduate courses require an M.B.B.S from an MCI-recognized institute and is based on common entrance tests i.e. INI-CET(PG) and NEET(PG). They are awarded corresponding degrees of MD or MS (Doctor of Medicine or Master of Surgery). In India MD or MS is equivalent to post graduation in medicine or surgery, those doctors are known as specialists. Further clinical and theoretical training leads to the Doctorate of Medicine (DM) or MCh (Master of Chirurgae), which is considered a PhD. equivalent, and those doctors are known as superspecialists, the exam involves preparing a thesis and defending it. Basically, MD is needed for entrance to DM courses, it is a non-surgical branch. For MCh, the requirement is MS, it is a surgical branch. ==== Indonesia ==== In Indonesia, the title of "dokter" (dr.) is awarded after 3.5–4 years of pre-clinical study (bachelor's of medicine) and 1.5–2 years of clinical study in a university hospital (medical doctor profession program). After a medical student finishes at least five years of the programs, they need to take the "Students' Proficiency Test in the Professional Medical Program" (Uji Kompetensi Mahasiswa Program Profesi Dokter or UKMPPD). If they pass the test, they can take the Hippocratic Oath and at then entitled to use Dokter (dr.) before their name. Note that "dr." is used for medical graduates, while Dr. (or incorrectly DR. i.e. Doktor) is used for PhD holders. Then they need to take a year-long internship course in primary health care clinics (also known as Puskesmas) or primary hospitals to practice as a general practitioner under supervision of senior doctors. Those who wished to further their study in a specialization can take a graduate course and will be entitled to use "Specialist of ..." after their name (e.g.: Sp.A for Spesialis Anak = Pediatrician). A graduate course of medicine is equal to a residency program. It requires candidates to study for four years followed by an internship in a hospital. ==== Iran ==== In Iran, Medical education begins after high school. No pre-med course or BSc degree is required. The eligibility is determined through the rank applicants obtain in the public university entrance exam being held every year throughout the country. The entry to medical school is competitive and only students with the highest rank are accepted into medical program. The primary medical degree is completed in 7–7.5 years. On the final years (last 1–2 years) medical students need to do a research on a medical topic and provide thesis as part of their trainings. Medical graduates are awarded a certificate in general medicine, called "Professional Doctorate in Medicine" validated by the "Ministry of Health and Medical Education" of Iran. All physicians will obtain license and medical council registration number from the "Medical Council of Iran" before they officially begin to practice. They may subsequently specialize in a specific medical field at medical schools offering the necessary qualifications. ==== Israel ==== There are seven university medical schools in Israel, located at the Technion in Haifa, Ben-Gurion University of the Negev in Beersheba, Tel Aviv University, the Hebrew University of Jerusalem, the medical school of Bar-Ilan University in Safed, Reichman University in Herzliya, and Ariel University. Most follow the European 6-year model although some have 4-year programs for students with degrees in certain biological sciences similar to the US system. The entrance requirements of the various schools of medicine are very strict. Israeli students require a high school Baccalaureate average above 100 and psychometric examination grade over 740, which corresponds to the 99th percentile. Candidates achieving these demanding cognitive requirements are then selected according to their ranking in the Mor and Mirkam MMI personality tests. Approximately 30% of applicants pass the Mor and Mirkam tests and are accepted into medical school. There is a shortage of medical school spots in Israel. In the past, the Technion Medical School, Ben Gurion University, and Tel Aviv University Sackler Faculty of Medicine offered 4-year MD programs for North American students who with college degrees who took the MCAT and were interested in completing rigorous medical education in Israel before returning to the US or Canada, but discontinued those programs to free up resources to train more Israeli doctors. Two additional medical schools are planned to open at the Weizmann Institute of Science in Rehovot and the University of Haifa. Following graduation from the 6-year or 4-year program, all graduates are required to do a 1-year internship to be licensed by the Ministry of Health and practice medicine professionally. Residency takes 4 (Internal Medicine, Family Medicine) to 7 (Neurosurgery) years. ==== Italy ==== In Italy, before the Bologna process, the degree of "Dottore in Medicina e Chirurgia" (literally Doctor in Medicine and Surgery, from the Latin Medicinae Doctor et Chirurgiae) is awarded after completion of at least six years of study and clinical training in a university and after the submission of a thesis, that consists of original research. However, spurred by the Bologna process, a major reform instituted in 1999 to align University programmes with the more universal system of undergraduate (bachelor's degree) and postgraduate studies (master's and doctoral degrees) and as such the degree of 'Dottore in Medicina e Chirurgia' is no longer offered and was replaced with the 'Laurea Magistrale in Medicina e Chirurgia' (Master of Medicine and Surgery). In this context, the new Laurea Magistrale a ciclo unico in Medicina e Chirurgia is a six-year second cycle degree, equivalent to a master's degree (360 ECTS credits) which can be earned in a six-year programme and requires a scientific research thesis. Consequently, the new medical degrees in Italy is considered to be equivalent to a Medical Doctor or Doctor of Medicine (MD) Master's degree academically and legally. ==== Latvia ==== In Latvia, the duration of basic medical education is six years and leads to the Doctor of Medicine degree (ārsta grāds or MD). This degree is done full time and earns you 240 credits or 360 ECTS. The level acquired by this degree at the Latvian Qualifications Framework is similar to (EQF) level which is at is Level 7 and at the International Standard Classification of Education (ISCED) level is also Level 7. These levels indicate this qualification to be Masters level which is contrary to what North American MD is since it is considered a higher standing Bachelor or 1st Professional degree. ==== Lithuania ==== In Lithuania, the duration of basic medical education is six years and leads to the Doctor of Medicine degree (Aukštojo mokslo diplomas, nurodantis suteiktą gydytojo kvalifikaciją or MD). This degree is considered a Masters of Health Science degree. ==== Malaysia ==== In Malaysia, there are two types of MDs, one being for a basic medical degree while the other being a doctoral degree, depending on the awarding universities. The basic medical degree MDs (Similar to the MBBS awarded by other local universities) are awarded by both private and public universities, mostly are trained as an undergraduate 5-year course, however, with the establishment of Perdana University, it became the first university in Malaysia to provide a 4-year graduate entry course. Examples of universities in Malaysia offering the M.D degree are: University Sains Malaysia National University of Malaysia University Putra Malaysia Universiti Tunku Abdul Rahman UCSI University MDs are being awarded as a doctoral degree in public universities such as University of Malaya. ==== Philippines ==== In the Philippines, the MD is a first professional degree in medicine. To be accepted in Philippine medical schools, one must have finished a college degree before one can proceed to have a medical education. It is attained by either completing a 4-year degree or a 5-year degree (with internship included) from an accredited institution private and public Medical School by the Association of Philippine Medical Colleges and the Commission on Higher Education. The MD degree does not permit the practice of medicine but qualifies the degree-holder to apply for registration to the Professional Regulatory Commission. Registration to the commission through completion of internship and examinations will grant the privilege of practicing medicine in the Philippines. Moreover, the licensed Physician has the option to proceed for medical specialization and the taking of diplomate board examinations conducted by the respective board of medical specialists in a particular field. ==== Poland ==== In Poland the title/professional degree of lekarz (abbreviated lek.), also the name of the profession (physician), is granted after completing a six-year medical program, study (students apply to it directly after graduating high school with matura) and is equivalent to magister, magister inżynier or magister sztuki (master). Many medical higher schools in Poland also offer medicine programs in English, which award the Doctor of Medicine (MD) degree. In contrast, a higher, doctoral academic research degree in medicine resembling a PhD is named doktor nauk medycznych (abbreviated dr n. med.) (Doctor of Medical Sciences), or even higher scientific degree after habilitation, doktor habilitowany nauk medycznych (dr hab. n. med.) (can be treated as doctor of science). Specialization is valued similarly to a specialization in the English system. It is not a pre-requisite for a dr n. med. or dr hab. n. med. which are an academic/scientific, not a professional titles in Poland. ==== Romania ==== Romanian medical programs last for six years (including clinical practice), which is the long-cycle first professional degree and concludes with a final licensing examination (licența), based on the dissertation of the student's original research. The degree awarded is 'Doctor-Medic' and graduates are entitled to use the title "Dr." ==== Russia ==== Medical universities in Russia offer a six-year curriculum leading to award a professional graduate degree, called qualification (degree) of "specialist" (Diploma of Specialist; in medicine, Diploma of Physician). The title of Doctor of Medical Sciences (Russian: доктор медицинских наук, "doktor medicinskikh nauk" abbreviated д. м. н.) is a higher research doctoral degree, which may be earned after the Candidate of Medical Sciences (the latter is informally regarded in Russia as equivalent to the PhD). ==== Serbia ==== In Serbia, MD degree is awarded upon completion of six years of study at a School of Medicine immediately after high school, after which a six-month residency followed a national exam has to be completed in order to complete the degree. ==== Singapore ==== The American Duke University has a medical school based in Singapore (Duke-NUS Medical School), and follows the North-American model of styling its first professional degree "Doctor of Medicine" ("MD"), consid. By contrast, the Yong Loo Lin School of Medicine at the National University of Singapore confers MB BS as the first professional degree. ==== Slovakia ==== Slovakia's medical education is offered at four medical schools in the country. Two of them are faculties of the Comenius UniversityJessenius School of Medicine in Martin, and there is a second medical school in Bratislava Slovak Medical University in Bratislava (SZU) while the fourth one is the Pavol Josef Šafarik University in Košice. Both the Jessenius School of Medicine and the Faculty of Medicine in Košice have several international students. The Jessenius School of Medicine has almost a thousand international students, most from Norway. Admission to the medical schools is based on entrance examination that can be undergone once a year. The program is a six-year program in general medicine with a strictly preclinical and clinical division. The preclinical years are the two first, and are purely theoretical. They consist of subjects such as cell biology, genetics, biophysics, medical chemistry, anatomy, biochemistry, histology, embryology and so on. From the third year onwards, the study is integrated with practical learning at the faculty's associated teaching hospital, including major multi-year subjects such internal medicine, surgery, pediatrics, etc. In the sixth and final year, the student must pass four final state examinations and defend a self-composed thesis in order to graduate with a professional doctorate granting them the title of MUDr. for practicing in Slovakia or the Czech Republic or MD when practicing outside of Slovakia. ==== Slovenia ==== In Slovenia, the title of "doktor medicine" (abbreviated "dr. med.") is awarded upon completion of six years of study at one of the two Slovenian Faculties of Medicine ("medicinska fakulteta") in Ljubljana or Maribor. Studying at these faculties is only possible if the student has finished a gymnasium/grammar school ("gimnazija") with a general diploma called "splošna matura". ==== South Africa ==== Medical faculties attached to South African universities award the MBChB degree, except the University of the Witwatersrand, which stylises the degree as MBBCh. Excluding the University of the Free State (5 year program), medical school is 6 years in duration. Doctors are required to complete a 2-year internship program and one year of compulsory community service after medical school to register with the Health Professions Council of South Africa as an independent medical practitioner. ==== South Korea ==== In South Korea, there is a Medical Doctor (MD) license. The medical educations in South Korea (Republic of Korea) are six or four years in duration, six-year courses starting right after high schools, and four-year course starting after four-year's university education (to start the four-year course, the student needs a bachelor's degree). The first two years in the six-year system is composed of basic sciences and liberal art courses. ==== Taiwan ==== In Taiwan, the MD is a first awarded professional degree that goes up and beyond the limits of upper education. ==== Tanzania ==== In Tanzania, MD is the first awarded degree and takes five years of medical school, plus a sixth-year internship, Students are awarded the degree of Doctor of Medicine (MD). The famous medical school in the country includes the Muhimbili University of Health and Allied Sciences (MUHAS), the University of Dar es Salaam, Mbeya College of Health and Allied Sciences (UDSM - MCHAS), The University of Dodoma- School of Medicine and Dentistry (UDOM) and Catholic University of health and allied sciences (CUHAS) After undergraduate studies, the students pursue residency termed Master of Medicine for 3, 4, or 5 years, depending on the specialty they are interested in. After that, the students are awarded a Master of Medicine degree, after which they can further go on to do superspecialities for two more years and after that do a fellowship. ==== Thailand ==== The Thai medical education follows the six-year European system, consisting of one year in basic-science, two years in pre-clinical training, and three years for clinical training. Upon graduation, all medical students must pass national medical licensing examinations and a university-based comprehensive test. After medical school, newly graduated doctors are under contract to spend a year of internship and two years of tenure in rural areas before they are eligible for any other residency positions or specialized training. The students will receive Doctor of Medicine (MD) degree. However, the degree is equivalent to master's degree in Thailand. Specialty training after the MD degree requires at least four–six years residency program in the training university hospitals and must pass the board examination. Board-certified specialized degree is equivalent to doctorate degree. ==== Tunisia ==== In Tunisia, education is free for all Tunisian citizens and for foreigners who have scholarships. The oldest Medical school is a faculty of the University of Tunis. There are four medicine faculties situated in the major cities of Tunis, Sfax, Sousse and Monastir. Admission is bound to the success and score in the baccalaureate examination. Admission score threshold is very high, based on competition among all applicants throughout the nation. Medical school curriculum consists of six years. The first two years are medical theory (PCEM), containing all basic sciences related to medicine, and the last four years (DCEM) consists of clinical issues related to all medical specialties. During these last four years, the student gets the status of "Externe". The student has to attend at the university hospital every day, rotating around all wards. Every period is followed by a clinical exam regarding the student's knowledge in that particular specialty. After those five years, there are two years on internship, in which the student is a physician but under the supervision of the chief doctor; the student rotates over the major and most essential specialties during period of four months each. After that, student has the choice of either passing the residency national exam or extending his internship for another year, after which he gains the status of family physician. The residency program consists of four to five years in the specialty he qualifies, depending on his score in the national residency examination under the rule of highest score chooses first. Whether the student chooses to be a family doctor or a specialist, he has to write a doctoral thesis, which he will be defending in front of a jury, after which he gains his degree of Docteur d'état en Medecine (MD). ==== Turkey ==== In Turkey, the title of "Tıp Doktoru" (literally "Doctor of Medicine") is awarded upon completion of six years continuous study started with five years university education including three years basic sciences, two years clinical courses followed by one year of internship in university hospitals. The internal structure and methodology of training vary among universities; however vertical integration between basic and clinical sciences and horizontal integration between disciplines have become more prevalent approaches as well as student oriented practices. Regardless of the university, the whole program is equivalent to a combined degree of bachelors and masters, thus every students graduates with a master's degree. The graduates, becoming Doctors of Medicine, are eligible to practice general medicine through state assigned slots, start residency training through a state exam called "TUS"(short for "Tıpta Uzmanlık Sınavı"), or apply for a PhD program in a relevant field. ==== Ukraine ==== In Ukraine, by 2018, graduates of the school with completed secondary education that have coped with the relevant exams (in the disciplines designated by these universities) in the nationwide system for assessing graduates' knowledge – EIT (Ukrainian: ЗНО, External independent testing) based on the rating – may be admitted to the Medical Universities. Ukrainian medical universities offer a six-year curriculum, which should end with the passing of the State Complex Examination. The graduate receives the Diploma of the State Standard with the title "Specialist Diploma", which specifies a specialty and qualification (for example, "Physician"), or "Magister's Diploma" also of a state standard. After that, the graduate according to the rating division (at the university) is required to undergo a practical internship course (working as a doctor under the supervision of an experienced doctor) with a duration of two to three years, in the corresponding specialty. Successful completion of internship implies that an intern passes an examination on a specialty, including testing and receives a certificate of a specialist physician of the Ministry of Health, which is a formal permission for practical activity. Thus, the American MD and the Ukrainian Physician have identical titles. On the other hand, the colloquial (not official terminology) Doctor of Medicine means that a Physician with a higher education successfully defended his thesis, after a two-year postgraduate course and corresponding term of research (Candidate of Medical Sciences before 2015, or PhD after 2015 – until 2020), which is closer to the English system of degrees. ==== United States ==== In the United States, the MD awarded by medical schools is a professional doctorate and is accredited by the Liaison Committee on Medical Education (LCME), an independent body sponsored by the Association of American Medical Colleges, and the American Medical Association (AMA). (as opposed to the Doctor of Philosophy degree which requires completion of novel research, a written dissertation of that research which is in principle worthy of publication in a peer reviewed journal, and an examination or defense of that dissertation). Although MDs are eligible to compete for and attain federal research grants in the United States and perform research it is contested that MD's are qualified to do research due to their lack of training and experience in that field. In addition to the MD, the Doctor of Osteopathic Medicine (DO) is an equivalent professional doctoral degree for physicians and surgeons offered by medical schools in the United States. According to Harrison's Principles of Internal Medicine, "the training, practice, credentialing, licensure, and reimbursement of osteopathic physicians is virtually indistinguishable from those of MD physicians, with 4 years of osteopathic medical school followed by specialty and subspecialty training and certification." Admission to medical school in the United States is highly competitive, and in the United States there were 21,869 matriculants to medical school out of 53,371 applicants (≈41%) in 2019. While some medical school admission policies do not require students to complete a four-year undergraduate degree (see admission criteria at Yale University, Emory University, Cornell University, University of Chicago, and others), the overwhelming majority of incoming medical students in the United States have completed a four-year undergraduate degree. They must also take the Medical College Admission Test (MCAT). Before graduating from a medical school and being awarded the Doctor of Medicine degree, students are required to take the United States Medical Licensing Examination (USMLE) Step 1 and the clinical knowledge Step 2 exam. As of 2020, the requirement of the Clinical Skills portion of the Step 2 exam was removed. The MD degree is typically earned in four years and is a professional doctoral degree. Following the awarding of the MD, physicians who wish to practice in the United States are required to complete at least one internship year (PGY-1) and pass the USMLE Step 3. In order to receive board eligible or board accredited status in a specialty of medicine such as general surgery or internal medicine, physicians undergo additional specialized training in the form of a residency. Those who wish to further specialize in areas such as cardiology or infectious diseases then complete a fellowship. Depending upon the physician's chosen field, residencies and fellowships involve an additional three to eight years of training after obtaining the MD. This can be lengthened with additional research years, which can last one, two, or more years. Even though the MD is a professional degree and not a research doctorate (i.e., a PhD), many holders of the MD degree conduct research and publish in journals during training and after graduation. Combined medical and research training is offered through programs granting an MD-PhD. The grade Doctor of Medical Research for physicians specialized in "research" work has become quite rare since the 1980s with the highly respected PhD being more attractive nationally and globally. The National Institutes of Health (NIH), through its Medical Scientist Training Program, funds MD-PhD training programs at many universities. Some MDs choose a quasi-research career and receive funding from the NIH as well as other sources such as the Howard Hughes Medical Institute. The United States Department of Education and the National Science Foundation do not include the MD or other professional doctorates among the degrees that are equivalent to research doctorates. ==== Venezuela ==== After graduating from high school in Venezuela students can apply for federal appointment to a six-year medical program within a university. Only Public Universities offer this degree in Venezuela. Any student can apply for federal appointment by Ministry of Higher Education. So that, the student is allowed to register at university and follow a medical program. This a six-year program divided within three cycles. First cycle: Theory and lectures (1–2), second cycle: pre-clinical training (3–4) and third cycle: clinical training (5–6). First year consists mainly of theoretical classes. however there are practical experiences since first day in laboratories and institutes, such as biochemistry, anatomy which includes lectures and teaching sessions with cadavers in dissection tables, molecular biology, histology, embryology and many others general subjects. The second year is mainly theoretical, although most teaching sessions take place in laboratories. After completing these years the student knows how the human body is and how it works. There is also a Medical Exercise demonstration which includes a guided visit to primary care centers during a complete semester or year-round depending on the university. During the third year medical students start studying pharmacology, pathology, and physical examination. Passing successfully first, second, and the third year is commonly considered a filter, almost half of previously admitted students leave voluntarily. The fourth-year medical students enter the field starting to visit hospitals and healthcare services. This is called Pre-Clinical Cycle were they acquire deep knowledge about clinical examination visiting specialized units such as Internal Medicine, Trauma and orthopedics, surgery, and gynecology and obstetrics. They start to be members of a medical team. Every morning at the hospital, plus one night shift per week, and lectures in the afternoon. Each internship lasts between four and six months and takes place in a different department. The fifth and sixth years are very similar but this time they applied their previously earned clinical knowledge and skills starting to follow patients independently. At the end of the sixth year, they need to pass a highly supervised medical practice examination in an unserved outpatient center or specialized hospital in order to earn the degree. During these years, there is training at the hospital almost exclusively. Very few theoretical courses are meant to balance the training. Once completed they earn a university degree and a title granted by the Bolivarian Republic of Venezuela as "Medical Surgeon" this is considered equivalent to a M.D degree. There is also a five years program the "Médico Integral Comunitario" title and degree granted by newly created universities and headed by Cuban nationals from the Cuba – Venezuela cooperation agreements. This program has been subject of controversy in the country over the legitimacy of the Cuban doctors' licensure for teaching and practice medicine. After graduation, recently graduated doctors acquire the right to use Dr. before their names but still must follow a one-year exercise in the countryside or a two years training in a specialized hospital. So that, They can be enabled to practice medicine with a full license in Venezuela and the right to work as a medical doctor, generally as a general practitioner (Artículo 8). That is the point from which they also start getting paid. They can follow specialized studies which usually last between three or five years depending on specialization and furthermore a Doctorate degree for relevant research and a thesis, which usually take three or more years. === Postgraduate clinical degrees === ==== Bhutan ==== In Bhutan, a medical doctor who completes four to five years of medical school is awarded with MBBS or Dr.title by their respective universities ( usually from universities in Sri Lanka, India, Thailand and Bangladesh). Upon recognition by Bhutan Health and Medical council, they work as medical doctor in country. M.D title is usually given to those who completes three to four years of residency for specialised course like surgery, medicine pediatrics, etc. ==== India ==== The MBBS (Bachelor of Medicine/Bachelor of Surgery) degree represents the first (undergraduate) level of training required to be licensed as a physician (other degrees in alternative medicine are present like BAMS, BHMS, BSMS etc.) The MS or MD degree is a postgraduate degree, representative of speciality training. The equivalent training in the US or Canada would be the completion of a medical (post-graduate) degree. Eligibility for the MS or MD course is restricted to medical graduates holding the MBBS degree. The MBBS course is for 5+1⁄2 years, and training imparted is as follows: Pre-clinical (Anatomy, Physiology, and Biochemistry) Para-clinical (Pathology, Microbiology, Pharmacology, Forensic Medicine and Community Medicine) Clinical (Ophthalmology, Otorhinolaryngology, General Medicine, General Surgery, Pediatrics and Obstetrics/Gynecology; with speciality rotations such as Orthopaedics, Radiology, Pulmonary Medicine, Psychiatry, Dermatology, Anesthesiology and Dentistry) After 5+1⁄2 years of study and the successful completion of an examination, the candidate receives a Bachelor of Medicine & Bachelor of Surgery (MBBS) degree. A further 3-year course which includes both theoretical and practical elements, in a pre-clinical or clinical subject of a non-surgical nature such as Physiology, Pharmacology, Internal Medicine, Pediatrics, Pathology, Psychiatry, Microbiology, results in the award of the MD (Doctor of Medicine) degree. Whereas in a pre-clinical or clinical subject of a surgical nature (e.g. Anatomy, General Surgery, Orthopaedics, Obstetrics/Gynaecology, Ophthalmology), the candidate gets a MS (Master of Surgery) degree, these are specialist or Post Graduate doctors. The Doctor of Medicine awarded by Medical Universities in India and regulated by Medical Council of India are doctorate level qualification incorporating high level specialist clinical training, research and teaching. Doctor of Philosophy (PhD) in medical subjects is a research doctorate level qualification and could be done under supervision of a guide who is DM qualified from India (rather than PhD) and usually does not involve direct clinical work or teaching of scholars of that specialty. Scope for PhD in medical subjects is very limited in India as all faculty appointments mostly (except for some pre-clinical subjects) require a person to hold MD/MS in their respective specialties rather than a PhD. A second alternate qualification termed DNB (Diplomate of National Board), is considered equivalent to the MD and MS degrees. However, the DNB is not awarded by Medical Universities and thus is not a doctorate level qualification. It can be obtained by passing the exam conducted by the National Board of Examinations after completing three years of post-MBBS residency training in teaching hospitals recognised by the board but not necessarily by the Medical Council. The College of Physicians & Surgeons of Mumbai (established in 1912) also awards higher postgraduate qualifications in clinical and pre-clinical specialities, called FCPS (Fellowship of CPS); it involves three years of study and the successful completion of an examination, which includes both theoretical and practical elements, and a research thesis and a viva. The FCPS is representative of speciality clinical training, and equivalent to MD/MS/DNB/PhD Medical in Medical Doctorate in other parts of the world. Until 2007, the Government of India and the Medical Council of India recognised the FCPS qualification – since then, this is being done by State Medical Councils. After obtaining the first postgraduate degree, that is MD/MS/FCPS/DNB/PhD Medical, one can go for further specialisation in medical or surgical fields. This involves a highly competitive entrance examination. This course has three years of additional training and requires the submission of a dissertation (thesis). This is also considered a clinical doctorate as the focus is on preparing a super-specialist with adequate clinical as well as research training. After the dissertation is approved and the exit examination (theory and practical) is cleared, the degree awarded is DM (Doctor of Medicine), (PhD Medical). Based on the specific field of training, the degree awarded is DM in Cardiac Anaesthesia, Cardiology, Neurology, Nephrology, Gastroenterology, Neuroradiology, Critical Care, Pulmonology, Hematology, Medical Oncology, Clinical Pharmacology, Pediatric Critical Care, Pediatric Neurology, Neonatology, Pediatric Gastroenterology, Neuroanaesthesia, etc. For surgical superspecialities the degree awarded is MCh (Magister Chirurgiae), like MCh in Cardio-thoracic and Vascular Surgery, Endocrine Surgery, Neurosurgery, Surgical Gastroenterology, Urology, Plastic Surgery, Pediatric Surgery etc. DM and MCh are the clinical equivalent of a doctorate degree. A third alternate qualification is DNB (superspecialties), offered by National Board of Examinations, like DNB in Cardiology, Neurology, Cardiac Surgery, Neurosurgery. Following DM or MCh, one can also go for postdoctoral fellowship programs of one-year duration in specific subspecialties like Cardiac Electrophysiology, Invasive cardiology, Pediatric cardiology, Epilepsy, stroke, electroencephalography, movement disorders, neuromuscular disorders, cerebrovascular surgery, skull base surgery, neurocritical care, pediatric cardiac surgery etc. offered by prestigious government institutes and abroad. The National Board of Examinations also awards the DNB degree for six year integrated surgical courses in specialties of Neurosurgery, Cardio-thoracic and Vascular Surgery, Pediatric Surgery and Plastic surgery. The residency period lasts six years post MBBS and thus alleviates the need to undergo a three-year residency in General Surgery. ==== Pakistan ==== In Pakistan MBBS is the undergraduate degree. The MD is a higher doctorate, awarded by medical universities based on successful completion of a residency program of four to six years' duration in a university hospital. Many universities are offering MD. Parallel to MD, MS is a higher doctorate awarded on successful completion of four to six years' duration of a residency program in surgical field. ==== Sri Lanka ==== In Sri Lanka, the MD degree is a higher postgraduate degree that is awarded by the Postgraduate Institute of Medicine after completion of a postgraduate course, examinations and speciality training. The MD degree in Sri Lanka is representative of specialty training in clinical, para clinical, and preventive medicine (e.g., general medicine, cardiology, nephrology, oncology, para clinical such as microbiology, haematology and preventive such as community medicine). Entry for the MD course is open only for medical graduates holding the MBBS degree (with a duration of 5+1⁄2 years), and training is obtained in medical disciplines that are non-surgical in nature (e.g., internal medicine, radiology, pathology, etc.) After three or four years of study and the successful completion of an examination with written as well as cases and via examinations, the MD degree in the respective field of study is awarded. In community medicine and medical administration, part I examination consists of a theoretical exam while the degree is conferred after completion of a thesis as a PhD. This thesis has to be completed within a period of five years. After successfully defending the academic thesis, the MD degree is conferred to the candidate. The MD degree holder is certified as a board certified specialist by the respective board of study of the Postgraduate Institute of Medicine after he or she undergoes two–four years of local and foreign training depending on the specialty/subspecialty selected. === Research degrees === ==== United Kingdom, Ireland and some Commonwealth countries ==== The entry-level first professional degree in these countries for the practice of medicine is that of Bachelor of Medicine and Bachelor of Surgery (MBBS, MB, MB BCh BAO, BMBS, MBBChir, or MBChB). This degree typically requires between four and six years of study and clinical training, and is equivalent to the North American MD degree. Due to the UK code for higher education, first degrees in medicine comprise an integrated programme of study and professional practice spanning several levels. These degrees may retain, for historical reasons, "Bachelor of Medicine, Bachelor of Surgery" and are abbreviated to MBChB, MBBS or BMBS. In the UK, Ireland and many Commonwealth countries, as well as Hong Kong which continues to follow Commonwealth practices, the MD is a postgraduate research degree in medicine. At most universities, this takes the form of a first doctorate, analogous to the PhD, awarded upon submission of a thesis and a successful viva voce. The thesis may consist of new research undertaken on a full- or part-time basis, with much less supervision (in the UK) than for a PhD, or a portfolio of previously published work. In order to be eligible to apply for an MD degree from a UK or Commonwealth University one must hold either a "Bachelor of Medicine, Bachelor of Surgery" (MBBS, MBChB, BMBS for example) degree, or an equivalent U.S.-MD degree and must usually have at least five years of postgraduate experience. Therefore, graduates from the MBBS/MBChB/BMBS degrees do not hold doctorates; however, physicians holding these degrees are referred to as "doctor" as they are fully licensed as medical practitioners. In some commonwealth nations, these interns are designated as "house officers". Traditionally, the MD in the UK and Commonwealth was a higher doctorate (similar to a DSc) awarded upon submission of a portfolio of published work representing a substantial contribution to medical research. Many universities have now changed its status, but this has happened only recently: for example, the University of Cambridge in 2012 introduced a new higher degree of MedScD (more akin to the ScD degree) awarded on the basis of a career's contribution to the science or art of medicine, while redesignating the MD as an initial research doctorate awarded on the basis of a thesis. Oxford, which had changed the regulations for the MD degree to bring it more in line with initial doctorates in 2002, removed its status as a higher doctorate after a review in 2016. Some Commonwealth institutions retain the MD as a higher degree, such as the relatively new James Cook University. In the case where the MD is awarded (either as a first or higher doctorate) for previously published research, the candidate is usually required to be either a graduate or a full-time member of staff, of several years' standing of the university in question. === Equivalent degrees in other countries === In Belgian medical education, in the first three years, which are theoretical in nature and lead to a university bachelor's degree, general scientific courses are taken such as chemistry, biophysics, physiology, biostatistics, anatomy, virology, etc. To enter the bachelor course in Flanders, prospective students have to pass an exam, as a result of the numerus clausus. After the bachelor courses, students are allowed to enter the 'master in medicine' courses, which consist of three years of theoretical and clinical study. In general, the first two master years are theoretical and teach the students human pathology, diseases and pharmacology. The third year consists of internships in a wide range of specialities in different clinics. The seventh, final year serves as a kind of 'pre-specialization' year in which the students are specifically trained in the specialty they wish to pursue after medical school. In Bangladesh, the basic medical degree is the MBBS. After completing the intermediate level of education (12 years) the candidate must undergo 5 years of medical training in any medical college to achieve the MBBS degree. After obtaining the degree, the candidate needs to undergo one year of internship to obtain BMDC (Bangladesh medical and dental council) accreditation in order to practice in the country. In mainland China, some medical schools award MBBS to foreign students while all medical schools award Bachelor of Medicine to nationals. Some MD degrees are higher academic research degrees. In Colombia, the medicine faculties of the universities awards the title of "Medico Cirujano" after taking 12 semesters of studies on "all clinic and surgery discipline a two semester on internship. After receiving the degree there is a mandatory year "obliged social work" were the doctors practice as GP in the countryside. Residency programs last between three–four years depends on the specialty. The Czech and Slovak title MUDr. (Medicinae Universae doctor or doktor medicíny) is a professional doctorate granted upon completion of six years pregraduate Master's study at medical schools. The postgraduate academic research degree in medicine is a PhD degree. The Danish and Norwegian Candidatus medicinae or Candidata medicinae degrees (cand. med.) is awarded after completing a six-year medical programme, to which students apply directly upon finishing secondary school. The programme usually includes a small thesis. However, the cand. med. degree must not be confused with the previous Danish and Norwegian Dr. Med. degree, which is a separate degree from the PhD and represents a higher degree of medical research experience. It typically consists of at least 5–6 original publications. In Finland, the duration of basic medical education is six years and the course leads to the degree of Licentiate of Medicine. In Greece, after a six-year study, a medical student acquires his medical degree and the right to use "Δρ.", (Dr.) before his name. This is considered equivalent to the MD title. In Kosovo, there are medical high schools. Students from elementary school can choose to attend the medical high school, which lasts three years. When they finish the three years of medical high school, they practice for 4 months. After that, they can be a nurse or they can go to medical facilities in Pristina, with the education there taking around six years, including practice, to become a doctor. In Mexico and Peru, schools of medicine award the "Título de Médico Cirujano" degree after completing either six or seven years of study. This curriculum includes a rotating internship year and a year of social service providing care to an underserved community. In Nepal, a MBBS degree is awarded. This is an undergraduate level degree, which is awarded after completion of 4+1⁄2 years of medical school followed by one year of clinical internship. Most medical schools also offer postgraduate MD and MS degrees, which requires three years of further training. Post-doctorate DM and MCh terminal degrees are awarded by a few elite institutions after three more years of super-speciality training. In the Netherlands, medical students receive six years of university education prior to their graduation. Prospective students can apply for medical education directly after finishing the highest level of secondary school, vwo; previous undergraduate education is not a precondition for admittance. Medical students receive three years of preclinical training, followed by three years of clinical training (co-assistentschappen, or co-schappen) in hospitals. At one medical faculty (Utrecht University), clinical training already begins in the third year of medical school. After six years, students graduate as basisartsen (non-specialized physicians). As a result of the Bologna process, medical students in the Netherlands receive a bachelor's degree (BSc) after successfully concluding three years of medical university curriculum, and a master's degree (MSc) upon graduation. After graduation, physicians may choose to apply for and complete a research doctorate, earning them a PhD in Medicine. In international communication, Dutch medical graduates may identify themselves as MD. Whilst this title is neither officially awarded nor regulated in the Netherlands, its use is legally permitted. In Portugal, to practice medicine, a master's degree in medicine (awarded after a six-year Integrated master's program in medicine) is mandatory. Before the 2007 Bologna Process, the same course was only a Licentiate Degree. After the six-year program, students must go through the National Seriation Exam (Prova Nacional de Seriação), and then a year of General Medical Internship (Ano Comum). When the internship ends, the students are placed in their choice of Medical Specialty, according to their ranking in the aforementioned Exam and the vacancies available for each medical specialty. Only when each student finishes the Medical Internship, will they be allowed to practice medicine without supervision. Entry to the Integrated Masters Program in Medicine is done directly after high school, based on the student's grade – each year there are about 1800 new Medical Students in Portugal, in eight different Medical Schools. In Sudan the awarded degree in most of the medical schools is, Bachelor of Medicine and Basic Surgery (MBBS). In schools that are based on the English system of medical teaching, the degree is granted after six years of studying. As for the schools that are adopting the American system, they grant their students the degree of MBBS in only five years. In Sweden, medical education begins with a five-and-a-half-year undergraduate university program including the successful completion of examinations, which includes both theoretical and practical elements. Depending upon university, a research thesis must also be completed during this time. This leads to the degree "Master of Science in Medicine" (Swedish: Läkarexamen). Following this, the National Board of Health and Welfare requires a minimum of 18 months of clinical internship (Swedish: AT (Allmäntjänstgöring)) before granting a medical license (Swedish: Läkarlegitimation) to be fully qualified as the Swedish equivalent to Medical Doctor (MD). This internship consists of surgery (3–6 months), internal medicine (3–6 months), psychiatry (three months) and family medicine (six months). Upon receiving a license to practice, a physician is able to apply for a post to start specialist training. There are currently 52 recognised medical specialties in Sweden. The specialist training (Swedish: ST (Specialiseringstjänstgöring)) has a duration of minimum five years, which upon completion grants formal qualification as a specialist. === Other postgraduate clinical degrees === There is also a similar advanced professional degree to the postgraduate MD: the Master of Surgery (usually ChM or MS, but MCh in Scotland, Ireland, Wales and at Oxford and MChir at Cambridge). The equivalence of these degrees, but their differing names, prevents the need for surgeons (addressed as Mr. in the UK) having to revert to the title Dr., which they once held as new MBBS graduates. In Ireland, where the basic medical qualification includes a degree in obstetrics, there is a similar higher degree of Master of the Art of Obstetrics (MAO). A Master of Midwifery was formerly examined by the Worshipful Society of Apothecaries of London (hence MMSA) but fell into abeyance in the 1960s; in this case, the term Master referred not to a university degree but rather a professional rank that is common among craft guilds. In East Africa, the medical schools in Kenya, Tanzania and Uganda award the degree of Master of Medicine (MMed) degree in both surgical and medical specialty disciplines following a three to six-year period of instruction. In Ethiopia students first finish high school then take a university entrance exam then based on their result (it is highly competitive) then start medical school. Recently, there is a further requirement to take another one year in university studying a common course and then take another exam to join medicine. After that the students begins studying preclinical medicine for three years studying anatomy, physiology, biochemistry, histology, embryology, pathology, pharmacology, microbiology and other minor courses of public health then at 4th year students join the clinical rotation ranging from physical examination and history taking to different specialities like internal medicine, surgery, paediatrics, and obstetrics and gynaecology for two years, and other minor specialities like psychiatry, ophthalmology, dermatology, ENT. After finishing these courses students take a qualification exam and become intern doctors for one year, before graduating as a general practitioner and serving two or more years in primary hospitals. They can then take a national residency exam, and pending good results, join their speciality. In West Africa, the West African College of Physicians and the West African College of Surgeons award the Fellowship of the West African College of Physicians (FWACP) and the Fellowship of the West African College of Surgeons (FWACS) in medical and surgical disciplines respectively after a minimum of four-year residency training period. The Doctor of Osteopathic Medicine or DO degree allows the same practice rights in the United States and Canada to the MD degree and Doctors of Osteopathic Medicine are fully licensed physicians. Holders of the MD degree must pass MD level board exams while DO holders can pass either the DO (COMLEX) exam or MD exam (USMLE). Similarly, MDs must attend MD rated residency and fellowship programs while DOs can attend either MD programs or Osteopathic (DO) programs. As a result of this, the Accreditation Council for Graduate Medical Education (ACGME) are currently transitioning to a single accreditation system for medical residencies in the U.S. The American MD degree is also recognized by most countries in the world, while DO physicians are only licensed to practice the full scope of medicine and surgery in approximately 50 countries, as of 2012, with partial rights in a number of other nations. == See also == Bachelor of Medicine, Bachelor of Surgery Pre-medical == References ==	Wikipedia/Medical_doctorate
Legionnaires' disease is a form of atypical pneumonia caused by any species of Legionella bacteria, quite often Legionella pneumophila. Signs and symptoms include cough, shortness of breath, high fever, muscle pains, and headaches. Nausea, vomiting, and diarrhea may also occur. This often begins 2–10 days after exposure. A legionellosis is any disease caused by Legionella, including Legionnaires' disease (a pneumonia) and Pontiac fever (a related upper respiratory tract infection), but Legionnaires' disease is the most common, so mentions of legionellosis often refer to Legionnaires' disease. The bacterium is found naturally in fresh water. It can contaminate hot water tanks, hot tubs, and cooling towers of large air conditioners. It is usually spread by breathing in mist that contains the bacteria. It can also occur when contaminated water is aspirated. It typically does not spread directly between people, and most people who are exposed do not become infected. Risk factors for infection include older age, a history of smoking, chronic lung disease, and poor immune function. Those with severe pneumonia and those with pneumonia and a recent travel history should be tested for the disease. Diagnosis is by a urinary antigen test and sputum culture. No vaccine is available. Prevention depends on good maintenance of water systems. Treatment of Legionnaires' disease is commonly conducted with antibiotics. Recommended agents include fluoroquinolones, azithromycin, or doxycycline. Hospitalization is often required. The fatality rate is around 10% for healthy persons and 25% for those with underlying conditions. The number of cases that occur globally is not known. Legionnaires' disease is the cause of an estimated 2–9% of pneumonia cases that are acquired outside of a hospital. An estimated 8,000 to 18,000 cases a year in the United States require hospitalization. Outbreaks of disease account for a minority of cases. While it can occur any time of the year, it is more common in the summer and autumn. The disease is named after the outbreak where it was first identified, at a 1976 American Legion convention in Philadelphia. == Signs and symptoms == The length of time between exposure to the bacteria and the appearance of symptoms (incubation period) is generally 2–10 days, but can more rarely extend to as long as 20 days. For the general population, among those exposed, between 0.1 and 5.0% develop the disease, while among those in hospital, between 0.4 and 14% develop the disease. Those with Legionnaires' disease usually have fever, chills, and a cough, which may be dry or may produce sputum. Almost all experience fever, while around half have cough with sputum, and one-third cough up blood or bloody sputum. Some also have muscle aches, headache, tiredness, loss of appetite, loss of coordination (ataxia), chest pain, or diarrhea and vomiting. Up to half of those with Legionnaires' disease have gastrointestinal symptoms, and almost half have neurological symptoms, including confusion and impaired cognition. "Relative bradycardia" may also be present, which is low to normal heart rate despite the presence of a fever. Laboratory tests may show that kidney functions, liver functions, and electrolyte levels are abnormal, which may include low sodium in the blood. Chest X-rays often show pneumonia with consolidation in the bottom portion of both lungs. Distinguishing Legionnaires' disease from other types of pneumonia by symptoms or radiologic findings alone is difficult; other tests are required for definitive diagnosis. People with Pontiac fever, a much milder illness caused by the same bacterium, experience fever and muscle aches without pneumonia. They generally recover in 2–5 days without treatment. For Pontiac fever, the time between exposure and symptoms is generally a few hours to two days. == Cause == Over 90% of cases of Legionnaires' disease are caused by Legionella pneumophila. Other types include L. longbeachae, L. feeleii, L. micdadei, and L. anisa. === Transmission === Legionnaires' disease is usually spread by the breathing in of aerosolized water or soil contaminated with the Legionella bacteria. Experts have stated that Legionnaires' disease is not transmitted from person to person. In 2014, one case of possible spread from someone sick to the caregiver occurred. Rarely, it has been transmitted by direct contact between contaminated water and surgical wounds. The bacteria grow best at warm temperatures and thrive at water temperatures between 25 and 45 °C (77 and 113 °F), with an optimum temperature of 35 °C (95 °F). Temperatures above 60 °C (140 °F) kill the bacteria. Sources where temperatures allow the bacteria to thrive include hot water tanks, cooling towers, and evaporative condensers of large air conditioning systems, such as those commonly found in hotels and large office buildings. Pre-1988, energy conservation programs from the late 1970s and early 1980s still mandated a maximum hot water generation, storage and distribution temperature of 110 °F (43 °C), unknowingly, legionella bacteria's ideal breeding temperature. To minimize risks of bacterial growth, the American Society of Heating, Refrigerating and Air-Conditioning Engineers' 1988 ASHRAE Standard 188 and subsequent ASHRAE Guideline 12-2000 increased recommended hot water generation and storage temperatures to 135–140 °F (57–60 °C) with minimum distribution temperatures of 124 °F (51 °C). Though the first known outbreak was in Philadelphia, cases of legionellosis have occurred throughout the world. === Reservoirs === L. pneumophila thrives in aquatic systems, where it is established within amoebae in a symbiotic relationship. Legionella bacteria survive in water as intracellular parasites of water-dwelling protozoa, such as amoebae. Amoebae are often part of biofilms, and once Legionella and infected amoebae are protected within a biofilm, they are particularly difficult to destroy. In the built environment, central air conditioning systems in office buildings, hotels, and hospitals are sources of contaminated water. Other places the bacteria can dwell include cooling towers used in industrial cooling systems, evaporative coolers, nebulizers, humidifiers, whirlpool spas, hot water systems, showers, windshield washers, fountains, room-air humidifiers, ice-making machines, and misting systems typically found in grocery-store produce sections. The bacteria may also be transmitted from contaminated aerosols generated in hot tubs if the disinfection and maintenance programs are not followed rigorously. Freshwater ponds, creeks, and ornamental fountains are potential sources of Legionella. The disease is particularly associated with hotels, fountains, cruise ships, and hospitals with complex potable water systems and cooling systems. Respiratory-care devices such as humidifiers and nebulizers used with contaminated tap water may contain Legionella species, so using sterile water is very important. Other sources include exposure to potting mix and compost. == Mechanism == Legionella spp. enter the lungs either by aspiration of contaminated water or inhalation of aerosolized contaminated water or soil. In the lung, the bacteria are consumed by macrophages, a type of white blood cell, inside of which the Legionella bacteria multiply, causing the death of the macrophage. Once the macrophage dies, the bacteria are released from the dead cell to infect other macrophages. Virulent strains of Legionella kill macrophages by blocking the fusion of phagosomes with lysosomes inside the host cell; normally, bacteria are contained inside the phagosome, which merges with a lysosome, allowing enzymes and other chemicals to break down the invading bacteria. == Diagnosis == People of any age may develop Legionnaires' disease, but the illness most often affects middle-aged and older people, particularly those who smoke cigarettes or have chronic lung disease. Immunocompromised people are also at higher risk. Pontiac fever most commonly occurs in those who are otherwise healthy. The most useful diagnostic tests detect the bacteria in coughed-up mucus, find Legionella antigens in urine samples, or allow comparison of Legionella antibody levels in two blood samples taken 3–6 weeks apart. A urine antigen test is simple, quick, and very reliable, but only detects L. pneumophila serogroup 1, which accounts for 70% of disease caused by L. pneumophila, which means use of the urine antigen test alone may miss as many as 30% of cases. This test was developed by Richard Kohler in 1982. When dealing with L. pneumophila serogroup 1, the urine antigen test is useful for early detection of Legionnaire's disease and initiation of treatment, and has been helpful in early detection of outbreaks. However, it does not identify the specific subtypes, so it cannot be used to match the person with the environmental source of infection. The Legionella bacteria can be cultured from sputum or other respiratory samples. Legionella spp. stain poorly with Gram stain, stain positive with silver, and are cultured on charcoal yeast extract with iron and cysteine (CYE agar). A significant under-reporting problem occurs with legionellosis. Even in countries with effective health services and readily available diagnostic testing, about 90% of cases of Legionnaires' disease are missed. This is partly due to the disease being a relatively rare form of pneumonia, which many clinicians may not have encountered before, thus may misdiagnose. A further issue is that people with legionellosis can present with a wide range of symptoms, some of which (such as diarrhea) may distract clinicians from making a correct diagnosis. == Prevention == Although the risk of Legionnaires' disease being spread by large-scale water systems cannot be eliminated, it can be greatly reduced by writing and enforcing a highly detailed, systematic water safety plan appropriate for the specific facility involved (office building, hospital, hotel, spa, cruise ship, etc.) Some of the elements that such a plan may include are: Keep water temperature either below or above the 20–55 °C (68–131 °F) range in which the Legionella bacterium thrives. Prevent stagnation, for example, by removing from a network of pipes any sections that have no outlet (dead ends). Where stagnation is unavoidable, as when a wing of a hotel is closed for the off-season, remedial measures are recommended, e.g., maintaining elevated temperatures throughout the hot-water distribution system and periodic disinfection or permanent chlorination of cold-water systems. Prevention of biofilms is crucial because once established they become more difficult to remove from piping systems. The likelihood of formation is increased by pipe scale and corrosion; warm water temperatures; stagnation and the quantity of nutrients that enter the system. Periodically disinfect the system, by high heat or a chemical biocide, and use chlorination where appropriate. Monochloramine is likely more effective than free chlorine (sodium hypochlorite), being more resistant with residuals likely to persist to the point of delivery. Monochloramine is also more likely to penetrate legionella biofilms. Treatment of water with copper-silver ionization or ultraviolet light may also be effective. System design (or renovation) can reduce the production of aerosols and reduce human exposure to them, by directing them well away from building air intakes. An effective water safety plan also covers such matters as training, record-keeping, communication among staff, contingency plans, and management responsibilities. The format and content of the plan may be prescribed by public health laws or regulations. To inform the water safety plan, the undertaking of a site specific legionella risk assessment is often recommended in the first instance. The legionella risk assessment identifies the hazards, the level of risk they pose and provides recommendations of control measures to put in place within the overarching water safety plan. == Treatment == Effective antibiotics include most macrolides, tetracyclines, ketolides, and quinolones. Legionella spp. multiply within the cell, so any effective treatment must have excellent intracellular penetration. Current treatments of choice are the respiratory tract quinolones (levofloxacin, moxifloxacin, gemifloxacin) or newer macrolides (azithromycin, clarithromycin, roxithromycin). The antibiotics used most frequently have been levofloxacin, doxycycline, and azithromycin. Macrolides (azithromycin) are used in all age groups, while tetracyclines (doxycycline) are prescribed for children above the age of 12 and quinolones (levofloxacin) above the age of 18. Rifampicin can be used in combination with a quinolone or macrolide. Whether rifampicin is an effective antibiotic to take for treatment is uncertain. The Infectious Diseases Society of America does not recommend the use of rifampicin with added regimens. Tetracyclines and erythromycin led to improved outcomes compared to other antibiotics in the original American Legion outbreak. These antibiotics are effective because they have excellent intracellular penetration in Legionella-infected cells. The recommended treatment is 5–10 days of levofloxacin or 3–5 days of azithromycin, but in people who are immunocompromised, have severe disease, or other pre-existing health conditions, longer antibiotic use may be necessary. During outbreaks, prophylactic antibiotics have been used to prevent Legionnaires' disease in high-risk individuals who have possibly been exposed. The mortality at the original American Legion convention in 1976 was high (29 deaths in 182 infected individuals) because the antibiotics used (including penicillins, cephalosporins, and aminoglycosides) had poor intracellular penetration. Mortality has plunged to less than 5% if therapy is started quickly. Delay in giving the appropriate antibiotic leads to higher mortality. == Prognosis == The fatality rate of Legionnaires' disease has ranged from 5–30% during various outbreaks and approaches 50% for nosocomial infections, especially when treatment with antibiotics is delayed. Hospital-acquired Legionella pneumonia has a fatality rate of 28%, and the principal source of infection in such cases is the drinking-water distribution system. == Epidemiology == Legionnaires' disease acquired its name in July 1976, when an outbreak of pneumonia occurred among people attending a convention of the American Legion at the Bellevue-Stratford Hotel in Philadelphia. Of the 182 reported cases, mostly men, 29 died. On 18 January 1977, the causative agent was identified as a previously unknown strain of bacteria, subsequently named Legionella, and the species that caused the outbreak was named Legionella pneumophila. Following this discovery, unexplained outbreaks of severe respiratory disease from the 1950s were retrospectively attributed to Legionella. Legionnaires' disease also became a prominent historical example of an emerging infectious disease. Outbreaks of Legionnaires' disease receive significant media attention, but this disease usually occurs in single, isolated cases not associated with any recognized outbreak. When outbreaks do occur, they are usually in the summer and early autumn, though cases may occur at any time of year. Most infections occur in those who are middle-aged or older. National surveillance systems and research studies were established early, and in recent years, improved ascertainment and changes in clinical methods of diagnosis have contributed to an upsurge in reported cases in many countries. Environmental studies continue to identify novel sources of infection, leading to regular revisions of guidelines and regulations. About 8,000 to 18,000 cases of Legionnaires' disease occur each year in the United States, according to the Bureau of Communicable Disease Control. Between 1995 and 2005, over 32,000 cases of Legionnaires' disease and more than 600 outbreaks were reported to the European Working Group for Legionella Infections. The data on Legionella are limited in developing countries, and Legionella-related illnesses likely are underdiagnosed worldwide. Improvements in diagnosis and surveillance in developing countries would be expected to reveal far higher levels of morbidity and mortality than are currently recognised. Similarly, improved diagnosis of human illness related to Legionella species and serogroups other than Legionella pneumophila would improve knowledge about their incidence and spread. A 2011 study successfully used modeling to predict the likely number of cases during Legionnaires' outbreaks based on symptom onset dates from past outbreaks. In this way, the eventual likely size of an outbreak can be predicted, enabling efficient and effective use of public-health resources in managing an outbreak. During the COVID-19 pandemic, some researchers and organisations raised concerns about the impact of the COVID-19 lockdowns on Legionnaire's disease outbreaks. Additionally, at least two people in England died from a co-infection of Legionella and SARS-CoV-2. === Outbreaks === An outbreak is defined as two or more cases where the onset of illness is closely linked in time (weeks rather than months) and space, where a suspicion or evidence exists of a common source of infection, with or without microbiological support (i.e. common spatial location of cases from travel history). In April 1985, 175 people in Stafford, England, were admitted to the District or Kingsmead Stafford Hospitals with chest infection or pneumonia. A total of 28 people died. Medical diagnosis showed that Legionnaires' disease was responsible and the immediate epidemiological investigation traced the source of the infection to the air-conditioning cooling tower on the roof of Stafford District Hospital. In March 1999, a large outbreak in the Netherlands occurred during the Westfriese Flora flower exhibition in Bovenkarspel; 318 people became ill and at least 32 people died. This was the second-deadliest outbreak since the 1976 outbreak and possibly the deadliest, as several people were buried before Legionnaires' disease had been diagnosed. The world's largest outbreak of Legionnaires' disease happened in July 2001, with people appearing at the hospital on 7 July, in Murcia, Spain. More than 800 suspected cases were recorded by the time the last case was treated on 22 July; 636–696 of these cases were estimated and 449 confirmed (so, at least 16,000 people were exposed to the bacterium) and six died, a case-fatality rate around 1%. In September 2005, 127 residents of a nursing home in Canada became ill with L. pneumophila. Within a week, 21 of the residents had died. Culture results at first were negative, which is not unusual, as L. pneumophila is a "fastidious" bacterium, meaning it requires specific nutrients, living conditions, or both to grow. The source of the outbreak was traced to the air-conditioning cooling towers on the nursing home's roof. In an outbreak in lower Quebec City, Canada, 180 people were affected with 13 resulting deaths due to contaminated water in a cooling tower. In November 2014, 302 people were hospitalized following an outbreak of legionellosis in Portugal, and seven related deaths were reported. All cases emerged in three civil parishes from the municipality of Vila Franca de Xira in the northern outskirts of Lisbon, and were treated in hospitals of the greater Lisbon area. The source is suspected to be located in the cooling towers of the fertilizer plant Fertibéria. Twelve people were diagnosed with the disease in an outbreak in the Bronx, New York, in December 2014; the source was traced to contaminated cooling towers at a housing development. In July and August 2015, another, unrelated outbreak in the Bronx killed 12 people and made about 120 people sick; the cases arose from a cooling tower on top of a hotel. At the end of September, another person died of the disease and 13 were sickened in yet another unrelated outbreak in the Bronx. The cooling towers from which the people were infected in the latter outbreak had been cleaned during the summer outbreak, raising concerns about how well the bacteria could be controlled. On 28 August 2015, an outbreak of Legionnaire's disease was detected at San Quentin State Prison in Northern California; 81 people were sickened and the cause was sludge that had built up in cooling towers. Between June 2015, and January 2016, 87 cases of Legionnaires' disease were reported by the Michigan Department of Health and Human Services for the city of Flint, Michigan, and surrounding areas. The outbreak may have been linked to the Flint water crisis, in which the city's water source was changed to a cheaper and inadequately treated source. Ten of those cases were fatal. In November 2017, an outbreak was detected at Hospital de São Francisco Xavier, Lisbon, Portugal, with up to 53 people being diagnosed with the disease and five of them dying from it. In Quincy, Illinois, at the Illinois Veterans Home, a 2015 outbreak of the disease killed 12 people and sickened more than 50 others. It was believed to be caused by infected water supply. Three more cases were identified by November 2017. In the autumn of 2017, 22 cases were reported in a Legionnaires' disease outbreak at Disneyland in Anaheim, California. It was believed to have been caused by a cooling tower that releases mist for the comfort of visitors. The contaminated droplets likely spread to the people in and beyond the park. In July 2019, 11 former guests of the Sheraton Atlanta hotel were diagnosed with the disease, with 55 additional probable cases. In September 2019, 141 visitors to the Western North Carolina Mountain State Fair were diagnosed with Legionnaires' disease, with four reported deaths, after a hot tub exhibit is suspected to have developed and spread the bacteria. At least one additional exposure apparently occurred during the Asheville Quilt Show that took place a few weeks after the fair in the same building where the hot tub exhibit was held. The building had been sanitized after the outbreak. In December 2019, the government of Western Australia's Department of Health was notified of four cases of Legionnaires' disease. Those exposed had recently visited near Bali's Ramayana Resort and Spa in central Kuta. In February 2024, Minnesota Department of Health issued a news release stating that fourteen (14) cases were identified in Grand Rapids, Minnesota since April 2023 which they attributed to the municipal water supply. In January 2024, NSW Health issued an alert for Legionnaires' disease for Sydney CBD. As of 3 January 2024, 7 known cases requiring hospitalization had been reported. == References == == External links == "Legionnaires' Disease". MedlinePlus. U.S. National Library of Medicine.	Wikipedia/Legionnaire's_disease
Minimally invasive procedures (also known as minimally invasive surgeries) encompass surgical techniques that limit the size of incisions needed, thereby reducing wound healing time, associated pain, and risk of infection. Surgery by definition is invasive, and many operations requiring incisions of some size are referred to as open surgery. Incisions made during open surgery can sometimes leave large wounds that may be painful and take a long time to heal. Advancements in medical technologies have enabled the development and regular use of minimally invasive procedures. For example, endovascular aneurysm repair, a minimally invasive surgery, has become the most common method of repairing abdominal aortic aneurysms in the US as of 2003. The procedure involves much smaller incisions than the corresponding open surgery procedure of open aortic surgery. Interventional radiologists were the forerunners of minimally invasive procedures. Using imaging techniques, radiologists were able to direct interventional instruments through the body by way of catheters instead of the large incisions needed in traditional surgery. As a result, many conditions once requiring surgery can now be treated non-surgically. Diagnostic techniques that do not involve incisions, puncturing the skin, or the introduction of foreign objects or materials into the body are known as non-invasive procedures. Several treatment procedures are classified as non-invasive. A major example of a non-invasive alternative treatment to surgery is radiation therapy, also called radiotherapy. == Medical uses == Minimally invasive procedures were pioneered by interventional radiologists who had first introduced angioplasty and the catheter-delivered stent. Many other minimally invasive procedures have followed where images of all parts of the body can be obtained and used to direct interventional instruments by way of catheters (needles and fine tubes), so that many conditions once requiring open surgery can now be treated non-surgically. A minimally invasive procedure typically involves the use of arthroscopic (for joints and the spine) or laparoscopic devices and remote-control manipulation of instruments with indirect observation of the surgical field through an endoscope or large scale display panel, and is carried out through the skin or through a body cavity or anatomical opening. Interventional radiology now offers many techniques that avoid the need for surgery. By use of a minimally invasive procedure, a patient may require only an adhesive bandage on the incision, rather than multiple stitches or staples to close a large incision. This usually results in less infection, a quicker recovery time and shorter hospital stays, or allow outpatient treatment. However, the safety and effectiveness of each procedure must be demonstrated with randomized controlled trials. The term was coined by John E. A. Wickham in 1984, who wrote of it in British Medical Journal in 1987. == Specific procedures == Many medical procedures are called minimally invasive; those that involve small incisions through which an endoscope is inserted, end in the suffix -oscopy, such as endoscopy, laparoscopy, arthroscopy. Other examples of minimally invasive procedures include the use of hypodermic injection, and air-pressure injection, subdermal implants, refractive surgery, percutaneous surgery, cryosurgery, microsurgery, keyhole surgery, endovascular surgery using interventional radiology (such as angioplasty or embolization), coronary catheterization, permanent placement of spinal and brain electrodes, stereotactic surgery, the Nuss procedure, radioactivity-based medical imaging methods, such as gamma camera, positron emission tomography and SPECT (single photon emission tomography). Related procedures are image-guided surgery, and robot-assisted surgery. == Equipment == Special medical equipment may be used, such as fiber optic cables, miniature video cameras and special surgical instruments handled via tubes inserted into the body through small openings in its surface. The images of the interior of the body are transmitted to an external video monitor and the surgeon has the possibility of making a diagnosis, visually identifying internal features and acting surgically on them. == Benefits == Minimally invasive surgery should have less operative trauma, other complications and adverse effects than an equivalent open surgery. It may be more or less expensive (for dental implants, a minimally invasive method reduces the cost of installed implants and shortens the implant-prosthetic rehabilitation time with four–six months). Operative time is longer, but hospitalization time is shorter. It causes less pain and scarring, speeds recovery, and reduces the incidence of post-surgical complications, such as adhesions and wound rupture. Some studies have compared heart surgery. == Risks == Risks and complications of minimally invasive procedures are the same as for any other surgical operation, among the risks are: death, bleeding, infection, organ injury, and thromboembolic disease. There may be an increased risk of hypothermia and peritoneal trauma due to increased exposure to cold, dry gases during insufflation. The use of surgical humidification therapy, which is the use of heated and humidified CO2 for insufflation, may reduce this risk. == Invasive procedures == Sometimes the use of non-invasive methods is not an option, so that the next level of minimally invasive techniques are looked to. These include the use of hypodermic injection (using the syringe), an endoscope, percutaneous surgery which involves needle puncture of the skin, laparoscopic surgery commonly called keyhole surgery, a coronary catheter, angioplasty and stereotactic surgery. === Open surgery === "Open surgery" is any surgical procedure where the incision made is enough to allow the surgery to take place. With tissues and structures exposed to the air, the procedure can be performed either with the unaided vision of the surgeon or with the use of loupes or microscopes. Some examples of open surgery used are for herniated disc commonly called a "slipped disc", and most types of cardiac surgery and neurosurgery. == Associations == Society of American Gastrointestinal and Endoscopic Surgeons (SAGES) for adults. International Pediatric Endosurgery Group (IPEG) for pediatrics. == See also == == References == == Further reading == == External links == Minimally invasive heart surgery. Medical Encyclopedia, MedlinePlus.	Wikipedia/Invasive_surgery
Magnetic resonance elastography (MRE) is a form of elastography that specifically leverages MRI to quantify and subsequently map the mechanical properties (elasticity or stiffness) of soft tissue. First developed and described at Mayo Clinic by Muthupillai et al. in 1995, MRE has emerged as a powerful, non-invasive diagnostic tool, namely as an alternative to biopsy and serum tests for staging liver fibrosis. Diseased tissue (e.g. a breast tumor) is often stiffer than the surrounding normal (fibroglandular) tissue, providing motivation to assess tissue stiffness. This principle of operation is the basis for the longstanding practice of palpation, which, however, is limited (except at surgery) to superficial organs and pathologies, and by its subjective, qualitative nature, depending on the skill and touch sensitivity of the practitioner. Conventional imaging techniques of CT, MRI, US, and nuclear medicine are unable to offer any insight on the elastic modulus of soft tissue. MRE, as a quantitative method of assessing tissue stiffness, provides reliable insight to visualize a variety of disease processes which affect tissue stiffness in the liver, brain, heart, pancreas, kidney, spleen, breast, uterus, prostate, and skeletal muscle. MRE is conducted in three steps: first, a mechanical vibrator is used on the surface of the patient's body to generate shear waves that travel into the patient's deeper tissues; second, an MRI acquisition sequence measures the propagation and velocity of the waves; and finally this information is processed by an inversion algorithm to quantitatively infer and map tissue stiffness in 3-D. This stiffness map is called an elastogram, and is the final output of MRE, along with conventional 3-D MRI images as shown on the right. == Mechanics of soft tissue == MRE quantitatively determines the stiffness of biological tissues by measuring its mechanical response to an external stress. Specifically, MRE calculates the shear modulus of a tissue from its shear-wave displacement measurements. The elastic modulus quantifies the stiffness of a material, or how well it resists elastic deformation as a force is applied. For elastic materials, strain is directly proportional to stress within an elastic region. The elastic modulus is seen as the proportionality constant between stress and strain within this region. Unlike purely elastic materials, biological tissues are viscoelastic, meaning that it has characteristics of both elastic solids and viscous liquids. Their mechanical responses depend on the magnitude of the applied stress as well as the strain rate. The stress-strain curve for a viscoelastic material exhibits hysteresis. The area of the hysteresis loop represents the amount of energy lost as heat when a viscoelastic material undergoes an applied stress and is distorted. For these materials, the elastic modulus is complex and can be separated into two components: a storage modulus and a loss modulus. The storage modulus expresses the contribution from elastic solid behavior while the loss modulus expresses the contribution from viscous liquid behavior. Conversely, elastic materials exhibit a pure solid response. When a force is applied, these materials elastically store and release energy, which does not result in energy loss in the form of heat. Yet, MRE and other elastography imaging techniques typically utilize a mechanical parameter estimation that assumes biological tissues to be linearly elastic and isotropic for simplicity purposes. The effective shear modulus μ {\displaystyle \mu } can be expressed with the following equation: μ = E / [ 2 ( 1 + ν ) ] {\displaystyle \mu =E/[2(1+\nu )]} where E {\displaystyle E} is the elastic modulus of the material and ν {\displaystyle \nu } is the Poisson's ratio. The Poisson's ratio for soft tissues is approximated to equal 0.5, resulting in the ratio between the elastic modulus and shear modulus to equal 3. This relationship can be used to estimate the stiffness of biological tissues based on the calculated shear modulus from shear-wave propagation measurements. A driver system produces and transmits acoustic waves set at a specific frequency (50–500 Hz) to the tissue sample. At these frequencies, the velocity of shear waves can be about 1–10 m/s. The effective shear modulus can be calculated from the shear wave velocity with the following: μ = ρ v s 2 {\displaystyle \mu =\rho {v_{s}}^{2}} where ρ {\displaystyle \rho } is the tissue density and v s {\displaystyle v_{s}} is the shear wave velocity. Recent studies have been focused on incorporating mechanical parameter estimations into post-processing inverse algorithms that account for the complex viscoelastic behavior of soft tissues. Creating new parameters could potentially increase the specificity of MRE measurements and diagnostic testing. == Applications == === Liver === Liver fibrosis is a common condition arising in many liver diseases. Progression of fibrosis can lead to cirrhosis and end-stage liver disease. MRE-based measurement of liver stiffness has emerged as the most accurate non-invasive technique for detecting and staging liver fibrosis. MRE provides quantitative maps of tissue stiffness over large regions of the liver. Abnormally increased liver stiffness is a direct consequence of liver fibrosis. The diagnostic performance of MRE in assessing liver fibrosis has been established in multiple studies. Liver MRE examinations are performed in MRI systems that have been equipped for the technique. Patients should fast for 3 to 4 hours prior to their MRE exam to allow for the most accurate measurement of liver stiffness. Patients lie supine in the MRI scanner for the examination. A special device is placed on the right side of the chest wall over the liver to apply gentle vibration which generates propagating shear waves in the liver. Imaging is for MRE is very quick, with data acquired in a series of 1-4 periods of breath-holding, each lasting 15–20 seconds. A standardized approach for performing and analyzing liver MRE exams has been documented by the RSNA Quantitative Imaging Biomarkers Alliance. The technical success rate of Liver MRE is very high (95-100%) === Brain === MRE of the brain was first presented in the early 2000s. Elastogram measures have been correlated with memory tasks, fitness measures, and progression of various neurodegenerative conditions. For example, regional and global decreases in brain viscoelasticity have been observed in Alzheimer's disease and multiple sclerosis. It has been found that as the brain ages, it loses its viscoelastic integrity due to degeneration of neurons and oligodendrocytes. A recent study looked into both the isotropic and anisotropic stiffness in brain and found a correlation between the two and with age, particularly in gray matter. MRE may also have applications for understanding the adolescent brain. Recently, it was found that adolescents have regional differences in brain viscoelasticity relative to adults. MRE has also been applied to functional neuroimaging. Whereas functional magnetic resonance imaging (fMRI) infers brain activity by detecting relatively slow changes in blood flow, functional MRE is capable of detecting neuromechanical changes in the brain related to neuronal activity occurring on the 100-millisecond scale. === Kidney === MRE has also been applied to investigate the biomechanical properties of the kidney. The feasibility of clinical renal MRE was first reported in 2011 for healthy volunteers and in 2012 for renal transplant patients. Renal MRE is more challenging than MRE of larger organs such as the brain or liver due to fine mechanical features in the renal cortex and medulla as well as the acoustically shielded position of the kidneys within the abdominal cavity. To overcome these challenges, researchers have been looking at different passive drivers and imaging techniques to best deliver shear waves to the kidneys. Studies investigating renal diseases such as renal allograft dysfunction, lupus nephritis, immunoglobulin A nephropathy (IgAN), diabetic nephrology, renal tumors and chronic kidney disease demonstrate that kidney stiffness is sensitive to kidney function and renal perfusion. === Prostate === The prostate can also be examined by MRE, in particular for the detection and diagnosis of prostate cancer. To ensure good shear wave penetration in the prostate gland, different actuator systems were designed and evaluated. Preliminary results in patients with prostate cancer showed that changes in stiffness allowed differentiation of cancerous tissue from normal tissue. Magnetic Resonance Elastography has been successfully used in patients with prostate cancer showing high specificity and sensitivity in differentiating prostate cancer from benign prostatic diseases (see figure on right (b)). Even higher specificity of 95% for prostate cancer was achieved when Magnetic Resonance Elastography was combined with systematic image interpretation using PI-RADS (version 2.1). === Pancreas === The pancreas is one of the softest tissues in the abdomen. Given that pancreatic diseases including pancreatitis and pancreatic cancer significantly increase stiffness, MRE is a promising tool for diagnosing benign and malignant conditions of the pancreas. Abnormally high pancreatic stiffness was detected by MRE in patients with both acute and chronic pancreatitis. Pancreatic stiffness was also used to distinguish pancreatic malignancy from benign masses and to predict the occurrence of pancreatic fistula after pancreaticoenteric anastomosis. Quantification of the volume of pancreatic tumors based on tomoelastographic measurement of stiffness was found to be excellently correlated with tumor volumes estimated by contrast-enhanced computed tomography. In patients with pancreatic ductal adenocarcinoma stiffness was found to be elevated in the tumor as well as in pancreatic parenchyma distal to the tumor, suggesting heterogeneous pancreatic involvement (figure on right (c)). == See also == Strain–encoded magnetic resonance imaging Tomoelastography == References ==	Wikipedia/Magnetic_resonance_elastography
Physics in Medicine & Biology is a biweekly peer-reviewed medical journal covering research on the application of physics to medicine, physiology, and biology. It was established in 1956 and is published by IOP Publishing on behalf of the Institute of Physics and Engineering in Medicine. It is also an official journal of the following medical societies: Canadian Organization of Medical Physics, Deutsche Gesellschaft für Medizinische Physik, Japanese Association of Radiological Physics, European Federation of Organisations for Medical Physics, and the International Organization for Medical Physics. The editor-in-chief is Katia Parodi (Ludwig Maximilian University of Munich). == Abstracting and indexing == The journal is abstracted and indexed in: Inspec Chemical Abstracts BIOSIS Previews/Biological Abstracts Compendex Embase/Excerpta Medica PASCAL Science Citation Index Current Contents Index Medicus/MEDLINE/PubMed VINITI Database RAS According to the Journal Citation Reports, the journal has a 2023 impact factor of 3.3. == References == == External links == Official website	Wikipedia/Physics_in_Medicine_and_Biology
Fatty liver disease (FLD), also known as hepatic steatosis and steatotic liver disease (SLD), is a condition where excess fat builds up in the liver. Often there are no or few symptoms. Occasionally there may be tiredness or pain in the upper right side of the abdomen. Complications may include cirrhosis, liver cancer, and esophageal varices. The main subtypes of fatty liver disease are metabolic dysfunction–associated steatotic liver disease (MASLD, formerly "non-alcoholic fatty liver disease" (NAFLD)) and alcoholic liver disease (ALD), with the category "metabolic and alcohol associated liver disease" (metALD) describing an overlap of the two. The primary risks include alcohol, type 2 diabetes, and obesity. Other risk factors include certain medications such as glucocorticoids, and hepatitis C. It is unclear why some people with NAFLD develop simple fatty liver and others develop nonalcoholic steatohepatitis (NASH), which is associated with poorer outcomes. Diagnosis is based on the medical history supported by blood tests, medical imaging, and occasionally liver biopsy. Treatment of NAFLD is generally by dietary changes and exercise to bring about weight loss. In those who are severely affected, liver transplantation may be an option. More than 90% of heavy drinkers develop fatty liver while about 25% develop the more severe alcoholic hepatitis. NAFLD affects about 30% of people in Western countries and 10% of people in Asia. NAFLD affects about 10% of children in the United States. It occurs more often in older people and males. == Classification == Fatty liver disease was classified into: Non-alcoholic fatty liver disease (NAFLD) made up of: Non-alcoholic fatty liver (NAFL) or simple fatty liver Non-alcoholic steatohepatitis (NASH) Alcoholic liver disease (ALD). In 2023, a new nomenclature was chosen, with the classifications including: Metabolic dysfunction–associated steatotic liver disease (MASLD), including: Metabolic dysfunction-associated steatohepatitis (MASH) Metabolic and alcohol associated liver disease (metALD). Describes those with MASLD who consume greater amounts of alcohol per week but not enough to be categorized as ALD) Alcohol-associated liver disease (ALD) Specific aetiology SLD (including drug-induced, monogenic diseases and others) == Signs and symptoms == Often there are no or few symptoms. Occasionally there may be tiredness or pain in the upper right side of the abdomen. === Complications === Fatty liver can develop into hepatic fibrosis, cirrhosis or liver cancer. For people affected by NAFLD, the 10-year survival rate was about 80%. The rate of progression of fibrosis is estimated to be one per 7 years in NASH and one per 14 years in NAFLD, with an increasing speed. There is a strong relationship between these pathologies and metabolic illnesses (diabetes type II, metabolic syndrome). These pathologies can also affect non-obese people, who are then at a higher risk. Less than 10% of people with cirrhotic alcoholic FLD will develop hepatocellular carcinoma, the most common type of primary liver cancer in adults, but up to 45% people with NASH without cirrhosis can develop hepatocellular carcinoma. The condition is also associated with other diseases that influence fat metabolism. == Causes == Fatty liver (FL) is commonly associated with metabolic syndrome (diabetes, hypertension, obesity, and dyslipidemia), but can also be due to any one of many causes: Alcohol Alcohol use disorder is one of the causes of fatty liver due to production of toxic metabolites like aldehydes during metabolism of alcohol in the liver. This phenomenon most commonly occurs with chronic alcohol use disorder. Metabolic abetalipoproteinemia, glycogen storage diseases, Weber–Christian disease, acute fatty liver of pregnancy, lipodystrophy Nutritional obesity, malnutrition, total parenteral nutrition, severe weight loss, refeeding syndrome, jejunoileal bypass, gastric bypass, jejunal diverticulosis with bacterial overgrowth Drugs and toxins amiodarone, methotrexate, diltiazem, expired tetracycline, highly active antiretroviral therapy, glucocorticoids, tamoxifen, environmental hepatotoxins (e.g., phosphorus, mushroom poisoning) Other celiac disease, inflammatory bowel disease, HIV, hepatitis C (especially genotype 3), and alpha 1-antitrypsin deficiency == Pathology == The fatty change represents the intracytoplasmatic accumulation of triglycerides (neutral fats). At the beginning, the hepatocytes present small fat vacuoles (liposomes) around the nucleus (microvesicular fatty change). In this stage, liver cells are filled with multiple fat droplets that do not displace the centrally located nucleus. In the late stages, the size of the vacuoles increases, pushing the nucleus to the periphery of the cell, giving a characteristic signet ring appearance (macrovesicular fatty change). These vesicles are well-delineated and optically "empty" because fats dissolve during tissue processing. Large vacuoles may coalesce and produce fatty cysts, which are irreversible lesions. Macrovesicular steatosis is the most common form and is typically associated with alcohol, diabetes, obesity, and corticosteroids. Acute fatty liver of pregnancy and Reye's syndrome are examples of severe liver disease caused by microvesicular fatty change. The diagnosis of steatosis is made when fat in the liver exceeds 5–10% by weight. Defects in fatty acid metabolism are responsible for pathogenesis of FLD, which may be due to imbalance in energy consumption and its combustion, resulting in lipid storage, or can be a consequence of peripheral resistance to insulin, whereby the transport of fatty acids from adipose tissue to the liver is increased. Impairment or inhibition of receptor molecules (PPAR-α, PPAR-γ and SREBP1) that control the enzymes responsible for the oxidation and synthesis of fatty acids appears to contribute to fat accumulation. In addition, alcohol use disorder is known to damage mitochondria and other cellular structures, further impairing cellular energy mechanism. On the other hand, non-alcoholic FLD may begin as excess of unmetabolised energy in liver cells. Hepatic steatosis is considered reversible and to some extent nonprogressive if the underlying cause is reduced or removed. Severe fatty liver is sometimes accompanied by inflammation, a situation referred to as steatohepatitis. Progression to alcoholic steatohepatitis (ASH) or non-alcoholic steatohepatitis (NASH) depends on the persistence or severity of the inciting cause. Pathological lesions in both conditions are similar. However, the extent of inflammatory response varies widely and does not always correlate with degree of fat accumulation. Steatosis (retention of lipid) and onset of steatohepatitis may represent successive stages in FLD progression. Liver disease with extensive inflammation and a high degree of steatosis often progresses to more severe forms of the disease. Hepatocyte ballooning and necrosis of varying degrees are often present at this stage. Liver cell death and inflammatory responses lead to the activation of hepatic stellate cells, which play a pivotal role in hepatic fibrosis. The extent of fibrosis varies widely. Perisinusoidal fibrosis is most common, especially in adults, and predominates in zone 3 around the terminal hepatic veins. The progression to cirrhosis may be influenced by the amount of fat and degree of steatohepatitis and by a variety of other sensitizing factors. In alcoholic FLD, the transition to cirrhosis related to continued alcohol consumption is well-documented, but the process involved in non-alcoholic FLD is less clear. == Diagnosis == Most individuals are asymptomatic and are usually discovered incidentally because of abnormal liver function tests or hepatomegaly noted in unrelated medical conditions. Elevated liver enzymes are found in as many as 50% of patients with simple steatosis.: 1794 The serum alanine transaminase (ALT) level usually is greater than the aspartate transaminase (AST) level in the nonalcoholic variant and the opposite in alcoholic FLD (AST:ALT more than 2:1). Simple blood tests may help to determine the magnitude of the disease by assessing the degree of liver fibrosis. For example, AST-to-platelets ratio index (APRI score) and several other scores, calculated from the results of blood tests, can detect the degree of liver fibrosis and predict the future formation of liver cancer. Imaging studies are often obtained during the evaluation process. Ultrasonography reveals a "bright" liver with increased echogenicity. Pocket-sized ultrasound devices might be used as point-of-care screening tools to diagnose liver steatosis. Medical imaging can aid in diagnosis of fatty liver; fatty livers have lower density than spleens on computed tomography (CT), and fat appears bright in T1-weighted magnetic resonance images (MRIs). Magnetic resonance elastography, a variant of magnetic resonance imaging, is investigated as a non-invasive method to diagnose fibrosis progression. Histological diagnosis by liver biopsy is the most accurate measure of fibrosis and liver fat progression as of 2018. Conventional imaging methods, such as ultrasound, CT and MRI, are not specific enough to detect fatty liver disease unless fat occupies at least 30% of the liver volume. == Treatment == Decreasing caloric intake by at least 30% or by approximately 750–1,000 kcal/day results in improvement in hepatic steatosis. For people with NAFLD or NASH, weight loss via a combination of diet and exercise was shown to improve or resolve the disease. In more serious cases, medications that decrease insulin resistance, hyperlipidemia, and those that induce weight loss such as bariatric surgery as well as vitamin E have been shown to improve or resolve liver function. Bariatric surgery, while not recommended in 2017 as a treatment for FLD alone, has been shown to revert FLD, NAFLD, NASH and advanced steatohepatitis in over 90% of people who have undergone this surgery for the treatment of obesity. In the case of long-term total-parenteral-nutrition-induced fatty liver disease, choline has been shown to alleviate symptoms. This may be due to a deficiency in the methionine cycle. == Epidemiology == NAFLD affects about 30% of people in Western countries and 10% of people in Asia. In the United States, rates are around 35% with about 7% having the severe form NASH. NAFLD affects about 10% of children in the United States. Recently the term Metabolic dysfunction-associated fatty liver disease (MAFLD) has been proposed to replace NAFLD. MAFLD is a more inclusionary diagnostic name as it is based on the detection of fatty liver by histology (biopsy), medical imaging or blood biomarkers but should be accompanied by either overweight/obesity, type 2 diabetes mellitus, or metabolic dysregulation. The new definition no longer excludes alcohol consumption or coexistence of other liver diseases such as viral hepatitis. Using this more inclusive definition, the global prevalence of MAFLD is an astonishingly high 50.7%. Indeed, also using the old NAFLD definition, the disease is observed in up to 80% of obese people, 35% of whom progress to NASH, and in up to 20% of normal weight people, despite no evidence of excessive alcohol consumption. FLD is the most common cause of abnormal liver function tests in the United States. Fatty liver is more prevalent in Hispanic people than white, with black people having the lowest prevalence. In the study Children of the 90s, 2.5% born in 1991 and 1992 were found by ultrasound at the age of 18 to have non-alcoholic fatty liver disease; five years later transient elastography found over 20% to have the fatty deposits on the liver, indicating non-alcoholic fatty liver disease; half of those were classified as severe. The scans also found that 2.4% had a degree of liver fibrosis, which can lead to cirrhosis. After the lockdown of the COVID-19 pandemic, a study demonstrated that 48% of patients with liver steatosis gained weight, while 16% had a worsened steatosis grade. Weight gain was associated with poor adherence to the suggested diet, reduced levels of physical activity, and increased prevalence of homozygosity for the PNPLA3 rs738409 single nucleotide polymorphism. PNPLA3 rs738409 is already a known risk factor for NAFLD. == Research == A systematic review and meta-analysis, published in 2024, found that growth hormone therapy may help in the management of fatty liver disease. == In animals == Fatty liver disease can occur in pets such as reptiles (particularly turtles) and birds as well as mammals like cats and dogs. The most common cause is overnutrition. A distinct sign in birds is a misshapen beak. Fatty livers can be induced via gavage in geese or ducks to produce foie gras. Fatty liver can also be induced in ruminants such as sheep by a high-caloric diet. == References == == External links == 00474 at CHORUS Photo at Atlas of Pathology	Wikipedia/Fatty_liver_disease
A para-functional habit or parafunctional habit is the habitual exercise of a body part in a way that is other than the most common use of that body part. In dentistry, orthodontics, and oral and maxillofacial pathology, the body part in question is usually the mouth, tongue, or jaw. Oral para-functional habits may include bruxism (tooth-clenching, grinding, or both), tongue tension ("tongue thrusting"), fingernail biting, pencil or pen chewing, mouth breathing, and any other habitual use of the mouth unrelated to eating, drinking, or speaking. Crenated tongue is when scalloping develops on the lateral margins of the tongue as a result of habitual forcing of the tongue against the teeth. Contrary to common belief, functional activities such as chewing are not the main cause of tooth wear. Parafunctional habits are the most destructive forces for several reasons. Whereas teeth rarely come into contact during normal chewing, grinding of teeth may occur 1-4 hours in a 24-hour period, most often during sleep. The amount of pressure placed on teeth during functional habits is 140–550 kilopascals (20–80 psi), but the pressure can range from 2–20.7 megapascals (290–3,000 psi) during parafunctional habits. The direction of forces during functional habits is placed vertically along the long axis of teeth, which is the least harmful because of the anatomical structure of the attachment of teeth to the bone. On the other hand, parafunctional habits direct their forces horizontally. Normally, the temporomandibular joint (TMJ) acts as a class III lever, which helps to restrict the amount of force generated. Class I or class II levers may be created during bruxism, which generates more force from the same amount of muscle activity and subsequently delivers more force to the teeth. Extreme force upon the teeth can occur during some situations as a protective reflex. When a person senses the risk of an imminent car crash, for example, the teeth arches are normally firmly occluded. This overclenching is still considered parafunctional, although it serves a functional purpose; the maxillomandibular complex is much less vulnerable to harm and dislocation because it is bonded by muscles and interposed teeth. When this kind of reflex acts, having a good memory of one's "best bite" position helps avoid fractures. It is one hypothesis for why military jet pilots crack more teeth than auxiliary crew. == References ==	Wikipedia/Parafunctional_habit
Occupational lung diseases comprise a broad group of diseases, including occupational asthma, industrial bronchitis, chronic obstructive pulmonary disease (COPD), bronchiolitis obliterans, inhalation injury, interstitial lung diseases (such as pneumoconiosis, hypersensitivity pneumonitis, lung fibrosis), infections, lung cancer and mesothelioma. These can be caused directly or due to immunological response to an exposure to a variety of dusts, chemicals, proteins or organisms. Occupational cases of interstitial lung disease may be misdiagnosed as COPD, idiopathic pulmonary fibrosis, or a myriad of other diseases; leading to a delay in identification of the causative agent. == Types == === Asthma === Asthma is a respiratory disease that can begin or worsen due to exposure at work and is characterized by episodic narrowing of respiratory airways. Occupational asthma has a variety of causes, including sensitization to a specific substance, causing an allergic response; or a reaction to an irritant that is inhaled in the workplace. Exposure to various substances can also worsen pre-existing asthma. People who work in isocyanate manufacturing, who use latex gloves, or who work in an indoor office environment are at higher risk for occupational asthma than the average US worker. Approximately 2 million people in the US have occupational asthma. === Bronchiolitis obliterans === Bronchiolitis obliterans, also known as constrictive bronchiolitis or obliterative bronchiolitis is a respiratory disease caused by injury to the smallest airways, called bronchioles. It has been reported to occur from exposure to inhaled toxins and gases including sulfur mustard gas, nitrogen oxides, diacetyl (used in many food and beverage flavorings), 2,3-pentanedione, fly ash and fiberglass. === COPD === Chronic obstructive pulmonary disease is a respiratory disease that can encompass chronic bronchitis and/or emphysema. 15% of the cases of COPD in the United States can be attributed to occupational exposure, including exposure to silica and coal dust. People who work in mining, construction, manufacturing (specifically textiles, rubber, plastic, and leather), building, and utilities are at higher risk for COPD than the average US worker. === Hypersensitivity pneumonitis === Hypersensitivity pneumonitis (HP; also called allergic alveolitis, bagpipe lung, or extrinsic allergic alveolitis, EAA) is an inflammation of the alveoli within the lung caused by hypersensitivity to inhaled organic dusts. === Lung cancer === Numerous categories of ionizing radiation, chemicals and mixtures, occupational exposures, metals, dust and fibers have been linked to occurrence of lung cancer. === Mesothelioma === Mesothelioma is a cancer of the mesothelium, part of which is the pleura, the lining of the lungs. Mesothelioma is caused by exposure to asbestos. === Pneumoconiosis === Pneumoconiosis are occupational lung diseases that are caused due to accumulation of dust in the lungs and body's reaction to its presence. Most common pneumoconiosis are silicosis, coal workers’ pneumoconiosis (CWP), and asbestosis. Other examples include minerals (such kaolin, talc, mica), beryllium lung disease, hard metal disease and silicon carbide pneumoconiosis. == Environmental exposure == === Arsenic === Arsenic is classified as an IARC Group 1 carcinogen and is a cause of lung cancer. Workers can be exposed to arsenic through work with some pesticides or in copper smelting. === Asbestos === Asbestos is a mineral which was extensively used in the United States to fireproof buildings and textiles, among other items, in the 1950s-1980s. Workers are frequently exposed to asbestos during demolition and renovation work, which can cause asbestosis and/or mesothelioma. Asbestos exposure can also cause pleural effusion, diffuse pleural fibrosis, pleural plaques, and non-mesothelioma lung cancer. Smoking greatly increases the lung cancer risk of asbestos exposure. Residents and workers of asbestos mining centers such as the town of Asbest, Russia experience dangerous exposure to asbestos and asbestos dust. === BCME === BCME (Bis(chloromethyl) ether) is associated with small cell lung cancer in workers who have been exposed. Exposure can occur via direct manufacture of BCME or its presence as a byproduct. === Beryllium === Beryllium is classified as an IARC Group 1 carcinogen and can also cause interstitial lung disease. Manufacturing workers, dental technicians, machinists, jewelers, plumbers, electricians, precious metal reclamation workers, and welders are at risk for beryllium exposure. === Cadmium === Cadmium is classified as an IARC Group 1 carcinogen and it is a cause of several cancers, including lung cancer. Workers can be exposed to cadmium through welding, zinc smelting, copper smelting, lead smelting, electroplating, battery manufacture, plastics manufacture, and in alloying. === Chromium === Chromium is classified as an IARC Group 1 carcinogen and is linked to lung cancer. Workers can be exposed to chromium via welding, steel manufacturing, pigment/dye manufacturing, and electroplating. === Coal dust === Exposure to coal dust is the cause of coalworker's pneumoconiosis, also called "black lung disease", is an interstitial lung disease caused by long-term exposure (over 10 years) to coal dust. Symptoms include shortness of breath and lowered pulmonary function. It can be fatal when advanced. Between 1970 and 1974, prevalence of CWP among US coal miners who had worked over 25 years was 32%; the same group saw a prevalence of 9% in 2005–2006. It can also exacerbate or cause COPD. === Diesel exhaust === Diesel exhaust contains a variety of gaseous and particulate chemicals, including soot, polycyclic aromatic hydrocarbons, and other known carcinogens. === Flock === Flocking is the technique of adding small pieces of nylon or other material to a backing, usually a textile, to create a contrasting texture. Inhalation of flock can cause flock worker's lung. === Indium lung === Indium lung is an interstitial lung disease caused by occupational exposure to indium tin oxide. === Nanoparticles === The high surface area to volume ratio of nanoparticles may make them an inhalation hazard for workers exposed to them. This is a topic of ongoing research as of 2015 and 2023.https://www.frontiersin.org/journals/bioengineering-and-biotechnology/articles/10.3389/fbioe.2023.1199230/full === Nickel === Nickel is classified by the IARC as a Group 1 carcinogen; nickel compound exposure is associated with nasal cancer as well as lung cancer. Workers may be exposed to nickel in machining/grinding industry, nickel extraction/production, welding, and electroplating. === Polycyclic aromatic hydrocarbons === Polycyclic aromatic hydrocarbons (PAHs), fused-ring chemicals formed during the combustion of fossil fuels, are metabolized by the cytochrome P450 complex to highly reactive carbocations, which can mutate DNA and cause cancer. Workers may be exposed to PAHs while working in a foundry, in the roofing industry, or due to environmental tobacco smoke. === Silica === Exposure to silica can cause Silicosis, which is a fibrosing interstitial lung disease caused by inhaling fine particles of silica, most commonly in the form of quartz or cristobalite. Short-term exposures of large amounts of silica or long-term (10 years or more) exposure of lower levels of silica can cause silicosis. In 1968, more than 1060 US workers died of silicosis; this number fell to 170 by 2005. Besides causing silicosis, inhalation of silica can cause or exacerbate COPD. It can also impair lung function in general and cause cancer by oxidation damage. It is classified as a "known human carcinogen" (Group 1 carcinogen) by the IARC. Exposure is common for people working in tunneling, quarrying, construction, sandblasting, roadway repair, mining, and foundry work. === Silo-filler's disease === Silo-filler's disease (not to be confused with farmer's lung, associated with inhalation of biologic dusts) results from inhalation of nitrogen dioxide (NO2) gas from fresh silage. The presentation is variable depending on level of exposure. Often the gas penetrates throughout the lung and if severe can manifest as a form of acute respiratory distress syndrome, such as significant pulmonary edema, hyalinized alveolar membranes, congestion and other respiratory illnesses. === Tobacco smoke === Tobacco smoke is a known carcinogen. Workers in the hospitality industry may be exposed to tobacco smoke in the workplace, especially in environments like casinos and bars/restaurants. == Infectious exposure == === Influenza === Health care professionals are at risk of occupational influenza exposure; during a pandemic influenza, anyone in a close environment is at risk, including those in an office environment. === Tuberculosis === Tuberculosis is a lung disease endemic in many parts of the world. Health care professionals and prison guards are at high risk for occupational exposure to tuberculosis, since they work with populations with high rates of the disease. == Others == === World Trade Center lung === World Trade Center lung is a cluster of diseases caused by exposure to fallout at Ground Zero of the September 11 attacks in 2001. These diseases include asthma, asthmatic bronchitis, terminal airways disease, sarcoidosis, and acute eosinophilic pneumonia. == Examples == Pneumoconiosis Asbestosis Baritosis Bauxite fibrosis Berylliosis Caplan's syndrome Chalicosis Coalworker's pneumoconiosis (black lung) Siderosis Silicosis Byssinosis Hypersensitivity pneumonitis Bagassosis Bird fancier's lung Farmer's lung == References == 13. https://www.frontiersin.org/journals/bioengineering-and-biotechnology/articles/10.3389/fbioe.2023.1199230/full	Wikipedia/Occupational_lung_disease
Plant disease forecasting is a management system used to predict the occurrence or change in severity of plant diseases. At the field scale, these systems are used by growers to make economic decisions about disease treatments for control. Often the systems ask the grower a series of questions about the susceptibility of the host crop, and incorporate current and forecast weather conditions to make a recommendation. Typically a recommendation is made about whether disease treatment is necessary or not. Usually treatment is a pesticide application. Forecasting systems are based on assumptions about the pathogen's interactions with the host and environment, the disease triangle. The objective is to accurately predict when the three factors – host, environment, and pathogen – all interact in such a fashion that disease can occur and cause economic losses. In most cases the host can be suitably defined as resistant or susceptible, and the presence of the pathogen may often be reasonably ascertained based on previous cropping history or perhaps survey data. The environment is usually the factor that controls whether disease develops or not. Environmental conditions may determine the presence of the pathogen in a particular season through their effects on processes such as overwintering. Environmental conditions also affect the ability of the pathogen to cause disease, e.g. a minimum leaf wetness duration is required for grey leaf spot of corn to occur. In these cases a disease forecasting system attempts to define when the environment will be conducive to disease development. Good disease forecasting systems must be reliable, simple, cost-effective and applicable to many diseases. As such they are normally only designed for diseases that are irregular enough to warrant a prediction system, rather than diseases that occur every year for which regular treatment should be employed. Forecasting systems can only be designed if there is also an understanding on the actual disease triangle parameters. == Features == Models may predict dispersal – see Parry et al 2014 and Soubeyrand et al 2008 for especially successful estimations of patterns and speeds of spread; optimal strategy by goal, either epidemiological level or economic impact level – see Cunniffe et al 2015 for challenges in creating these models, and Papaïx et al 2014 specifically for implementation of these in ddal; and time to eradication – see Glasa et al 2004 for an example in aphid transmission of Plum pox virus. Model quality has benefited both from improvements in the technology being supplied from the computer industry, and from improvements in statistical techniques. == Examples of disease forecasting systems == Forecasting systems may use one of several parameters in order to work out disease risk, or a combination of factors. One of the first forecasting systems designed was for Stewart's wilt and based on winter temperature index as low temperatures would kill the vector of the disease so there would be no outbreak. An example of a multiple disease/pest forecasting system is the EPIdemiology, PREdiction, and PREvention (EPIPRE) system developed in the Netherlands for winter wheat that focused on multiple pathogens. USPEST.org graphs risks of various plants diseases based on weather forecasts with hourly resolution of leaf wetness. Forecasting models are often based on a relationship like simple linear regression where x is used to predict y. Other relationships can be modelled using population growth curves. The growth curve that is used will depend on the nature of the epidemic. Polycyclic epidemics such as potato late blight are usually best modelled by using the logistic model, whereas monocyclic epidemics may be best modelled using the monomolecular model. Correct choice of a model is essential for a disease forecasting system to be useful. Plant disease forecasting models must be thoroughly tested and validated after being developed. Interest has arisen lately in model validation through the quantification of the economic costs of false positives and false negatives, where disease prevention measures may be used when unnecessary or not applied when needed respectively. The costs of these two types of errors need to be weighed carefully before deciding to use a disease forecasting system. == Future developments == In the future, disease forecasting systems may become more useful as computing power increases and the amount of data that is available to plant pathologists to construct models increases. Good forecasting systems also may become increasingly important with climate change. It will be important to be able to accurately predict where disease outbreaks may occur, since they may not be in the historically known areas. == References ==	Wikipedia/Plant_disease_forecasting
Dutch elm disease (DED) is caused by a member of the sac fungi (Ascomycota) affecting elm trees, and is spread by elm bark beetles. Believed to be originally native to Asia, the disease was accidentally introduced into America, Europe, and New Zealand. In these regions it has devastated native populations of elms that did not have resistance to the disease. The name "Dutch elm disease" refers to its identification in 1921 and later in the Netherlands by Dutch phytopathologists Bea Schwarz and Christine Buisman, who both worked with Johanna Westerdijk. The disease affects species in the genera Ulmus and Zelkova, therefore it is not specific to the Dutch elm hybrid. == Overview == Dutch elm disease (DED) is caused by ascomycete microfungi. Three species are now recognized: Ophiostoma ulmi, which afflicted Europe from 1910, reaching North America on imported timber in 1928. Ophiostoma himal-ulmi, a species endemic to the western Himalaya. Ophiostoma novo-ulmi, an extremely virulent species from Japan which was first described in Europe and North America in the 1940s and has devastated elms in both continents since the late 1960s. DED is spread in North America by three species of bark beetles (Family: Curculionidae, Subfamily: Scolytinae): The native elm bark beetle, Hylurgopinus rufipes. The smaller European elm bark beetle, Scolytus multistriatus. The banded elm bark beetle, Scolytus schevyrewi. In Europe, while S. multistriatus still acts as a vector for infection, it is much less effective than the large elm bark beetle, S. scolytus. H. rufipes can be a vector for the disease, but is inefficient compared to the other vectors. S. schevyrewi was found in 2003 in Colorado and Utah. Other reported DED vectors include Scolytus sulcifrons, S. pygmaeus, S. laevis, Pteleobius vittatus and Р. kraatzi. Other elm bark beetle species are also likely vectors. === Field resistance === 'Field resistance' is an umbrella term covering the various factors by which some elms avoid infection in the first place, rather than survive it. A clear example would be the European White Elm (Ulmus laevis) which, while having little or no genetic resistance to DED, synthesizes a triterpene, Alnulin, rendering the bark distasteful to the vector beetles, obliging them to look further afield for more suitable elms. Another would be the inability of the beetles to see elms which did not break the silhouette. 'Weeping' elms are often spared infection owing to the beetles' aversion to hanging upside-down while feeding. === Mechanism === In an attempt to block the fungus from spreading farther, the tree reacts by plugging its own xylem tissue with gum and tyloses, bladder-like extensions of the xylem cell wall. As the xylem (one of the two types of vascular tissue produced by the vascular cambium, the other being the phloem) delivers water and nutrients to the rest of the plant, these plugs prevent them from travelling up the trunk of the tree, starving the tree of water and nutrients, which eventually kills it. === Symptoms === The first symptom of infection usually appears in an upper branch of the tree. Here, the leaves start to wither and yellow during summer, which is months before the normal autumnal leaf shedding. This morbidity spreads in a progressive manner throughout the tree, with further dieback of branches. Eventually, the roots die, starved of nutrients from the leaves. Often, not all the roots die: the roots of some species, especially the English elm (formerly Ulmus procera), can repeatedly put up suckers, which flourish for approximately 15 years before dying off. == Disease range == === Europe === Dutch elm disease was first noticed in continental Europe in 1910, and spread slowly and eventually extended to all other countries except Greece and Finland. Barendina Gerarda Spierenburg compiled records of trees displaying symptoms from 1900 - 1905 onwards in the Netherlands and her publication of this information in 1921 was one part of the start of extensive research and practical measures to try to halt the disease. In addition the fungus that caused the disease was isolated in 1921 in The Netherlands by Bea Schwarz, a pioneering Dutch phytopathologist, and this discovery would lend the disease its name. Following this, in the 1920s and 30s Christine Buisman, working in the Netherlands and USA, identified the sexual stage of the fungal pathogen and also developed methods for experimental infections of elm seedlings that led to selection of resistant trees. In Britain, the disease was first identified in 1927 by T R Peace on English elm in Hertfordshire. This first strain was a relatively mild one, which killed only a small proportion of elms, more often just killing a few branches, and had largely died out by 1940 owing to its susceptibility to viruses. In around 1967, a new, far more virulent, strain arrived in Britain, apparently via east coast ports on shipments of rock elm U. thomasii logs from Canada destined for the small-boat industry, confirmed in 1973 when another consignment was examined at Southampton Docks. This strain proved both highly contagious and lethal to European elms; more than 25 million trees died in the United Kingdom alone, while France lost 97% of its elms. The disease spread rapidly northwards, reaching Scotland within 10 years. By 1990, very few mature elms were left in Britain or much of continental Europe. One of the most distinctive English countryside trees (See John Constable's painting Salisbury Cathedral from Lower Marsh Close), the English elm U. minor 'Atinia', is particularly susceptible as it is the elm most favoured by the Scolytus beetles. Thirty years after the outbreak of the epidemic, nearly all these trees, which often grew to more than 45 m high, are gone. The species still survives in hedgerows, as the roots are not killed and send up root sprouts ("suckers"). These suckers rarely reach more than 5 m tall before dying off from a new attack. However, established hedges kept low by clipping have remained apparently healthy throughout the nearly 40 years since the onset of the disease in the United Kingdom. The largest concentrations of mature elms in Europe are now in Amsterdam and The Hague. In 2005, Amsterdam was declared the "Elm City of Europe": the city's streets and canals are lined with at least 75,000 elms, including several generations of research-elms (see below: Resistant trees). Some 30,000 of the 100,000 mature trees in The Hague are elms, planted because of their tolerance of salty sea-winds. Since the 1990s, a programme of antifungal injections of the most prominent 10,000 elms, and of sanitation felling, has reduced annual elm losses in The Hague from 7% to less than 1% (see below: Preventive treatment). The losses are made up by the planting of disease-resistant cultivars. The largest concentration of mature elm trees remaining in England is in Brighton and Hove, East Sussex, where of the 30,000 elms in 1983 15,000 still stand (2005 figures), several of which are estimated to be over 400 years old. Their survival is owing to the isolation of the area, between the English Channel and the South Downs, and the assiduous efforts of local authorities to identify and remove infected sections of trees immediately when they show symptoms of the disease. Empowered by the Dutch Elm Disease (Local Authorities) (Amendment) Order 1988, local authorities may order the destruction of any infected trees or timber, although in practice they usually do it themselves, successfully reducing the numbers of elm bark beetle Scolytus spp. Sanitary felling has also, to date, preserved most of the 250,000 elms on the Isle of Man, where average temperature and wind speed inhibit the activity of the beetles, which need a temperature of at least 20 degrees to fly and a wind speed of less than five metres per second. The largest concentration of mature elms in Scotland is in Edinburgh, where over 5,000 remained in 2009 from some 35,000 in 1976. The city council gives the overall number of elms as 15,000 (2016). Edinburgh's Leith Links and Meadows have some of the highest concentrations of mature elms among U.K. parks (2014). A policy of sanitary felling has kept losses in the city to an average of 1,000 a year (2009). Between 2013 and 2020 losses were below 1,000 a year. Elm was the most common tree in Paris from the 17th century; before the 1970s there were some 30,000 ormes parisiens. Today, only 1,000 mature elms survive in the city, including examples in the large avenues (Avenue d'Italie, Avenue de Choisy, Boulevard Lefebvre, Boulevard de Grenelle, Boulevard Garibaldi) and two very old specimens, one in the garden of the Tuileries in front of the l'Orangerie and another in the Place Saint-Gervais in front of l'hôtel de ville de Paris. Losses are now being made up with disease-resistant cultivars, especially the Dutch-French research elm 'Nanguen' (Lutèce), named for the ancient Roman name for the city: Lutetia. === North America === DED was first reported in the United States in 1928, with the beetles believed to have arrived in a shipment of logs from the Netherlands destined for use as veneer in the Ohio furniture industry. Quarantine and sanitation procedures held most cases within 150 mi (240 km) of metropolitan New York City until 1941 when war demands began to curtail them. The disease spread from New England westward and southward, almost completely destroying the famous elms in the "Elm City" of New Haven, Connecticut, reaching the Detroit area in 1950, the Chicago area by 1960, and Minneapolis by 1970. Of the estimated 77 million elms in North America in 1930, over 75% had been lost by 1989. The disease first appeared on the planted rows of American elm trees (Ulmus americana) on the National Mall in Washington, D.C., during the 1950s and reached a peak in the 1970s. The United States National Park Service (NPS) used a number of methods to control the epidemic, including sanitation, pruning, injecting trees with fungicide and replanting with DED-resistant American elm cultivars (see Ulmus americana cultivars). The NPS combated the disease's local insect vector, the smaller European elm bark beetle (Scolytus multistriatus), by trapping and by spraying with insecticides. As a result, the population of American elms planted on the Mall and its surrounding areas has remained intact for more than 80 years. DED reached eastern Canada during World War II, and spread to Ontario in 1967, Manitoba in 1975 and Saskatchewan in 1981. In Toronto, 80% of the elm trees have been lost to Dutch elm disease; many more fell victim in Ottawa, Montreal and other cities during the 1970s and 1980s. Quebec City still has about 21,000 elms, thanks to a prevention program initiated in 1981. Alberta and British Columbia are the only provinces that are currently free of Dutch elm disease, although, in an isolated case, an elm tree in Wainwright, Alberta, was found diseased in June 1998 and was immediately destroyed. The presence of DED was monitored in this area during subsequent years but was not seen again. Today, Alberta has the largest number of elms unaffected by Dutch elm disease in the world. The provinces of Alberta, Manitoba, and Saskatchewan all prohibit the pruning of elm trees during the middle of the year (taking effect in April, and lasting through the end of September, July, and August respectively), which they deem to be the most active time of year for bark beetles. It is also illegal to use, store, sell, or transport elm firewood. The largest surviving urban forest of elm trees in North America is believed to be in the city of Winnipeg, where close to 200,000 elms remain. The city spends $3 million annually to aggressively combat the disease using Dursban Turf and the Dutch Trig vaccine. === New Zealand === Dutch elm disease has reached New Zealand. It was found in Napier where it was eradicated and was also found in the Auckland Region in 1989. The Ministry of Agriculture funded a national management programme but it was cancelled to allow more funds to be available for pests of a higher priority. A major outbreak occurred in New Zealand in July 2013, particularly at the site of Kingseat Hospital, south of Auckland. Auckland has 20,000 elms. == Preventive treatment == === Mechanical === The first attempts to control Dutch elm disease consisted of pruning trees to remove and burn diseased timber. While this method was effective in New York State and adjacent areas, its cost made it uneconomical except in large cities where elms were considered valuable attractions. === Chemical === In the US, when Dutch elm disease spread away from the Atlantic coast, control focused on controlling the bark beetle by using insecticides such as DDT and dieldrin, which were sprayed heavily across all parts of elm trees, usually twice a year in the spring and again at a lower concentration in the summer. In its early years, it was generally thought by observers that pesticides did slow the spread of the disease across the United States but as early as 1947, concern was raised that many bird species were killed in large numbers by ingesting poisoned invertebrates. In areas sprayed during the 1950s, local people observed birds such as the American woodcock, American robin, white-breasted nuthatch, brown creeper and various Poecile species dying. Biologist Rachel Carson consequently argued for improved sanitation and against spraying elms, which she saw as having been more effective in areas with earlier and greater experience countering Dutch elm disease. Spraying against elm bark beetles declined very rapidly after 1962, a trend aided by fungicides. Lignasan BLP (carbendazim phosphate), introduced in the 1970s, was the first fungicide used to control Dutch elm disease. This had to be injected into the base of the tree using specialized equipment, and was never especially effective. It is still sold under the name "Elm Fungicide". Arbotect (thiabendazole hypophosphite) became available some years later, and it has been proven effective. Arbotect must be injected every two to three years to provide ongoing control; the disease generally cannot be eradicated once a tree is infected. Arbotect is not effective on root graft infections from adjacent elm trees. It is more than 99.5% effective for three years from beetle infections, which is the primary mode of tree infection. Alamo (propiconazole) has become available more recently, though several university studies show it to be effective only for the current season in which it is injected. Alamo is primarily recommended for treatment of oak wilt. Multistriatin is a pheromone produced by female elm bark beetles, which can be produced synthetically. It has potential in being used to trap male beetles, which carry the fungus. === Biological === Because of the ban on the use of chemicals on street and park trees in the Netherlands, the University of Amsterdam developed a biological vaccine by the late 1980s. Dutch Trig is nontoxic, consisting of a suspension in distilled water of spores of a strain of the fungus Verticillium albo-atrum that has lost much of its pathogenic capabilities, injected in the elm in spring. The strain is believed to have enough pathogenicity left to induce an immune response in the elm, protecting it against DED during one growing season. This is called induced resistance. Trials with the American elm have been successful; in a six-year experiment with the American elm in Denver, CO, annual Dutch elm disease losses declined significantly after the first year from 7 percent to between 0.4 and 0.6 percent; a greater and more rapid reduction in disease incidence than the accompanying tree sanitation and plant health care programs. Preventive treatment is usually justified only when a tree has unusual symbolic value or occupies a particularly important place in the landscape. == Resistant trees == Research to select resistant cultivars and varieties began in the Netherlands in 1928, followed by the United States in 1937 (see Ulmus americana cultivars). Initial efforts in the Netherlands involved crossing varieties of U. minor and U. glabra, but later included the Himalayan or Kashmir elm U. wallichiana as a source of antifungal genes. Early efforts in the USA involved the hybridization of the Siberian elm U. pumila with American red elm U. rubra to produce resistant trees. Resulting cultivars lacked the traditional shape and landscape value of the American elm; few were planted. In 2005, the National Elm Trial (USA) began a 10-year evaluation of 19 cultivars in plantings across the United States. The trees in the trial were exclusively American developments; no European cultivars were included. Based on the trial's final ratings, the preferred cultivars of the American elm (Ulmus americana) are 'New Harmony' and 'Princeton'. The preferred cultivars of Asian elms are the Morton Arboretum introductions and 'New Horizon'. Recent research in Sweden has established that early-flushing clones are less susceptible to DED owing to an asynchrony between DED susceptibility and infection. === Testing for disease resistance === Elms are tested for resistance by inoculation with the fungal pathogen in late May when the tree's growth is at its annual peak. Clones raised for testing are grown to an age of 3 or 4 years. In Europe, the inoculum is introduced into the cambium by a knife wound. However this method, developed in the Netherlands, was considered too severe in America, where the principal disease vector is the bark beetle Scolytus multistriatus, a far less effective vector than the larger beetle endemic to Europe, Scolytus scolytus, which is unknown in America. In the method devised by the USDA, the inoculum is introduced to the cambium via a 2 mm-diameter hole drilled through the bark in the lower third of the tree. This method was further refined by the University of Wisconsin team, which drilled holes in the branches to simulate natural infection by the bark beetles feeding in the twig crotches, but results from this method were found to exaggerate the genetic resistance of the host. Consequently, tests were conducted on specimens in a controlled environment, either in greenhouses or customized plant chambers, facilitating more accurate evaluation of both internal and external symptoms of disease. Another variable is the composition of the inoculum; while an inoculum strength of 106 spores / ml is standard in both continents, its composition reflects the different Ophiostoma species, subspecies and hybrids endemic to the two continents. In Italy for example, two subspecies, americana and novo-ulmi, are present together with their hybrid, whereas in North America, ssp. novo-ulmi is unknown. The differences in method and inocula possibly explain why the American cultivar 'Princeton', displaying high resistance in the US, has often succumbed to Dutch elm disease in Europe. === Hybrid cultivars === Many attempts to breed disease-resistant cultivar hybrids have involved a genetic contribution from Asian elm species that are demonstrably resistant to this fungal disease. Much of the early work was undertaken in the Netherlands. The Dutch research programme began in 1928, and ended in 1992. During those 64 years, well over 1000 cultivars were raised and evaluated. Still in use are cultivars such as 'Groeneveld', 'Lobel', 'Dodoens', 'Clusius' and 'Plantijn', although the resistance levels in these trees aren't high enough to confer good protection. The programme had three major successes: 'Columella', 'Nanguen' Lutèce, and 'Wanoux' Vada, all found to have an extremely high resistance to the disease when inoculated with unnaturally large doses of the fungus. Only 'Columella' was released during the Dutch programme's lifetime—-in 1987. Patents for the Lutèce and Vada clones were purchased by the French Institut National de la Recherche Agronomique (INRA), which subjected the trees to 20 years of field trials in the Bois de Vincennes, Paris, before releasing them to commerce—-in 2002 and 2006, respectively. Asian species featured in the American DED research programs were the Siberian elm U. pumila, Japanese elm U. davidiana var. japonica, and the Chinese elm U. parvifolia, which gave rise to several dozen hybrid cultivars resistant not just to DED, but also to the extreme cold of Asian winters. Among the most widely planted of these, both in North America and in Europe, are 'Sapporo Autumn Gold', 'New Horizon' and 'Rebona'. Some hybrid cultivars, such as 'Regal' and 'Pioneer' are the product of both Dutch and American research. Hybridization experiments using the slippery (or red) elm U. rubra resulted in the release of 'Coolshade' and 'Rosehill' in the 1940s and 50s; the species last featured in hybridization as the female parent of 'Repura' and 'Revera', both patented in 1993, although neither has yet appeared in commerce. In Italy, research was initiated at the Istituto per la Protezione delle Piante, Florence, to produce a range of disease-resistant trees adapted to the warmer Mediterranean climate, using a variety of Asiatic species crossed with the early Dutch hybrid 'Plantyn' as a safeguard against any future mutation of the disease. Two trees with very high levels of resistance, 'San Zanobi' and 'Plinio', were released in 2003. 'Arno' and 'Fiorente' were patented in 2006 and entered commerce in 2012. All four have the Siberian elm U. pumila as a parent, the source of disease-resistance and drought-tolerance genes. 'Morfeo' was released in 2011; it arose from a crossing of the Dutch hybrid clone '405' (female parent) and the Chenmou Elm, the latter a small tree from the provinces of Anhui and Jiangsu in eastern China, The '405' clone is a crossing of an English U. × hollandica and a French U. minor. In the Netherlands a new program has been initiated. From the old proving grounds of the Dorschkamp Research Institute, 10 fourth-generation hybrids survive in a DED-ridden area. These have been tested and some have a very high level of resistance. At Noordplant Nursery new hybrids have been tested since 2013. === Species and species cultivars === ==== North America ==== Ten resistant American elm cultivars are now in commerce in North America. No cultivar is immune to DED; even highly resistant cultivars can become infected, particularly if already stressed by drought or other environmental conditions where the disease prevalence is high. With the exception of 'Princeton', no trees have yet been grown to maturity; trees cannot be said to be mature until they have reached an age of 60 years. Notable cultivars include: 'Princeton', is a cultivar selected in 1922 by Princeton Nurseries for its landscape merit. By coincidence, this cultivar was found to be highly resistant in inoculation studies carried out by the USDA in the early 1990s. As trees planted in the 1920s still survive, the properties of the mature plant are well known. However, 'Princeton' has not proven resistant in Europe, where the main vector of the disease—the larger elm bark beetle, Scolytus scolytus—is capable of introducing far more fungal spores into the tree; many of the 50 trees planted at Highgrove House in the south-west of England in 2006 had died from Dutch elm disease by 2011. 'American Liberty', is, in fact, a set of six cultivars of moderate to high resistance produced through selection over several generations starting in the 1970s. Although 'American Liberty' is marketed as a single variety, nurseries selling the "Liberty Elm" actually distribute the six cultivars at random and thus, unfortunately, the resistance of any particular tree cannot be known. One of the cultivars, 'Independence', is covered by patent (U. S. Plant patent 6227). The oldest 'American Liberty' elm was planted in about 1980. 'Valley Forge', released in 1995, has demonstrated the highest resistance of all the clones to Dutch elm disease in controlled USDA tests. 'Lewis and Clark' = Prairie Expedition TM, released in 2004 to commemorate the bicentenary of the Lewis & Clark expedition, was cloned from a tree found growing in North Dakota which had survived unscathed when all around had succumbed to disease. In 2007, the Elm Recovery Project of the University of Guelph Arboretum in Ontario, Canada, reported that cuttings from healthy surviving old elms surveyed across Ontario had been grown to produce a bank of resistant trees, isolated for selective breeding of highly resistant cultivars. The University of Minnesota USA is testing various elms, including a huge now-patented century-old survivor known as "The St. Croix Elm", which is located in a Minneapolis-St. Paul, MN suburb (Afton) in the St. Croix River valley—a designated National Scenic Riverway. The slippery or red elm U. rubra is marginally less susceptible to Dutch elm disease than the other American species, but this quality seems to have been largely ignored in American research. No cultivars were ever selected, although the tree was used in hybridization experiments (see above). In 1993, Mariam B. Sticklen and James L. Sherald reported the results of NPS-funded experiments conducted at Michigan State University in East Lansing that were designed to apply genetic engineering techniques to the development of DED-resistant strains of American elm trees. In 2007, AE Newhouse and F Schrodt of the State University of New York College of Environmental Science and Forestry in Syracuse reported that young transgenic American elm trees had shown reduced DED symptoms and normal mycorrhizal colonization. By 2013, researchers in both New York State and North Carolina were conducting field trials of genetically engineered DED-resistant American elms. ==== Europe ==== Among European species, there is the unique example of the European white elm U. laevis, which has little innate resistance to DED, but is eschewed by the vector bark beetles and only rarely becomes infected. Recent research has indicated it is the presence of certain organic compounds, such as triterpenes and sterols, which serves to make the tree bark unattractive to the beetle species that spread the disease. In Europe the testing of clones of surviving field elms for innate resistance has been carried out since the 1990s by national research institutes, with findings centrally assessed and published. The first results of this ongoing project suggest that in some countries a very small number of native field elm genotypes have comparatively high levels of tolerance to DED. In Spain, for example, of around 5,000 native elms evaluated to 2013, some 25 genotypes (0.5% of those tested) fall into this category; and it is now hoped that the controlled crossing of the best seven of these (genetically and aesthetically) will produce Ulmus minor hybrids with effective 'field resistance' and market appeal. Similar results are beginning to emerge in trials on surviving field elms in Greece. ===== United Kingdom ===== Much of the work in the United Kingdom is by the Forestry Commission's research arm, which has had Dutch elm disease on its agenda since the 1920s. In 1994 a Research Information Note (no 252) was published, written by John Gibbs, Clive Brasier and Joan Webber, and in 2010 a Pathology Advisory Note, as well as throughout the period a stream of more academic papers: notable results have been the observation that the progress of the disease through Scotland has been quite slow, and that genetic engineering has been tried to improve the resistance of the English elm. In England the Conservation Foundation had been propagating, distributing and planting clones of surviving indigenous elms, including field elms (but not the highly susceptible English elm), as part of a scheme to return elms to city and countryside. The Foundation was running two elm programmes: the 'Great British Elm Experiment' and 'Ulmus londinium', an elm programme for London – these use saplings cultivated through micropropagation from mature parent elms found growing in the British countryside: parent trees are monitored for disease, while saplings were offered free to schools and community groups, who are asked to monitor their trees' progress on the Foundation's online elm map; in London, places with 'elm' in their name were offered a sapling – in an attempt to find out why some elms have survived while others succumbed to Dutch elm disease. Both these projects have been discontinued. The spread of DED to Scotland has focussed attention on a small number of wych elms U. glabra surviving in areas of high infectivity, prompting the Royal Botanic Garden Edinburgh to begin a programme of selecting trees, with a view to determining innate resistance (2009). The Garden is raising and distributing in Scotland seedlings derived from controlled crosses of rare survivors in these areas (2023). In 2001–2004, English elm U. minor 'Atinia' was genetically engineered to resist disease, in experiments at Abertay University, Dundee, Scotland, by transferring antifungal genes into the elm genome using minute DNA-coated ball bearings. However, owing to reservations to GM developments, there are no plans to release the trees into the countryside. ===== Spain ===== In Spain, the Escuela Técnica Superior de Ingenieros de Montes, Universidad Politecnica de Madrid, charged with discovering disease-resistant elms for use in forestry, has raised and patented seven cultivars of the field elm Ulmus minor, although two have subsequently been found to have Siberian elm U. pumila DNA, the species introduced to Spain in the 16th century. Although none have been released to commerce (2020), the clone 'Ademuz', pure U. minor, has been imported into the UK since 2014, and widely planted there. == Possible earlier occurrences == === The "Elm Decline" === From analysis of fossil pollen in peat samples, it is apparent that elms, an abundant tree in prehistoric times, all but disappeared from northwestern Europe during the mid-Holocene period around 4000 BC, and to a lesser extent around 1000 BC. This roughly synchronous and widespread event has come to be known as the "Elm Decline". When first detected in the mid-20th century, the decline was attributed to the impact of forest-clearance by Neolithic farmers, and of elm-coppicing for animal fodder, though the numbers of settlers could not have been large. The devastation caused recently by DED has provided an alternative explanation. Examination of subfossil elm wood showing signs of the changes associated with the disease has suggested that a form of DED may have been responsible. Fossil finds from this period of elm bark beetles support this theory. A consensus today is that the Elm Decline was probably driven by both factors. === Historic period === A less devastating form of the disease, caused by a different fungus, had possibly been present in north-west Europe for some time. Dr Oliver Rackham of Cambridge University presented evidence of an outbreak of elm disease in north-west Europe, c. 1819–1867. "Indications from annual rings [a reference to the dark staining in an annual ring in infected elms] confirm that Dutch elm disease was certainly present in 1867," he wrote, quoting contemporary accounts of diseased and dying elms, including this passage in Richard Jefferies' 1883 book, Nature near London: There is something wrong with elm trees. In the early part of this summer, not long after the leaves were fairly out upon them, here and there a branch appeared as if it had been touched with red-hot iron and burnt up, all the leaves withered and browned on the boughs. First one tree was thus affected, then another, then a third, till, looking round the fields, it seemed as if every fourth or fifth tree had thus been burnt. [...] Upon mentioning this I found that it had been noticed in elm avenues and groups a hundred miles distant, so that it is not a local circumstance. Earlier still, Rackham noted, "The name Scolytus destructor was given to the great bark beetle on evidence, dating from c. 1780, that it was destroying elms around Oxford." In Belgium, elm die-back and death was observed in 1836 and 1896 in Brussels, and in 1885–1886 in Ghent. In the later outbreaks the die-back was attributed to the elm bark beetle. It has been suggested that "for thousands of years elms have flourished in natural balance with the scolytidae, combating occasional infections of Dutch elm disease." Sir Thomas Browne, writing in 1658, noted in The Garden of Cyrus an elm disease that was spreading through English hedgerows, and described symptoms reminiscent of DED. == See also == Forest pathology Forest disturbance by invasive insects and diseases in the United States == References == == Further reading == Walter E. Burton "Army of Experts Wage War on Dutch Elm Disease" Popular Science Monthly, May 1937 == External links == resistantelms.co.uk Dutchelmdisease.org Elm Recovery Project – Guelph University, Canada Dutch elm disease at Government of British Columbia Dutch elm disease – gallery of pests Species profile – Dutch elm disease (Ophiostoma ulmi and Ophiostoma novo-ulmi), National Invasive Species Information Center, United States National Agricultural Library. Lists general information and resources for Dutch elm disease.	Wikipedia/Dutch_Elm_Disease
Plant diseases are diseases in plants caused by pathogens (infectious organisms) and environmental conditions (physiological factors). Organisms that cause infectious disease include fungi, oomycetes, bacteria, viruses, viroids, virus-like organisms, phytoplasmas, protozoa, nematodes and parasitic plants. Not included are ectoparasites like insects, mites, vertebrates, or other pests that affect plant health by eating plant tissues and causing injury that may admit plant pathogens. The study of plant disease is called plant pathology. == Plant pathogens == === Fungi === Most phytopathogenic fungi are Ascomycetes or Basidiomycetes. They reproduce both sexually and asexually via the production of spores and other structures. Spores may be spread long distances by air or water, or they may be soil borne. Many soil inhabiting fungi are capable of living saprotrophically, carrying out the role of their life cycle in the soil. These are facultative saprotrophs. Fungal diseases may be controlled through the use of fungicides and other agricultural practices. However, new races of fungi often evolve that are resistant to various fungicides. Biotrophic fungal pathogens colonize living plant tissue and obtain nutrients from living host cells. Necrotrophic fungal pathogens infect and kill host tissue and extract nutrients from the dead host cells. Significant fungal plant pathogens include: ==== Ascomycetes ==== Fusarium spp. (Fusarium wilt disease) Thielaviopsis spp. (canker rot, black root rot, Thielaviopsis root rot) Verticillium spp. Magnaporthe grisea (rice blast) Sclerotinia sclerotiorum (cottony rot) ==== Basidiomycetes ==== Ustilago spp. (smuts) Rhizoctonia spp. Phakospora pachyrhizi (soybean rust) Puccinia spp. (severe rusts of cereals and grasses)(fungus)\|rusts]]. Armillaria spp. (honey fungus species, virulent pathogens of trees) === Fungus-like organisms === ==== Oomycetes ==== The oomycetes are fungus-like organisms among the Stramenopiles. They include some of the most destructive plant pathogens, such as the causal agents of potato late blight root rot, and sudden oak death. Despite not being closely related to the fungi, the oomycetes have developed similar infection strategies, using effector proteins to turn off a plant's defenses. ==== Phytomyxea ==== Some slime molds in Phytomyxea cause important diseases, including clubroot in cabbage and its relatives and powdery scab in potatoes. These are caused by species of Plasmodiophora and Spongospora, respectively. === Bacteria === Most bacteria associated with plants are saprotrophic and do no harm to the plant itself. However, a small number, around 100 known species, cause disease, especially in subtropical and tropical regions of the world. Most plant pathogenic bacteria are bacilli. Erwinia uses cell wall–degrading enzymes to cause soft rot. Agrobacterium changes the level of auxins to cause tumours with phytohormones. Significant bacterial plant pathogens include: Burkholderia Pseudomonadota Xanthomonas spp. Pseudomonas spp. Pseudomonas syringae pv. tomato causes tomato plants to produce less fruit, and it "continues to adapt to the tomato by minimizing its recognition by the tomato immune system." ==== Mollicutes ==== Phytoplasma and Spiroplasma are obligate intracellular parasites, bacteria that lack cell walls and, like the mycoplasmas, which are human pathogens, they belong to the class Mollicutes. Their cells are extremely small, 1 to 2 micrometres across. They tend to have small genomes (roughly between 0.5 and 2 Mb). They are normally transmitted by leafhoppers (cicadellids) and psyllids, both sap-sucking insect vectors. These inject the bacteria into the plant's phloem, where it reproduces. === Viruses === Many plant viruses cause only a loss of crop yield. Therefore, it is not economically viable to try to control them, except when they infect perennial species, such as fruit trees. Most plant viruses have small, single-stranded RNA genomes. Some also have double stranded RNA or single or double stranded DNA. These may encode only three or four proteins: a replicase, a coat protein, a movement protein to facilitate cell to cell movement through plasmodesmata, and sometimes a protein that allows transmission by a vector. Plant viruses are generally transmitted by a vector, but mechanical and seed transmission also occur. Vectors are often insects such as aphids; others are fungi, nematodes, and protozoa. In many cases, the insect and virus are specific for virus transmission such as the beet leafhopper that transmits the curly top virus causing disease in several crop plants. === Nematodes === Some nematodes parasitize plant roots. They are a problem in tropical and subtropical regions. Potato cyst nematodes (Globodera pallida and G. rostochiensis) are widely distributed in Europe and the Americas, causing $300 million worth of damage in Europe annually. Root knot nematodes have quite a large host range, they parasitize plant root systems and thus directly affect the uptake of water and nutrients needed for normal plant growth and reproduction, whereas cyst nematodes tend to be able to infect only a few species. Nematodes are able to cause radical changes in root cells in order to facilitate their lifestyle. === Protozoa === A few plant diseases are caused by protozoa such as Phytomonas, a kinetoplastid. They are transmitted as durable zoospores that may be able to survive in a resting state in the soil for many years. Further, they can transmit plant viruses. When the motile zoospores come into contact with a root hair they produce a plasmodium which invades the roots. == Physiological plant disorders == Some abiotic disorders can be confused with pathogen-induced disorders. Abiotic causes include natural processes such as drought, frost, snow and hail; flooding and poor drainage; nutrient deficiency; deposition of mineral salts such as sodium chloride and gypsum; windburn and breakage by storms; and wildfires. == Epidemics == Plants are subject to disease epidemics. === Port and border inspection and quarantine === The introduction of harmful non native organisms into a country can be reduced by controlling human traffic (e.g., the Australian Quarantine and Inspection Service). Global trade provides unprecedented opportunities for the introduction of plant pests. In the United States, even to get a better estimate of the number of such introductions would require a substantial increase in inspections. In Australia a similar shortcoming of understanding has a different origin: Port inspections are not very useful because inspectors know too little about taxonomy. There are often pests that the Australian Government has prioritised as harmful to be kept out of the country, but which have near taxonomic relatives that confuse the issue. X-ray and electron-beam/E-beam irradiation of food has been trialed as a quarantine treatment for fruit commodities originating from Hawaii. The US FDA (Food and Drug Administration), USDA APHIS (Animal and Plant Health Inspection Service), producers, and consumers were all accepting of the results - more thorough pest eradication and lesser taste degradation than heat treatment. The International Plant Protection Convention (IPPC) anticipates that molecular diagnostics for inspections will continue to improve. Between 2020 and 2030, IPPC expects continued technological improvement to lower costs and improve performance, albeit not for less developed countries unless funding changes. === Chemical === Many natural and synthetic compounds can be employed to combat plant diseases. This method works by directly eliminating disease-causing organisms or curbing their spread; however, it has been shown to have too broad an effect, typically, to be good for the local ecosystem. From an economic standpoint, all but the simplest natural additives may disqualify a product from "organic" status, potentially reducing the value of the yield. === Biological === Crop rotation is a traditional and sometimes effective means of preventing pests and diseases from becoming well-established, alongside other benefits. Other biological methods include inoculation. Protection against infection by Agrobacterium tumefaciens, which causes gall diseases in many plants, can be provided by dipping cuttings in suspensions of Agrobacterium radiobacter before inserting them in the ground to take root. == Economic impact == Plant diseases cause major economic losses for farmers worldwide. Across large regions and many crop species, it is estimated that diseases typically reduce plant yields by 10% every year in more developed settings, but yield loss to diseases often exceeds 20% in less developed settings. The Food and Agriculture Organization estimates that pests and diseases are responsible for about 25% of crop loss. To solve this, new methods are needed to detect diseases and pests early, such as novel sensors that detect plant odours and spectroscopy and biophotonics that are able to diagnose plant health and metabolism. As of 2018 the most costly diseases of the most produced crops worldwide are: == See also == Burl or Burr Common names of plant diseases Plant disease forecasting Stunting == Notes == == References == == External links == Pacific Northwest Fungi, online mycology journal with papers on fungal plant pathogens The Pest and Pathogens Glossary	Wikipedia/Tree_disease
Plant disease epidemiology is the study of disease in plant populations. Much like diseases of humans and other animals, plant diseases occur due to pathogens such as bacteria, viruses, fungi, oomycetes, nematodes, phytoplasmas, protozoa, and parasitic plants. Plant disease epidemiologists strive for an understanding of the cause and effects of disease and develop strategies to intervene in situations where crop losses may occur. Destructive and non-destructive methods are used to detect diseases in plants. Additionally, understanding the responses of the immune system in plants will further benefit and limit the loss of crops. Typically successful intervention will lead to a low enough level of disease to be acceptable, depending upon the value of the crop. Plant disease epidemiology is often looked at from a multi-disciplinary approach, requiring biological, statistical, agronomic and ecological perspectives. Biology is necessary for understanding the pathogen and its life cycle. It is also necessary for understanding the physiology of the crop and how the pathogen is adversely affecting it. Agronomic practices often influence disease incidence for better or for worse. Ecological influences are numerous. Native species of plants may serve as reservoirs for pathogens that cause disease in crops. Statistical models are often applied in order to summarize and describe the complexity of plant disease epidemiology, so that disease processes can be more readily understood. For example, comparisons between patterns of disease progress for different diseases, cultivars, management strategies, or environmental settings can help in determining how plant diseases may best be managed. Policy can be influential in the occurrence of diseases, through actions such as restrictions on imports from sources where a disease occurs. In 1963 J. E. van der Plank published "Plant Diseases: Epidemics and Control", providing a theoretical framework for the study of the epidemiology of plant diseases. This book provides a theoretical framework based on experiments in many different host pathogen systems and moved the study of plant disease epidemiology forward rapidly, especially for fungal foliar pathogens. Using this framework we can now model and determine thresholds for epidemics that take place in a homogeneous environment such as a mono-cultural crop field. == Elements of an epidemic == Disease epidemics in plants can cause huge losses in yield of crops as well threatening to wipe out an entire species such as was the case with Dutch Elm Disease and could occur with Sudden Oak Death. An epidemic of potato late blight, caused by Phytophthora infestans, led to the Great Irish Famine and the loss of many lives. Commonly the elements of an epidemic are referred to as the “disease triangle”: a susceptible host, pathogen, and conducive environment. For a disease to occur all three of these must be present. Below is an illustration of this point. Where all three items meet, there is a disease. The fourth element missing from this illustration for an epidemic to occur is time. As long as all three of these elements are present disease can initiate, an epidemic will only ensue if all three continue to be present. Anyone of the three might be removed from the equation though. The host might out-grow susceptibility as with high-temperature adult-plant resistance, the environment changes and is not conducive for the pathogen to cause disease, or the pathogen is controlled through a fungicide application. Sometimes a fourth factor of time is added as the time at which a particular infection occurs, and the length of time conditions remain viable for that infection, can also play an important role in epidemics. The age of the plant species can also play a role, as certain species change in their levels of disease resistance as they mature; in a process known as ontogenic resistance. If all of the criteria are not met, such as a susceptible host and pathogen are present, but the environment is not conducive to the pathogen infecting and causing disease, a disease cannot occur. For example, corn is planted into a field with corn residue that has the fungus Cercospora zea-maydis, the causal agent of Grey leaf spot of corn, but if the weather is too dry, and there is no leaf wetness the spores of the fungus in the residue cannot germinate and initiate infection. Likewise, if the host is susceptible and the environment favours the development of disease but the pathogen is not present there is no disease. Taking the example above, the corn is planted into a ploughed field where there is no corn residue with the fungus Cercospora zea-maydis, the causal agent of Grey leaf spot of corn, present but the weather means extended periods of leaf wetness, there is no infection initiated. When a pathogen requires a vector to be spread then for an epidemic to occur the vector must be plentiful and active. === Types of epidemics === Pathogens cause monocyclic epidemics with a low birth rate and death rate, meaning they only have one infection cycle per season. They are typical of soil-borne diseases such as Fusarium wilt of flax. Polycyclic epidemics are caused by pathogens capable of several infection cycles a season. They are most often caused by airborne diseases such as powdery mildew. Bimodal polycyclic epidemics can also occur. For example, in brown rot of stone fruits the blossoms and the fruits are infected at different times. For some diseases the disease occurrence needs to be evaluated over several growing seasons, especially if growing the crops in monoculture year after year or growing perennial plants. Such conditions can mean that the inoculum produced in one season can be carried over to the next leading to a build-up over the years, especially in the tropics where there are no clear-cut breaks between growing seasons. Epidemics under these conditions are called polyetic; they can be caused by both monocyclic and polycyclic pathogens. Apple powdery mildew is an example of a polyetic epidemic caused by a polycyclic pathogen; Dutch Elm disease a polyetic epidemic caused by a monocyclic pathogen. == Detecting diseases == There are many different ways to spot a disease both destructively and non-destructively. In order to understand the cause, affects, and cure for a disease, the non-destructive method is more favorable. They are techniques where sample preparation and/or repetitive processes are not necessary for measuring and observing the conditions of the plants’ health. Non-destructive approaches may include image processing, imaging-based, spectroscopy based, and remote sensing. Photography, digital imaging, and image analysis technology are useful tools to set up for image processing. Valuable data are extracted from these images and then are analyzed for diseases. But before any analysis happens, image acquisition is the first step. And within this step contains three stages. First, is energy which is the light source of illuminating from the object of interest. Second, is the optical system such as a camera to focus on the energy. Third, is the energy measured by the sensor. To continue with the image processing, there is a pre-process where one can make certain that there are no factors such as background, size, shape of leave, light, and camera effects the analysis.After the pre-process, image segmentation is used to split the image between regions of disease and non-disease. In these images, there features of color, texture, and shape that can be extracted and used for the analysis. Imaging-based approaches for the detection has two main methods, fluorescence imaging and hyper-spectral imaging. Fluorescence imaging helps identify the metabolic conditions of the plant. In order to do so, a tool is used to present light onto the chlorophyll complex of the plant. Hyper-spectral imaging is used to obtain reflected images. Such methods consist of the spectral information divergence (SID) where it can assess the spectral reflectance by looking at wavelength bands. Another non-destructive approach is spectroscopy. This is where the electromagnetic spectrum and matter becomes involved. There are visible and infrared spectroscopy, fluorescence spectroscopy, and electric impedance spectroscopy. Each spectroscopy gives information including the types of radiation energy, the types of material, the nature of interaction, and more. Finally, the last non-destructive approach is the application of remote sensing in plant diseases. This is where data is obtained without having to be with the plant while observing. There is hyper-spectral and multispectral in remote sensing. Hyper-spectral helps provide high spectral and spatial resolution. Multispectral remote sensing provides the severity of the disease. As of 2015 there is a need for further development of antibody- and molecular marker-tests for new pathogens and occurrence of known pathogens in new hosts, and also a need for further global integration of quarantine and surveillance. == Immune System == Plants can show many signs or physical evidence of fungal, viral or bacterial infections. This can range from rusts or molds to not showing anything at all when a pathogen invades the plant (occurs in some viral diseases in plants). Symptoms which are visible effects of diseases on the plant consist of changes in color, shape or function. These changes in the plant coordinates with their response to pathogens or foreign organisms that is negatively effecting their system. Even though plants do not have cells that can move and fight foreign organisms and they do not have a somatic adaptive immune system, they do have and depend on innate immunity of each cell and on systemic signals. In responses to infections, plants have a two-branched innate immune system. The first branch has to recognize and respond to molecules that are similar to classes of microbes, this includes non-pathogens. On the other hand, the second branch responds to pathogen virulence factors, either directly or indirectly to the host. Pattern recognition receptors (PRRs) are activated by recognition of pathogen or microbial-associated molecular patterns known as PAMPs or MAMPs. These leads to PAMP-Triggered Immunity or Pattern-Triggered Immunity (PTI) where PRRs causes intracellular signaling, transcriptional reprogramming, and biosynthesis of a complex output response that decreases colonization. In addition, R genes also known as Effector-Triggered Immunity is activated by specific pathogen “effectors” that can trigger a strong antimicrobial response. Both PTI and ETI assist in plant defense through activation of DAMP which is Damage-associated Compounds. Cellular changes or changes in gene expression are activated through ion channel gating, oxidative burst, cellular redox changes, or protein kinase cascades through PTI and ETI receptors. == Impact == Through 2013, invasive tree diseases had killed about 100 million elm trees combined in the United Kingdom and United States and 3.5 billion American chestnut trees. == See also == Distance Diagnostics Through Digital Imaging (DDDI) Landscape epidemiology Plant disease forecasting Robert Hartig Forest pathology Phytopathology with historical landmarks in plant pathology == References == == Further reading == === Crop disease epidemiology === Carvajal-Yepes, M.; Cardwell, K.; Nelson, A.; Garrett, K. A.; Giovani, B.; Saunders, D. G. O.; Kamoun, S.; Legg, J. P.; Verdier, V.; Lessel, J.; Neher, R. A.; Day, R.; Pardey, P.; Gullino, M. L.; Records, A. R.; Bextine, B.; Leach, J. E.; Staiger, S.; Tohme, J. (2019-06-27). "A global surveillance system for crop diseases". Science. 364 (6447). American Association for the Advancement of Science (AAAS): 1237–1239. Bibcode:2019Sci...364.1237C. doi:10.1126/science.aaw1572. ISSN 0036-8075. PMID 31249049. S2CID 195750384. "Global crop surveillance system, bulwark against disease". Emerging Pathogens Institute. University of Florida. 2019-07-11. Retrieved 2021-02-12. "Crop disease surveillance activities". Agriculture and Food. Western Australia Department of Primary Industries and Regional Development Agriculture and Food. 2020-05-07. Retrieved 2021-02-12. Fletcher, Jacqueline; Stack, James P. "Surveillance Strategies§Agricultural Biosecurity: Threats and Impacts for Plant Pathogens". NCBI Bookshelf (National Center for Biotechnology Information). National Academies Press (National Academy of Sciences). Retrieved 2021-02-12. == External links == Ecology and epidemiology in the R programming environment - Open access modules published in The Plant Health Instructor	Wikipedia/Plant_disease_surveillance
In physics, the Sakuma–Hattori equation is a mathematical model for predicting the amount of thermal radiation, radiometric flux or radiometric power emitted from a perfect blackbody or received by a thermal radiation detector. == History == The Sakuma–Hattori equation was first proposed by Fumihiro Sakuma, Akira Ono and Susumu Hattori in 1982. In 1996, a study investigated the usefulness of various forms of the Sakuma–Hattori equation. This study showed the Planckian form to provide the best fit for most applications. This study was done for 10 different forms of the Sakuma–Hattori equation containing not more than three fitting variables. In 2008, BIPM CCT-WG5 recommended its use for radiation thermometry measurement uncertainty budgets below 960 °C. == General form == The Sakuma–Hattori equation gives the electromagnetic signal from thermal radiation based on an object's temperature. The signal can be electromagnetic flux or signal produced by a detector measuring this radiation. It has been suggested that below the silver point, a method using the Sakuma–Hattori equation be used. In its general form it looks like S ( T ) = C exp ⁡ ( c 2 λ x T ) − 1 , {\displaystyle S(T)={\frac {C}{\exp \left({\frac {c_{2}}{\lambda _{x}T}}\right)-1}},} where: C {\displaystyle C} is the scalar coefficient c 2 {\displaystyle c_{2}} is the second radiation constant (0.014387752 m⋅K) λ x {\displaystyle \lambda _{x}} is the temperature-dependent effective wavelength (in meters) T {\displaystyle T} is the absolute temperature (in K) == Planckian form == === Derivation === The Planckian form is realized by the following substitution: λ x = A + B T {\displaystyle \lambda _{x}=A+{\frac {B}{T}}} Making this substitution renders the following the Sakuma–Hattori equation in the Planckian form. Sakuma–Hattori equation (Planckian form) S ( T ) = C exp ⁡ ( c 2 A T + B ) − 1 {\displaystyle S(T)={\frac {C}{\exp \left({\frac {c_{2}}{AT+B}}\right)-1}}} Inverse equation T = c 2 A ln ⁡ ( C S + 1 ) − B A {\displaystyle T={\frac {c_{2}}{A\ln \left({\frac {C}{S}}+1\right)}}-{\frac {B}{A}}} First derivative d S d T = [ S ( T ) ] 2 A c 2 C ( A T + B ) 2 exp ⁡ ( c 2 A T + B ) {\displaystyle {\frac {dS}{dT}}=\left[S(T)\right]^{2}{\frac {Ac_{2}}{C\left(AT+B\right)^{2}}}\exp \left({\frac {c_{2}}{AT+B}}\right)} === Discussion === The Planckian form is recommended for use in calculating uncertainty budgets for radiation thermometry and infrared thermometry. It is also recommended for use in calibration of radiation thermometers below the silver point. The Planckian form resembles Planck's law. S ( T ) = c 1 λ 5 [ exp ⁡ ( c 2 λ T ) − 1 ] {\displaystyle S(T)={\frac {c_{1}}{\lambda ^{5}\left[\exp \left({\frac {c_{2}}{\lambda T}}\right)-1\right]}}} However the Sakuma–Hattori equation becomes very useful when considering low-temperature, wide-band radiation thermometry. To use Planck's law over a wide spectral band, an integral like the following would have to be considered: S ( T ) = ∫ λ 1 λ 2 c 1 λ 5 [ exp ⁡ ( c 2 λ T ) − 1 ] d λ {\displaystyle S(T)=\int _{\lambda _{1}}^{\lambda _{2}}{\frac {c_{1}}{\lambda ^{5}\left[\exp \left({\frac {c_{2}}{\lambda T}}\right)-1\right]}}d\lambda } This integral yields an incomplete polylogarithm function, which can make its use very cumbersome. The standard numerical treatment expands the incomplete integral in a geometric series of the exponential ∫ 0 λ 2 c 1 λ 5 [ exp ⁡ ( c 2 λ T ) − 1 ] d λ = c 1 ( T c 2 ) 4 ∫ c 2 / ( λ 2 T ) ∞ x 3 e x − 1 d x {\displaystyle \int _{0}^{\lambda _{2}}{\frac {c_{1}}{\lambda ^{5}\left[\exp \left({\frac {c_{2}}{\lambda T}}\right)-1\right]}}d\lambda =c_{1}\left({\frac {T}{c_{2}}}\right)^{4}\int _{c_{2}/(\lambda _{2}T)}^{\infty }{\frac {x^{3}}{e^{x}-1}}dx} after substituting λ = c 2 x T , d λ = − c 2 x 2 T d x . {\displaystyle \lambda ={\tfrac {c_{2}}{xT}},\ d\lambda ={\tfrac {-c_{2}}{x^{2}Tdx}}.} Then J ( c ) ≡ ∫ c ∞ x 3 e x − 1 d x = ∫ c ∞ x 3 e − x 1 − e − x d x = ∫ c ∞ ∑ n ≥ 1 x 3 e − n x d x = ∑ n ≥ 1 e − n c ( n c ) 3 + 3 ( n c ) 2 + 6 n c + 6 n 4 {\displaystyle {\begin{aligned}J(c)&\equiv \int _{c}^{\infty }{\frac {x^{3}}{e^{x}-1}}dx=\int _{c}^{\infty }{\frac {x^{3}e^{-x}}{1-e^{-x}}}dx\\[4pt]&=\int _{c}^{\infty }\sum _{n\geq 1}x^{3}e^{-nx}dx\\[4pt]&=\sum _{n\geq 1}e^{-nc}{\frac {(nc)^{3}+3(nc)^{2}+6nc+6}{n^{4}}}\end{aligned}}} provides an approximation if the sum is truncated at some order. The Sakuma–Hattori equation shown above was found to provide the best curve-fit for interpolation of scales for radiation thermometers among a number of alternatives investigated. The inverse Sakuma–Hattori function can be used without iterative calculation. This is an additional advantage over integration of Planck's law. == Other forms == The 1996 paper investigated 10 different forms. They are listed in the chart below in order of quality of curve-fit to actual radiometric data. == See also == == Notes == == References ==	Wikipedia/Sakuma–Hattori_equation
Active thermography is an advanced nondestructive testing procedure, which uses a thermographic measurement of a tested material thermal response after its external excitation. This principle can be used also for non-contact infrared non-destructive testing (IRNDT) of materials. The IRNDT method is based on an excitation of a tested material by an external source, which brings some energy to the material. Halogen lamps, flash-lamps, ultrasonic horn or other sources can be used as the excitation source for the IRNDT. The excitation causes a tested material thermal response, which is measured by an infrared camera. It is possible to obtain information about the tested material surface and sub-surface defects or material inhomogeneities by using a suitable combination of excitation source, excitation procedure, infrared camera and evaluation method. Modern thermographic systems with high-speed and high-sensitivity IR cameras extend the possibilities of the inspection method. Modularity of the systems allows their usage for research and development applications as well as in modern industrial production lines. Thermovision nondestructive testing of components can be carried out on a wide range of various materials. Thermographic inspection of material can be regarded as a method of infrared defectoscopy, that is capable of revealing material imperfections such as cracks, defects, voids, cavities and other inhomogeneities. The thermographic testing can be provided on individual components in a laboratory or directly on technology facilities that are in duty. == Theory == Active thermography uses an external source for measured object excitation, that means introducing an energy into the object. The excitation sources can be classified by the principles: optical radiation or microwaves absorption, electromagnetic induction, elastic waves transformation (e.g. ultrasound), convection (e.g. hot air), plastic deformation transformation (thermoplastic effect during mechanical loading). Various excitation sources can be used for the active thermography and nondestructive testing, for example laser heating, flash lamps, halogen lamps, electrical heating, ultrasonic horn, eddy currents, microwaves, and others. The measured object can be heated by an external source directly, e.g. by halogen lamps or hot air. The material inhomogeneities or defects cause then a distortion of temperature field. This distortion is detected as temperature differences on the material surface. Another possibility is to use thermophysical processes in the material, when mechanical or electrical energy is transformed into thermal energy due to defects and inhomogeneities. It creates local temperature sources, which cause temperature differences detected on the object surface by infrared techniques, such as in the case of ultrasound excitation. == Methods == A lot of methods were developed for active thermography for the nondestructive testing measurement evaluation. The evaluation methods selection depends on application, used excitation source and excitation type (pulse, periodic, continuous). In the simplest case, the response is evident from a thermogram directly. However, it is necessary to use advanced analysis techniques in most cases. The most common methods include Lock-In, Pulse or Transient (Step thermography) evaluation techniques, with continuous excitation used in some cases: Lock-In thermography (periodic excitation method). A modulated periodic source is used for the excitation. The phase and amplitude shift of the measured signal are evaluated and the analysis can be done by various techniques. Halogen lamps, LED lamps, ultrasound, laser or an electric current are suitable excitation sources. It has the advantage that it can be used on large surfaces, and it puts a low thermal energy on the part being inspected. The disadvantage is a longer measurement time and dependence of detection capabilities on a geometrical orientation of defects (except of an indirect excitation such as ultrasound). The Lock-In method is suitable for testing components with a low thermal diffusivity and it has many modifications for various specific applications (such as Lock-In Ref, Lock-In Online, etc.). Pulse thermography (pulse method). A very short pulse – usually in the units of milliseconds – is used to excite the object. The cooling process is then analyzed. A flash lamp is typically used as an excitation source. The advantage of this method is the speed of the analysis and a possibility to estimate the defects depth. The disadvantage is a limited depth of the analysis, a limited area that can be inspected (with regard to a usable power of excitation sources) and a dependence of detection capabilities on geometrical orientation of defects. Transient thermography (step thermography, thermal wave method). In principle, the excitation and evaluation are similar to the pulse thermography, however, the pulse length is much bigger. Less powerful excitation sources are required compared to the pulse thermography. It is therefore possible to analyze larger areas and the measurement time is shorter than in the case of Lock-In thermography. As in the pulse thermography, the sensitivity of the method is limited by the geometrical orientation of defects. Halogen lamps are the suitable excitation source for this type of evaluation. Continual excitation. The simplest method usable only in special applications. A high-speed cooled infrared camera with a high sensitivity is commonly used for IRNDT applications. However, an uncooled bolometric infrared camera can be used for specific applications. It can significantly reduce acquisition costs of the measurement system. The IR nondestructive testing system are usually modular. It means that various excitation sources can be combined with various infrared cameras and various evaluation methods depending on application, tested material, measuring time demands, size of a tested area, etc. The modularity allows universal usage of the system for various industrial, scientific and research applications. == Applications == IRNDT (infra-red nondestructive testing) method is suitable for detection and inspection of cracks, defects, cavities, voids and inhomogeneities in material, it is also possible to use the method for inspection of welded joints of metal and plastic parts, inspection of solar cells and solar panels, determination of internal structure of material etc. The main advantage of IRNDT method is availability for inspection of various materials in wide range of industrial and research applications. IRNDT measurement is fast, nondestructive and noncontact. Restrictive condition for IRNDT method is inspection depth combined with dimension and orientation of defect/crack/inhomogeneity in material. === Inspection of laser welded plastic parts === Laser welding of plastics is a progressive technology of connecting materials with different optical properties. Classical methods for testing of welding performance and weld joints quality – such as the metallographic cut microscopic analysis or X-ray tomography – are not suitable for routine measurements. Pulse IRNDT analysis can be successfully used for weld inspection in many cases. The images show an example of plastic parts inspection with a defective weld and with a correct weld. The gaps in the defective weld and the correct uninterrupted weld line are both well visible in the results of the IRNDT flash-pulse analysis. === Inspection of laser welded joints === Laser beam welding is a modern technology of fusion welding. Currently finds its wide usage not only in the field of scientific research but also establishes itself in a variety of industries. Among the most frequent users belong the automotive industry, which due to its stable continuous innovation enables fast implementation of advanced technologies in their production. It is clear that laser welding significantly enhances engineering designs and thus brings a number of new products which previously could not be made by conventional methods. The laser welding can produce quality welds of different types, both extremely thin and thick blanks. Weldable are common carbon steels, stainless steels, aluminum and its alloys, copper, titanium and last but not least, special materials and its combinations. An integral part of the weldment production is a quality control. Unlike conventional non-destructive test methods, IRNDT is used not only after the laser welding process, but also during it. This makes possible to decide whether or not to the weldment comply with established quality criteria during manufacture process. === Solar cells testing === Active thermography, particularly lock-in thermography, is widely employed for inspecting solar cells. While effective, lock-in thermography often requires physical contact with the solar cell for excitation. However, techniques that involve periodic excitation using light sources allow for non-contact testing of electrode-free cells. Common methods such as Illuminated Lock-In Thermography (ILIT) and Open Circuit Voltage Illuminated Lock-In Thermography (VOC-ILIT) are used to investigate defects or issues like ohmic shunts, cracks, open or short circuits, and degradation in photovoltaic materials. Pulsed thermography, another method under investigation, provides a non-contact alternative with significantly reduced inspection times; however, it usually offers lower detectability than the ILIT method. == References ==	Wikipedia/Active_thermography
Thermographic inspection refers to the nondestructive testing (NDT) of parts, materials or systems through the imaging of the temperature fields, gradients and/or patterns ("thermograms") at the object's surface. It is distinguished from medical thermography by the subjects being examined: thermographic inspection generally examines inanimate objects, while medical thermography generally examines living organisms. Generally, thermographic inspection is performed using an infrared sensor (thermographic camera). == Terminology == Thermography refers to the visualization of thermograms, and encompasses all thermographic inspection techniques regardless of the technique used. For instance, a temperature sensitive coating applied to a surface to measure its temperature fields is a thermographic inspection contact technique based on heat conduction, and no infrared sensor is involved. Infrared thermography specifically refers to a nonintrusive, noncontact mapping of thermograms on the surface of objects using a detector that is sensitive to infrared radiation. There are many other terms widely used, all referring to infrared thermography; the adoption of specific term(s) depends on the author's background and preferences. For instance, video thermography and thermal imaging draw attention to the acquisition of a temporal sequence of images that may be displayed as a movie. Pulse-echo thermography and thermal wave imaging are adopted to emphasize the wave nature of heat. Pulsed video thermography, transient thermography, and flash thermography are used when the specimen is stimulated using a short energy pulse. == Characteristics == When compared with other classical NDT techniques such as ultrasonic or radiographic testing, thermographic inspection is safe, nonintrusive, and usually noncontact, allowing the detection of relatively shallow subsurface defects (a few millimeters in depth) under large surfaces (typically covering an area of 30 by 30 cm (12 by 12 in) at once, although inspection of larger surfaces is possible) and quickly (from a fraction of a second to a few minutes depending on the configuration). == Techniques == In addition, there are two mutually exclusive approaches in thermographic inspection: passive, in which the features of interest are naturally at a higher or lower temperature than the background and no energy is introduced to the system being inspected. For example, the surveillance of people on a scene using a thermal imaging camera. active, in which an energy source is required to produce a thermal contrast between the feature of interest and the background. For example, internal flaws in an aircraft part may be identified by exciting the part with ultrasonic energy; the flaw responds to the ultrasonic energy through frictional heating, which can then be detected with a thermal imaging camera. === Passive techniques === Typically, passive techniques display information from an infrared sensor on a monitor; these images can be visualized in black and white or in false color. Passive techniques are capable of detecting temperature differences as small as 0.01 °C above or below ambient temperatures. === Active techniques === Active techniques may be further subdivided depending on the type of energy imparted (typically, optical or acoustic), whether energy is applied externally or internally, and mode of excitation. A wide variety of energy sources can be used to induce a thermal contrast between defective and non-defective zones that can be divided in external, if the energy is delivered to the surface and then propagated through the material until it encounters a flaw; or internal, if the energy is injected into the specimen in order to stimulate exclusively the defects. Typically, external excitation is performed with optical devices such as photographic flashes (for heat pulsed stimulation) or halogen lamps (for periodic heating), whereas internal excitation can be achieved by means of mechanical oscillations, with a sonic or ultrasonic transducer for both burst and amplitude modulated stimulation. As depicted in the figure, there are three classical active thermographic techniques based on these two excitation modes: lock-in (or modulated) thermography and pulsed thermography, which are optical techniques applied externally; and vibrothermography, which uses ultrasonic waves (amplitude modulated or pulses) to excite internal features. In vibrothermography, an external mechanical energy source induces a temperature difference between the defective and non-defective areas of the object. In this case, the temperature difference is the main factor that causes the emission of a broad electromagnetic spectrum of infrared radiation, which is not visible to the human eye. The locations of the defects can then be detected by infrared cameras through the process of mapping temperature distribution on the surface of the object. == See also == Thermography Infrared camera Infrared detector Infrared Non-Destructive Testing == References == == External links == Canada Research Chair in Multipolar Infrared Vision – MiViM Active thermography and IR non-destructive testing, University of West Bohemia, New Technologies - Research Centre, department Thermomechanics of Technological Processes	Wikipedia/Thermographic_inspection
Physical therapy (PT), also known as physiotherapy, is a healthcare profession, as well as the care provided by physical therapists who promote, maintain, or restore health through patient education, physical intervention, disease prevention, and health promotion. Physical therapist is the term used for such professionals in the United States, and physiotherapist is the term used in many other countries. The career has many specialties including musculoskeletal, orthopedics, cardiopulmonary, neurology, endocrinology, sports medicine, geriatrics, pediatrics, women's health, wound care and electromyography. PTs practice in many settings, both public and private. In addition to clinical practice, other aspects of physical therapy practice include research, education, consultation, and health administration. Physical therapy is provided as a primary care treatment or alongside, or in conjunction with, other medical services. In some jurisdictions, such as the United Kingdom, physical therapists may have the authority to prescribe medication. == Overview == Physical therapy addresses the illnesses or injuries that limit a person's abilities to move and perform functional activities in their daily lives. PTs use an individual's history and physical examination to arrive at a diagnosis and establish a management plan and, when necessary, incorporate the results of laboratory and imaging studies like X-rays, CT-scan, or MRI findings. Physical therapists can use sonography to diagnose and manage common musculoskeletal, nerve, and pulmonary conditions. Electrodiagnostic testing (e.g., electromyograms and nerve conduction velocity testing) may also be used. PT management commonly includes prescription of or assistance with specific exercises, manual therapy, and manipulation, mechanical devices such as traction, education, electrophysical modalities which include heat, cold, electricity, sound waves, radiation, assistive devices, prostheses, orthoses, and other interventions. In addition, PTs work with individuals to prevent the loss of mobility before it occurs by developing fitness and wellness-oriented programs for healthier and more active lifestyles, providing services to individuals and populations to develop, maintain, and restore maximum movement and functional ability throughout the lifespan. This includes providing treatment in circumstances where movement and function are threatened by aging, injury, disease, or environmental factors. Functional movement is central to what it means to be healthy. Physical therapy is a professional career that has many specialties including musculoskeletal, orthopedics, cardiopulmonary, neurology, endocrinology, sports medicine, geriatrics, pediatrics, women's health, wound care and electromyography. Neurological rehabilitation is, in particular, a rapidly emerging field. PTs practice in many settings, such as privately-owned physical therapy clinics, outpatient clinics or offices, health and wellness clinics, rehabilitation hospital facilities, skilled nursing facilities, extended care facilities, private homes, education and research centers, schools, hospices, industrial and these workplaces or other occupational environments, fitness centers and sports training facilities. Physical therapists also practice in non-patient care roles such as health policy, health insurance, health care administration and as health care executives. Physical therapists are involved in the medical-legal field serving as experts, performing peer review and independent medical examinations. Education varies greatly by country. The span of education ranges from some countries having little formal education to others having doctoral degrees and post-doctoral residencies and fellowships. Regarding its relationship to other healthcare professions, physiotherapy is one of the allied health professions. World Physiotherapy has signed a "memorandum of understanding" with the four other members of the World Health Professions Alliance "to enhance their joint collaboration on protecting and investing in the health workforce to provide safe, quality and equitable care in all settings". == History == Physicians like Hippocrates and later Galen are believed to have been the first practitioners of physical therapy, advocating massage, manual therapy techniques and hydrotherapy to treat people in 460 BC. After the development of orthopedics in the eighteenth century, machines like the Gymnasticon were developed to treat gout and similar diseases by systematic exercise of the joints, similar to later developments in physical therapy. The earliest documented origins of actual physical therapy as a professional group date back to Per Henrik Ling, "Father of Swedish Gymnastics," who founded the Royal Central Institute of Gymnastics (RCIG) in 1813 for manipulation, and exercise. Up until 2014, the Swedish word for a physical therapist was sjukgymnast = someone involved in gymnastics for those who are ill, but the title was then changed to fysioterapeut (physiotherapist), the word used in the other Scandinavian countries. In 1887, PTs were given official registration by Sweden's National Board of Health and Welfare. Other countries soon followed. In 1894, four nurses in Great Britain formed the Chartered Society of Physiotherapy. The School of Physiotherapy at the University of Otago in New Zealand in 1913, and the United States 1914 Reed College in Portland, Oregon, which graduated "reconstruction aides." Since the profession's inception, spinal manipulative therapy has been a component of the physical therapist practice. Modern physical therapy was established towards the end of the 19th century due to events that affected on a global scale, which called for rapid advances in physical therapy. Following this, American orthopedic surgeons began treating children with disabilities and employed women trained in physical education, and remedial exercise. These treatments were further applied and promoted during the Polio outbreak of 1916. During the First World War, women were recruited to work with and restore physical function to injured soldiers, and the field of physical therapy was institutionalized. In 1918 the term "Reconstruction Aide" was used to refer to individuals practicing physical therapy. The first school of physical therapy was established at Walter Reed Army Hospital in Washington, D.C., following the outbreak of World War I. Treatment through the 1940s primarily consisted of exercise, massage, and traction. Manipulative procedures to the spine and extremity joints began to be practiced, especially in the British Commonwealth countries, in the early 1950s. Around the time polio vaccines were developed, physical therapists became a normal occurrence in hospitals throughout North America and Europe. In the late 1950s, physical therapists started to move beyond hospital-based practice to outpatient orthopedic clinics, public schools, colleges/universities health-centres, geriatric settings (skilled nursing facilities), rehabilitation centers and medical centers. Specialization in physical therapy in the U.S. occurred in 1974, with the Orthopaedic Section of the APTA being formed for those physical therapists specializing in orthopedics. In the same year, the International Federation of Orthopaedic Manipulative Physical Therapists was formed, which has ever since played an important role in advancing manual therapy worldwide. An international organization for the profession is the World Confederation for Physical Therapy (WCPT). It was founded in 1951 and has operated under the brand name World Physiotherapy since 2020. == Education == Educational criteria for physical therapy providers vary from state to state, country to country, and among various levels of professional responsibility. Most U.S. states have physical therapy practice acts that recognize both physical therapists (PT) and physical therapist assistants (PTA) and some jurisdictions also recognize physical therapy technicians (PT Techs) or aides. Most countries have licensing bodies that require physical therapists to be member of before they can start practicing as independent professionals. === Canada === The Canadian Alliance of Physiotherapy Regulators (CAPR) offers eligible program graduates to apply for the national Physiotherapy Competency Examination (PCE). Passing the PCE is one of the requirements in most provinces and territories to work as a licensed physiotherapist in Canada. CAPR has members which are physiotherapy regulatory organizations recognized in their respective provinces and territories: Government of Yukon, Consumer Services College of Physical Therapists of British Columbia College of Physiotherapists of Alberta Saskatchewan College of Physical Therapists College of Physiotherapists of Manitoba College of Physiotherapists of Ontario Ordre professionnel de la physiothérapie du Québec College of Physiotherapists of New Brunswick/Collège des physiothérapeutes du Nouveau-Brunswick Nova Scotia College of Physiotherapists Prince Edward Island College of Physiotherapists Newfoundland & Labrador College of Physiotherapists Physiotherapy programs are offered at fifteen universities, often through the university's respective college of medicine. Each of Canada's physical therapy schools has transitioned from three-year Bachelor of Science in Physical Therapy (BScPT) programs that required two years of prerequisite university courses (five-year bachelor's degree) to two-year Master's of Physical Therapy (MPT) programs that require prerequisite bachelor's degrees. The last Canadian university to follow suit was the University of Manitoba, which transitioned to the MPT program in 2012, making the MPT credential the new entry to practice standard across Canada. Existing practitioners with BScPT credentials are not required to upgrade their qualifications. In the province of Quebec, prospective physiotherapists are required to have completed a college diploma in either health sciences, which lasts on average two years, or physical rehabilitation technology, which lasts at least three years, to apply to a physiotherapy program or program in university. Following admission, physical therapy students work on a bachelor of science with a major in physical therapy and rehabilitation. The B.Sc. usually requires three years to complete. Students must then enter graduate school to complete a master's degree in physical therapy, which normally requires one and a half to two years of study. Graduates who obtain their M.Sc. must successfully pass the membership examination to become members of the Ordre Professionnel de la physiothérapie du Québec (PPQ). Physiotherapists can pursue their education in such fields as rehabilitation sciences, sports medicine, kinesiology, and physiology. In the province of Quebec, physical rehabilitation therapists are health care professionals who are required to complete a four-year college diploma program in physical rehabilitation therapy and be members of the Ordre Professionnel de la physiothérapie du Québec (OPPQ) to practice legally in the country according to specialist De Van Gerard. Most physical rehabilitation therapists complete their college diploma at Collège Montmorency, Dawson College, or Cégep Marie-Victorin, all situated in and around the Montreal area. After completing their technical college diploma, graduates have the opportunity to pursue their studies at the university level to perhaps obtain a bachelor's degree in physiotherapy, kinesiology, exercise science, or occupational therapy. The Université de Montréal, the Université Laval and the Université de Sherbrooke are among the Québécois universities that admit physical rehabilitation therapists in their programs of study related to health sciences and rehabilitation to credit courses that were completed in college. To date, there are no bridging programs available to facilitate upgrading from the BScPT to the MPT credential. However, research Master's of Science (MSc) and Doctor of Philosophy (Ph.D.) programs are available at every university. Aside from academic research, practitioners can upgrade their skills and qualifications through continuing education courses and curriculums. Continuing education is a requirement of the provincial regulatory bodies. The Canadian Physiotherapy Association offers a curriculum of continuing education courses in orthopedics and manual therapy. The program consists of 5 levels (7 courses) of training with ongoing mentorship and evaluation at each level. The orthopedic curriculum and examinations take a minimum of 4 years to complete. However, upon completion of level 2, physiotherapists can apply to a unique 1-year course-based Master's program in advanced orthopedics and manipulation at the University of Western Ontario to complete their training. This program accepts only 16 physiotherapists annually since 2007. Successful completion of either of these education streams and their respective examinations allows physiotherapists the opportunity to apply to the Canadian Academy of Manipulative Physiotherapy (CAMPT) for fellowship. Fellows of the Canadian Academy of manipulative Physiotherapists (FCAMPT) are considered leaders in the field, having extensive post-graduate education in orthopedics and manual therapy. FCAMPT is an internationally recognized credential, as CAMPT is a member of the International Federation of Manipulative Physiotherapists (IFOMPT), a branch of World Physiotherapy (formerly World Confederation of Physical Therapy (WCPT)) and the World Health Organization (WHO). === Scotland === Physiotherapy degrees are offered at four universities: Edinburgh Napier University in Edinburgh, Robert Gordon University in Aberdeen, Glasgow Caledonian University in Glasgow, and Queen Margaret University in Edinburgh. Students can qualify as physiotherapists by completing a four-year Bachelor of Science degree or a two-year master's degree (if they already have an undergraduate degree in a related field). To use the title 'Physiotherapist', a student must register with the Health and Care Professions Council, a UK-wide regulatory body, on qualifying. Many physiotherapists are also members of the Chartered Society of Physiotherapy (CSP), which provides insurance and professional support. === United States === The primary physical therapy practitioner is the Physical Therapist (PT) who is trained and licensed to examine, evaluate, diagnose and treat impairment, functional limitations, and disabilities in patients or clients. Physical therapist education curricula in the United States culminate in a Doctor of Physical Therapy (DPT) degree, with some practicing PTs holding a Master of Physical Therapy degree, and some with a Bachelor's degree. The Master of Physical Therapy and Master of Science in Physical Therapy degrees are no longer offered, and the entry-level degree is the Doctor of Physical Therapy degree, which typically takes 3 years after completing a bachelor's degree. PTs who hold a Masters or bachelors in PT are encouraged to get their DPT because APTA's goal is for all PT's to be on a doctoral level. WCPT recommends physical therapist entry-level educational programs be based on university or university-level studies, of a minimum of four years, independently validated and accredited. Curricula in the United States are accredited by the Commission on Accreditation in Physical Therapy Education (CAPTE). According to CAPTE, as of 2022 there are 37,306 students currently enrolled in 294 accredited PT programs in the United States while 10,096 PTA students are currently enrolled in 396 PTA programs in the United States. The physical therapist professional curriculum includes content in the clinical sciences (e.g., content about the cardiovascular, pulmonary, endocrine, metabolic, gastrointestinal, genitourinary, integumentary, musculoskeletal, and neuromuscular systems and the medical and surgical conditions frequently seen by physical therapists). Current training is specifically aimed to enable physical therapists to appropriately recognize and refer non-musculoskeletal diagnoses that may present similarly to those caused by systems not appropriate for physical therapy intervention, which has resulted in direct access to physical therapists in many states. Post-doctoral residency and fellowship education prevalence is increasing steadily with 219 residency, and 42 fellowship programs accredited in 2016. Residencies are aimed to train physical therapists in a specialty such as acute care, cardiovascular & pulmonary, clinical electrophysiology, faculty, geriatrics, neurology, orthopaedics, pediatrics, sports, women's health, and wound care, whereas fellowships train specialists in a subspecialty (e.g. critical care, hand therapy, and division 1 sports), similar to the medical model. Residency programs offer eligibility to sit for the specialist certification in their respective area of practice. For example, completion of an orthopedic physical therapy residency, allows its graduates to apply and sit for the clinical specialist examination in orthopedics, achieving the OCS designation upon passing the examination. Board certification of physical therapy specialists is aimed to recognize individuals with advanced clinical knowledge and skill training in their respective area of practice, and exemplifies the trend toward greater education to optimally treat individuals with movement dysfunction. Physical therapist assistants may deliver treatment and physical interventions for patients and clients under a care plan established by and under the supervision of a physical therapist. Physical therapist assistants in the United States are currently trained under associate of applied sciences curricula specific to the profession, as outlined and accredited by CAPTE. As of December 2022, there were 396 accredited two-year (Associate degree) programs for physical therapist assistants In the United States of America. == Employment == Physical therapy–related jobs in North America have shown rapid growth in recent years, but employment rates and average wages may vary significantly between different countries, states, provinces, or regions. A study from 2013 states that 56.4% of physical therapists were globally satisfied with their jobs. Salary, interest in work, and fulfillment in a job are important predictors of job satisfaction. In a Polish study, job burnout among the physical therapists was manifested by increased emotional exhaustion and decreased sense of personal achievement. Emotional exhaustion is significantly higher among physical therapists working with adults and employed in hospitals. Other factors that increased burnout include working in a hospital setting and having seniority from 15 to 19 years. === United States === According to the United States Department of Labor's Bureau of Labor Statistics, there were approximately 210,900 physical therapists employed in the United States in 2014, earning an average of $84,020 annually in 2015, or $40.40 per hour, with 34% growth in employment projected by 2024. The Bureau of Labor Statistics also reports that there were approximately 128,700 Physical Therapist Assistants and Aides employed in the United States in 2014, earning an average $42,980 annually, or $20.66 per hour, with 40% growth in employment projected by 2024. To meet their needs, many healthcare and physical therapy facilities hire "travel physical therapists", who work temporary assignments between 8 and 26 weeks for much higher wages; about $113,500 a year." Bureau of Labor Statistics data on PTAs and techs can be difficult to decipher, due to their tendency to report data on these job fields collectively rather than separately. O-Net reports that in 2015, PTAs in the United States earned a median wage of $55,170 annually or $26.52 hourly and that Aides/Techs earned a median wage of $25,120 annually or $12.08 hourly in 2015. The American Physical Therapy Association reports vacancy rates for physical therapists as 11.2% in outpatient private practice, 10% in acute care settings, and 12.1% in skilled nursing facilities. The APTA also reports turnover rates for physical therapists as 10.7% in outpatient private practice, 11.9% in acute care settings, 27.6% in skilled nursing facilities. Definitions and licensing requirements in the United States vary among jurisdictions, as each state has enacted its own physical therapy practice act defining the profession within its jurisdiction, but the Federation of State Boards of Physical Therapy has also drafted a model definition to limit this variation. The Commission on Accreditation in Physical Therapy Education (CAPTE) is responsible for accrediting physical therapy education curricula throughout the United States of America. === United Kingdom === The title of Physiotherapist is a protected professional title in the United Kingdom. Anyone using this title must be registered with the Health & Care Professions Council (HCPC). Physiotherapists must complete the necessary qualifications, usually an undergraduate physiotherapy degree (at university or as an intern), a master rehabilitation degree, or a doctoral degree in physiotherapy. This is typically followed by supervised professional experience lasting two to three years. All professionals on the HCPC register must comply with continuing professional development and can be audited for this evidence at intervals. == Specialty areas == The body of knowledge of physical therapy is large, and therefore physical therapists may specialize in a specific clinical area. While there are many different types of physical therapy, the American Board of Physical Therapy Specialties lists ten current specialist certifications. Most Physical Therapists practicing in a specialty will have undergone further training, such as an accredited residency program, although individuals are currently able to sit for their specialist examination after 2,000 hours of focused practice in their respective specialty population, in addition to requirements set by each respective specialty board. === Cardiovascular and pulmonary === Cardiovascular and pulmonary rehabilitation respiratory practitioners and physical therapists offer therapy for a wide variety of cardiopulmonary disorders or pre and post cardiac or pulmonary surgery. An example of cardiac surgery is coronary bypass surgery. The primary goals of this specialty include increasing endurance and functional independence. Manual therapy is used in this field to assist in clearing lung secretions experienced with cystic fibrosis. Pulmonary disorders, heart attacks, post coronary bypass surgery, chronic obstructive pulmonary disease, and pulmonary fibrosis, treatments can benefit from cardiovascular and pulmonary specialized physical therapists. === Clinical electrophysiology === This specialty area includes electrotherapy/physical agents, electrophysiological evaluation (EMG/NCV), physical agents, and wound management. === Geriatric === Geriatric physical therapy covers a wide area of issues concerning people as they go through normal adult aging but is usually focused on the older adult. There are many conditions that affect many people as they grow older and include but are not limited to the following: arthritis, osteoporosis, cancer, Alzheimer's disease, hip and joint replacement, balance disorders, incontinence, etc. Geriatric physical therapists specialize in providing therapy for such conditions in older adults. Physical rehabilitation can prevent deterioration in health and activities of daily living among care home residents. The current evidence suggests benefits to physical health from participating in different types of physical rehabilitation to improve daily living, strength, flexibility, balance, mood, memory, exercise tolerance, fear of falling, injuries, and death. It may be both safe and effective in improving physical and possibly mental state, while reducing disability with few adverse events. The current body of evidence suggests that physical rehabilitation may be effective for long-term care residents in reducing disability with few adverse events. However, there is insufficient to conclude whether the beneficial effects are sustainable and cost-effective. The findings are based on moderate quality evidence. === Wound management === Wound management physical therapy includes the treatment of conditions involving the skin and all its related organs. Common conditions managed include wounds and burns. Physical therapists may utilize surgical instruments, wound irrigations, dressings, and topical agents to remove the damaged or contaminated tissue and promote tissue healing. Other commonly used interventions include exercise, edema control, splinting, and compression garments. The work done by physical therapists in the integumentary specialty does work similar to what would be done by medical doctors or nurses in the emergency room or triage. === Neurology === Neurological physical therapy is a field focused on working with individuals who have a neurological disorder or disease. These can include stroke, chronic back pain, Alzheimer's disease, Charcot-Marie-Tooth disease (CMT), ALS, brain injury, cerebral palsy, multiple sclerosis, Parkinson's disease, facial palsy and spinal cord injury. Common impairments associated with neurologic conditions include impairments of vision, balance, ambulation, activities of daily living, movement, muscle strength and loss of functional independence. The techniques involve in neurological physical therapy are wide-ranging and often require specialized training. Neurological physiotherapy is also called neurophysiotherapy or neurological rehabilitation. It is recommended for neurophysiotherapists to collaborate with psychologists when providing physical treatment of movement disorders. This is especially important because combining physical therapy and psychotherapy can improve neurological status of the patients. === Orthopaedics === Orthopedic physical therapists diagnose, manage, and treat disorders and injuries of the musculoskeletal system including rehabilitation after orthopedic surgery, acute trauma such as sprains, strains, injuries of insidious onset such as tendinopathy, bursitis, and deformities like scoliosis. This specialty of physical therapy is most often found in the outpatient clinical setting. Orthopedic therapists are trained in the treatment of post-operative orthopedic procedures, fractures, acute sports injuries, arthritis, sprains, strains, back and neck pain, spinal conditions, and amputations. Joint and spine mobilization/manipulation, dry needling (similar to acupuncture), therapeutic exercise, neuromuscular techniques, muscle reeducation, hot/cold packs, and electrical muscle stimulation (e.g., cryotherapy, iontophoresis, electrotherapy) are modalities employed to expedite recovery in the orthopedic setting. Additionally, an emerging adjunct to diagnosis and treatment is the use of sonography for diagnosis and to guide treatments such as muscle retraining. Those with injury or disease affecting the muscles, bones, ligaments, or tendons will benefit from assessment by a physical therapist specialized in orthopedics. === Pediatrics === Pediatric physical therapy assists in the early detection of health problems and uses a variety of modalities to provide physical therapy for disorders in the pediatric population. These therapists are specialized in the diagnosis, treatment, and management of infants, children, and adolescents with a variety of congenital, developmental, neuromuscular, skeletal, or acquired disorders/diseases. Treatments focus mainly on improving gross and fine motor skills, balance and coordination, strength and endurance as well as cognitive and sensory processing/integration. === Sports === Physical therapists are closely involved in the care and wellbeing of athletes including recreational, semi-professional (paid), and professional (full-time employment) participants. This area of practice encompasses athletic injury management under 5 main categories: acute care – assessment and diagnosis of an initial injury; treatment – application of specialist advice and techniques to encourage healing; rehabilitation – progressive management for full return to sport; prevention – identification and address of deficiencies known to directly result in, or act as precursors to injury, such as movement assessment education – sharing of specialist knowledge to individual athletes, teams, or clubs to assist in prevention or management of injury Physical therapists who work for professional sports teams often have a specialized sports certification issued through their national registering organization. Most Physical therapists who practice in a sporting environment are also active in collaborative sports medicine programs too (See also: athletic trainers). === Women's health === Women's health or pelvic floor physical therapy mostly addresses women's issues related to the female reproductive system, child birth, and post-partum. These conditions include lymphedema, osteoporosis, pelvic pain, prenatal and post-partum periods, and urinary incontinence. It also addresses incontinence, pelvic pain, pelvic organ prolapse and other disorders associated with pelvic floor dysfunction. Manual physical therapy has been demonstrated in multiple studies to increase rates of conception in women with infertility. === Oncology === Physical therapy in the field of oncology and palliative care is a continuously evolving and developing specialty, both in malignant and non-malignant diseases. Physical therapy for both groups of patients is now recognized as an essential part of the clinical pathway, as early diagnoses and new treatments are enabling patients to live longer. it is generally accepted that patients should have access to an appropriate level of rehabilitation, so that they can function at a minimum level of dependency and optimize their quality of life, regardless of their life expectancy. == Physical therapist–patient collaborative relationship == People with brain injury, musculoskeletal conditions, cardiac conditions, or multiple pathologies benefit from a positive alliance between patient and therapist. Outcomes include the ability to perform activities of daily living, manage pain, complete specific physical function tasks, depression, global assessment of physical health, treatment adherence, and treatment satisfaction. Studies have explored four themes that may influence patient-therapist interactions: interpersonal and communication skills, practical skills, individualized patient-centered care, and organizational and environmental factors. Physical therapists need to be able to effectively communicate with their patients on a variety of levels. Patients have varying levels of health literacy so physical therapists need to take that into account when discussing the patient's ailments as well as planned treatment. Research has shown that using communication tools tailored to the patient's health literacy leads to improved engagement with their practitioner and their clinical care. In addition, patients reported that shared decision-making will yield a positive relationship. Practical skills such as the ability to educate patients about their conditions, and professional expertise are perceived as valuable factors inpatient care. Patients value the ability of a clinician to provide clear and simple explanations about their problems. Furthermore, patients value when physical therapists possess excellent technical skills that improve the patient effectively. Environmental factors such as the location, equipment used, and parking are less important to the patient than the physical therapy clinical encounter itself. Based on the current understanding, the most important factors that contribute to the patient-therapist interactions include that the physical therapist: spends an adequate amount of time with the patient, possesses strong listening and communication skills, treats the patient with respect, provides clear explanations of the treatment, and allows the patient to be involved in the treatment decisions. == Effectiveness == Physical therapy has been found to be effective for improving outcomes, both in terms of pain and function, in multiple musculoskeletal conditions. Spinal manipulation by physical therapists is a safe option to improve outcomes for lower back pain. Several studies have suggested that physical therapy, particularly manual therapy techniques focused on the neck and the median nerve, combined with stretching exercises, may be equivalent or even preferable to surgery for carpal tunnel syndrome. While spine manipulation and therapeutic massage are effective interventions for neck pain, electroacupuncture, strain-counterstrain, relaxation massage, heat therapy, and ultrasound therapy are not as effective, and thus not recommended. Studies also show physical therapy is effective for patients with other conditions. Physiotherapy treatment may improve quality of life, promote cardiopulmonary fitness and inspiratory pressure, as well as reduce symptoms and medication use by people with asthma. Physical therapy is sometimes provided to patients in the ICU, as early mobilization can help reduce ICU and hospital length of stay and improve long-term functional ability. Early progressive mobilization for adult, intubated ICU patients on mechanical ventilation is safe and effective. Psychologically informed physical therapy (PIPT), in which a physical therapist treats patients while other members of a multidisciplinary care team help in preoperative planning for patient management of pain and quality of life, helps improve patient outcomes, especially before and after spine, hip, or knee surgery. However, in the United States, there are obstacles affecting the effectiveness of physical therapy, such as racial disparities among patients. Studies have shown that patients who identified as black experiences were below standard compared to the white patients. Physical therapy has been experiencing disparities with Hispanic patients like many other medical fields. Whether not receiving a referral for inpatient Hispanic patients to follow-up with their care, despite insurance status. Another being limited access to physical therapy as a reason. Raising awareness of these racial disparities in physical therapy is crucial to improving treatment effectiveness across all demographics. == Telehealth == Telehealth (or telerehabilitation) is a developing form of physical therapy in response to the increasing demand for physical therapy treatment. Telehealth is online communication between the clinician and patient, either live or in pre-recorded sessions with mixed reviews when compared to usual, in-person care. The benefits of telehealth include improved accessibility in remote areas, cost efficiency, and improved convenience for people who are bedridden and home-restricted, or physically disabled. Some considerations for telehealth include: limited evidence to prove effectiveness and compliance more than in-person therapy, licensing and payment policy issues, and compromised privacy. Studies are controversial as to the effectiveness of telehealth in patients with more serious conditions, such as stroke, multiple sclerosis, and lower back pain. The interstate compact, enacted in March 2018, allows patients to participate in Telehealth appointments with medical practices located in different states. During the COVID-19 pandemic, the need for telehealth came to the fore as patients were less able to safely attend in-person, particularly if they were elderly or had chronic diseases. Telehealth was considered to be a proactive step to prevent decline in individuals that could not attend classes. Physical decline in at risk groups is difficult to address or undo later. The platform licensing or development are found to be the most substantial cost in telehealth. Telehealth does not remove the need for the physical therapist as they still need to oversee the program. == See also == == References == == External links == Europe: Regulated professions database – Physiotherapist, European Commission	Wikipedia/Physiotherapy
Non-contact thermography, thermographic imaging, or medical thermology is the field of thermography that uses infrared images of the human skin to assist in the diagnosis and treatment of medical conditions. Medical thermology is sometimes referred to as medical infrared imaging or tele-thermology and utilizes thermographic cameras. According to the American Academy of Thermology, Medical Thermology practitioners are licensed health care practitioners who utilize IR imaging in consistent with medically established paradigms of care. Non-medically licensed alternative practitioners who are not held to the same standard may offer thermography services but that should not be confused with the field of medical thermology. Restated, medical thermology is the use of infrared (IR) imaging to assess skin temperature as an extension of the clinician's physical exam to aid in the formation of a medical diagnosis or treatment plan. Medical Thermology does not condone those who purport that "Thermography" can find disease by looking for areas of the body that have abnormal heat or irregular blood flow. IR imaging simply does not have the ability to assess temperature beyond the surface of the skin. Thermography is a physiologic study and is not a replacement for structural studies such as X-Ray, MRI, or Mammography. As a physiologic study, however, medical thermology has many health-related indications. The American Academy of Thermology (AAT) (www.aathermology.org) has published internationally peer-reviewed guidelines for neuro-musculoskeletal (MSK), breast, veterinary, and oral-systemic disease. Examples of neuro-musculoskeletal indications for medical thermology include Reflex Sympathetic Dystrophy (RSD), Chronic Regional Pain Syndrome (CRPS), Dysautonomia, Migraine, Fibromyalgia (and other weather-sensitive pain syndromes), thoracic outlet syndrome, and vaso-motor migraine/headaches such as Barré-Liéou syndrome. This is especially true when used to monitor the results of a cold stress (cold presser) test. Thermography is not effective for any type of medical screening, and the FDA had repeatedly issued warning letters to fraudsters claiming otherwise. Veterinary thermography indications include, but are not limited to, assessment of shoring, limb inflammation, and sweating disorders. Telethermography systems are regulated as a medical device under 21 CFR 884.2980. == Medical Thermology versus Thermography == There is a difference between Medical Thermology as promulgated by medically based organizations such as the American Academy of Thermology (AAT), and thermography as practiced by alternative providers or physicians who overstate the benefits of thermography. As a result of this disparity organizations such as the FDA, ISO, and the AAT have published Guidelines and best use practices to help educate medical providers and the public to recognize the difference between providers who provide medical thermology services and those that offer something else. Thermography has been promoted by some alternative medicine practitioners as a means to diagnose cancer, although it is not effective for this purpose. Health Canada has issued "cease and desist" orders to clinics offering breast thermography as a cancer diagnostic device because thermography cameras are not licensed as a medical device in Canada, and because thermography for cancer detection is viewed as ineffective by medical experts. The FDA has issued a public warning notice stating that breast thermography is not an alternative to mammography and has ordered Joseph Mercola to stop making excessive claims for thermography. Thermography is discouraged in North America by the American Cancer Society, radiologists and the FDA for early breast cancer detection. Advertisements in the United Kingdom have been found to be misleading. The FDA has cleared thermography only as an adjunct method of screening. "Thermography devices have been cleared by the FDA for use as an adjunct, or additional, tool for detecting breast cancer." The FDA says it is not effective for any kind of medical screening. The AAT has published several Position Papers, including statements on Breast Thermography that clearly delineate its utility as an adjudicative breast risk health assessment only. == See also == Thermography == References ==	Wikipedia/Thermography_(medical)
The Strategic Defense Initiative (SDI), derisively nicknamed the "Star Wars" program, was a proposed missile defense system intended to protect the United States from attack by ballistic nuclear missiles. The program was announced in 1983, by President Ronald Reagan. Reagan called for a system that would render nuclear weapons obsolete, and to end the doctrine of mutual assured destruction (MAD), which he described as a "suicide pact". Elements of the program reemerged in 2019 under the Space Development Agency (SDA). The Strategic Defense Initiative Organization (SDIO) was set up in 1984 within the US Department of Defense to oversee development. Advanced weapon concepts, including lasers, particle-beam weapons, and ground and space-based missile systems were studied, along with sensor, command and control, and computer systems needed to control a system consisting of hundreds of combat centers and satellites spanning the globe. The US held a significant advantage in advanced missile defense systems through decades of extensive research and testing. Several concepts, technologies and insights obtained were transferred to subsequent programs. Under SDIO's Innovative Sciences and Technology Office, investment was made in basic research at national laboratories, universities, and in industry. These programs have continued to be key sources of funding for research scientists in particle physics, supercomputing/computation, advanced materials, and other critical science and engineering disciplines. In 1987, the American Physical Society concluded that the technologies were decades away from readiness, and at least another decade of research was required to know whether such a system was even possible. After the publication of the APS report, SDI's budget was cut. By the late 1980s, the effort had re-focused on the "Brilliant Pebbles" concept using small orbiting missiles. SDI was derisively nicknamed the "Star Wars" program, and criticized for threatening to destabilize the MAD-approach and to re-ignite "an offensive arms race". In a 1986 speech, Senator Joe Biden said, "Star Wars represents a fundamental assault on the concepts, alliances and arms-control agreements that have buttressed American security for several decades, and the president's continued adherence to it constitutes one of the most reckless and irresponsible acts in the history of modern statecraft." Declassified intelligence material revealed that through the potential neutralization of its arsenal and resulting loss of a balancing power factor, SDI was a cause of grave concern for the Soviet Union and its successor state Russia. Following the Cold War when nuclear arsenals were shrinking, political support for SDI collapsed. SDI ended in 1993, when the Clinton administration redirected the efforts towards theatre ballistic missiles and renamed the agency the Ballistic Missile Defense Organization (BMDO). In 2019, elements, specifically the observation portions, of the program re-emerged with President Trump's signing of the National Defense Authorization Act. The program is managed by the Space Development Agency (SDA) as part of the new National Defense Space Architecture (NDSA). CIA Director Mike Pompeo called for additional funding to achieve a full-fledged "Strategic Defense Initiative for our time, the SDI II." On May 20 2025, Donald Trump announced the Golden Dome, a project broadly similar to the Strategic Defense Initiative, to which he referenced in the announcement. == History == === National BMD === The US Army considered the issue of ballistic missile defense (BMD) after World War II. Studies suggested that attacking a V-2 rocket would be difficult because the flight time was so short that it would leave little time to forward information through command and control networks to missile batteries. Bell Labs pointed out that although longer-range missiles flew much faster, their longer flight times would ease the timing issue and their high altitudes would ease long-range radar detection. This led to a series of projects including Nike Zeus, Nike-X, Sentinel and ultimately the Safeguard Program, all aimed at developing a system to defend against attacks by Soviet ICBMs. The programs proliferated because of the changing threat; the Soviets claimed to be producing missiles "like sausages", and ever-more missiles would be needed to defend against their fleet. Low-cost countermeasures such as radar decoys required additional interceptors. An early estimate suggested $20 spent on defense would be required for every $1 the Soviets spent on offense. The addition of MIRV in the late 1960s further moved the balance in favor of offensive systems. This massively skewed cost-exchange ratio prompted observers to propose that an arms race was inevitable. President Dwight D. Eisenhower asked ARPA to consider alternative concepts. Their Project Defender studied many approaches before concentrating on Project BAMBI. BAMBI used satellites carrying interceptors that would attack the Soviet ICBMs upon launch. This boost phase intercept rendered MIRV impotent; a successful attack would destroy all of the warheads. Unfortunately, the operational cost of such a system was so large that the US Air Force rejected the concepts. Development was cancelled in 1963. During this period, the entire topic of BMD became increasingly controversial. Early deployment plans were met with little interest, but by the late 1960s, public meetings on the Sentinel system were met by thousands of angry protesters. After thirty years of effort, only one such system was built; a single base of the original Safeguard system became operational in April 1975, but was closed in February 1976. A Soviet military A-35 anti-ballistic missile system was deployed around Moscow to intercept enemy ballistic missiles targeting the city or its surrounding areas. The A-35 was the only Soviet ABM system allowed under the 1972 Anti-Ballistic Missile Treaty. In development since the 1960s and in operation from 1971 until the 1990s, it featured the nuclear-tipped A350 exoatmospheric interceptor missile. === Lead up to SDI === George Shultz, Reagan's secretary of state, suggested that a 1967 lecture by physicist Edward Teller was an important precursor to SDI. In the lecture, Teller talked about the idea of defending against nuclear missiles using nuclear weapons, principally the W65 and W71, with the latter an enhanced thermal/X-ray device used on the Spartan missile in 1975. Held at Lawrence Livermore National Laboratory (LLNL), the 1967 lecture was attended by Reagan shortly after he became governor of California. Development of laser weapons in the Soviet Union began in 1964–1965. Though classified at the time, a detailed study on a Soviet space-based laser system began no later than 1976 with the Polyus, a 1 MW Carbon dioxide laser-based orbital weapons platform prototype. Development was also started on the anti-satellite Kaskad in-orbit missile platform. A revolver cannon (Rikhter R-23) was mounted on the 1974 Soviet Salyut 3 space station, a satellite that successfully test-fired its cannon in orbit. In 1979, Teller contributed to a Hoover Institution publication where he claimed that the US would be facing an emboldened USSR due to their work on civil defense. Two years later at a conference in Italy, he made the same claims about their ambitions, now emboldened by new space-based weapons. According to popular opinion, shared by author Frances FitzGerald, no evidence validated that such research was carried out. Instead, Teller was promoting his latest weapon, the X-ray laser that was finding only limited funding, his speech in Italy was a new attempt to synthsize a missile gap. In 1979, Reagan visited the NORAD command base, Cheyenne Mountain Complex, where he was introduced to the extensive tracking and detection systems extending throughout the world and into space; however, he was struck by their comments that while they could track the attack down to the individual targets, they could not stop it. Reagan felt that in the event of an attack, this would place the president in a terrible position, having to choose between immediate counterattack or absorbing the attack while maintaining offensive dominance. Shultz suggested that this feeling of helplessness, coupled with Teller's defensive ideas combined to motivate SDI.: 261–62 In the fall of 1979, at Reagan's request, Lieutenant General Daniel O. Graham, the former head of the DIA, briefed Reagan on an updated BAMBI he called High Frontier, a missile shield composed of multi-layered ground- and space-based weapons that could track, intercept, and destroy ballistic missiles, theoretically enabled by emerging technologies. It was designed to replace the MAD doctrine. In September 1981, Graham formed a small, Virginia-based think tank called High Frontier to continue research on the missile shield. The Heritage Foundation provided High Frontier with research space, and Graham published a 1982 report entitled, "High Frontier: A New National Strategy" that examined in greater detail how the system would function. Since the late 1970s, another group had been pushing for the development of a high-powered orbital chemical laser attack ICBMs, the Space Based Laser (SBL). New developments under Project Excalibur by Teller's "O-Group" at Lawrence Livermore National Laboratory(LLNL) suggested that a single X-ray laser could shoot down dozens of missiles with a single shot. The groups began to meet in order to prepare their plans for the incoming president. The group met with Reagan several times during 1981 and 1982, apparently with little effect, while the buildup of new offensive weaponry like the B-1 Lancer and MX missile continued. However, in early 1983, the Joint Chiefs of Staff met with the president and outlined the reasons why they might consider shifting some of the funding from the offensive side to new defensive systems. According to a 1983 US Interagency Intelligence Assessment, good evidence indicated that in the late 1960s the Soviets were devoting serious thought to both explosive and non-explosive nuclear power sources for lasers. == Project and proposals == === Announcement === On March 23, 1983, Reagan announced SDI in a nationally televised speech, stating "I call upon the scientific community in this country, those who gave us nuclear weapons, to turn their great talents to the cause of mankind and world peace, to give us the means of rendering these nuclear weapons impotent and obsolete." === Strategic Defense Initiative Organization (SDIO) === In 1984, the Strategic Defense Initiative Organization (SDIO) was established to oversee the program, which was headed by Lt. General James Alan Abrahamson USAF, a past Director of the Space Shuttle program. In addition to original Heritage ideas, other concepts were considered. Notable among these were particle-beam weapons, updated versions of nuclear shaped charges, and various plasma weapons. SDIO invested in computer systems, component miniaturization, and sensors. Initially, the program focused on large-scale systems designed to defeat a massive Soviet offensive strike. For this mission, SDIO concentrated almost entirely on "high tech" solutions like lasers. Graham's proposal was repeatedly rejected by members of the Heritage group as well as within SDIO; when asked about it in 1985, Abrahamson suggested that the concept was underdeveloped and was not considered. By 1986, many of the promising ideas were failing. Teller's X-ray laser, run under Project Excalibur, failed several key tests in 1986 and was targeted to the anti-satellite role. The particle beam concept was demonstrated to basically not work, as was the case with several other concepts. Only the Space-Based Laser seemed to have any hope of developing in the short term, but it was growing in size due to its fuel consumption. === APS report === The American Physical Society (APS) had been asked by SDIO to provide a review of the various concepts. They put together an all-star panel including many of the inventors of the laser, including a Nobel laureate. Their initial report was presented in 1986, but was released to the public (in redacted form) in early 1987. The report considered all of the systems then under development and concluded none of them were anywhere near ready for deployment. Specifically, they noted that all of the systems had to improve their energy output by at least 100 times, and in some cases by as much as a million. In other cases, like Excalibur, they dismissed the concept entirely. Their summary stated simply: We estimate that all existing candidates for directed energy weapons (DEWs) require two or more orders of magnitude, (powers of 10) improvements in power output and beam quality before they may be seriously considered for application in ballistic missile defense systems. They concluded that none of the systems could be deployed as an anti-missile system until the next century. === Strategic Defense System === Faced with this report and accompanying negative press, SDIO changed direction. Beginning in late 1986, Abrahamson proposed that SDI would be based on the system he had previously dismissed, a version of High Frontier now named the "Strategic Defense System, Phase I Architecture". The name implied that the concept would be replaced by more advanced systems in future phases. Strategic Defense System (SDS) was the low-earth orbit (LEO) Smart Rocks concept with an added layer of ground-based missiles sited in the US. These missiles were intended to attack warheads that the Smart Rocks missed. In order to track them below the radar horizon, SDS added more LEO satellites that would feed tracking information to both the space-based "garages" as well as the ground-based missiles. Later ground-based systems trace derived from this concept. LLNL then introduced the Brilliant Pebbles concept. This was essentially the combination of the sensors on the garage satellites and the tracking stations. Advancements in sensors and microprocessors allowed this to be packaged in a small missile nose cone. Subsequent studies suggested that this approach would be cheaper, easier to launch and more resistant to counterattack, and in 1990 Brilliant Pebbles was selected as the baseline model for SDS Phase 1. === Global Protection Against Limited Strikes === While SDIO pursued SDS, the Warsaw Pact was rapidly disintegrating, culminating in the destruction of the Berlin Wall in 1989. One of the many reports on SDS considered these events and suggested that a massive defense against a Soviet launch would become unnecessary. However, short and medium range missile technology would likely proliferate as the Soviet Union disintegrated and sold off its hardware. One of the core ideas behind Global Protection Against Limited Strikes (GPALS) was that the Soviet Union would not always be the aggressor and the United States would not always be the target. Instead of a heavy defense aimed at ICBMs, this report suggested realigning GPALS deployment. Against novel threats the Brilliant Pebbles would have limited utility, largely because the missiles fired for only a short period and the warheads did not rise high enough for them to be easily tracked by a satellite above them. GPALS thus added a mobile ground-based missile and more low-orbit satellites known as Brilliant Eyes to feed the Pebbles. GPALS was approved by President George H.W. Bush in 1991. The system would cut the proposed costs of the SDI system from $53 billion to $41 billion over a decade. Instead of attempting to protect against thousands of incoming missiles, GPALS sought to provide protection from up to two hundred nuclear missiles. GPALS was tasked to protect the United States from attacks coming from all different parts of the world. === Ballistic Missile Defense Organization (BMDO) === In 1993, the Clinton administration further shifted the focus to ground-based interceptor missiles and theater-scale systems, renaming the SDIO to the Ballistic Missile Defense Organization (BMDO). In 2002, the George W. Bush administration in turn renamed the BMDO to the Missile Defense Agency (MDA), indicating plans for a layered missile defence system that integrates different types of defences, including sea- and ground-based defences. == Ground-based programs == === Extended Range Interceptor (ERINT) === The Extended Range Interceptor (ERINT) program was part of SDI's Theater Missile Defense Program and was an extension of the Flexible Lightweight Agile Guided Experiment (FLAGE), which included developing hit-to-kill technology and demonstrating the guidance accuracy of a small, agile, radar-homing vehicle. FLAGE scored a direct hit against a MGM-52 Lance missile in flight, at White Sands Missile Range in 1987. ERINT was a prototype missile similar to the FLAGE, but it used a new solid-propellant rocket motor that allowed it to fly faster and higher than FLAGE. ERINT was later chosen as the MIM-104 Patriot (Patriot Advanced Capability-3, PAC-3) missile. === Homing Overlay Experiment (HOE) === Given concerns about previous programs' nuclear-tipped interceptors, in the 1980s the US Army began studies about the feasibility of kinetic hit-to-kill vehicles, i.e. interceptors that would destroy incoming ballistic missiles by colliding with them. The Homing Overlay Experiment (HOE) was the first such system tested by the Army, and the first successful hit-to-kill intercept of a mock ballistic missile warhead outside the Earth's atmosphere. HOE used a kinetic kill vehicle (KKV). The KKV was equipped with an infrared seeker, guidance electronics and a propulsion system. Once in space, the KKV could extend a folded structure similar to an umbrella skeleton of 13 ft (4 m) diameter to enhance its effective cross section. This device was intended to destroy an ICBM reentry vehicle on collision. Four test launches were conducted in 1983 and 1984 at Kwajalein Missile Range in the Marshall Islands using first two stages of Minuteman missile, M55E1 and M56A1. For each test a Minuteman missile was launched from Vandenberg Air Force Base in California carrying a single mock re-entry vehicle targeted for Kwajalein lagoon more than 4,000 miles (6,400 km) away. After test failures with the first three flight tests because of guidance and sensor problems, the DOD reported that the fourth and final test on June 10, 1984, was successful, intercepting the Minuteman RV with a closing speed of about 3.8 mi/s (6.1 km/s) at an altitude of more than 100 mi (160 km). Although the fourth test was described as a success, the New York Times in August 1993 reported that the HOE4 test was rigged to increase the likelihood of success. At the urging of Senator David Pryor, the General Accounting Office investigated the claims and concluded that though steps were taken to make it easier for the interceptor to find its target (including some of those alleged by the New York Times), the available data indicated that the interceptor had been successfully guided by its onboard infrared sensors in the collision, and not by an onboard radar guidance system as alleged. Per the GAO report, the net effect of the DOD enhancements increased the infrared signature of the target vessel by 110% over the realistic missile signature initially proposed for the HOE program, but nonetheless the GAO concluded the enhancements to the target vessel were reasonable given the objectives of the program and the geopolitical consequences of its failure. Further, the report concluded that the DOD's subsequent statements before Congress about the HOE program "fairly characterize[d]" the success of HOE4, but confirmed that the DOD never disclosed to Congress the enhancements made to the target vessel. HOE technology was later expanded into the Exoatmospheric Reentry-vehicle Interception System program. === ERIS and HEDI === Developed by Lockheed as part of the ground-based interceptor portion of SDI, the Exoatmospheric Reentry-vehicle Interceptor Subsystem (ERIS) began in 1985, with at least two tests occurring in the early 1990s. This system was never deployed, but its technology was used in the Terminal High Altitude Area Defense (THAAD) system and the Ground-Based Interceptor currently deployed as part of the Ground-Based Midcourse Defense (GMD) system. == Directed-energy weapon (DEW) programs == === X-ray laser === An early SDI focus was an X-ray laser powered by nuclear explosions. Nuclear explosions give off a burst of X-rays, which the Excalibur concept intended to focus using a lasing medium consisting of metal rods. Many such rods would be placed around a warhead, each aimed at a different ICBM, thus destroying many ICBMs in a single attack. It would cost much less for the US to build another Excalibur than the Soviets would need to build enough new ICBMs to counter it. The idea was first based on satellites, but when it was pointed out that these could be attacked in space, the concept moved to a "pop-up" concept, with the device launched from a submarine off the northern Soviet coast. However, on March 26, 1983, the first test (known as the Cabra event), was performed in an underground shaft and resulted in marginally positive readings possibly caused by a faulty detector. Since a nuclear explosion was used as the power source, the detector was destroyed during the experiment, and the results therefore could not be confirmed. Technical criticism based upon unclassified calculations suggested that the X-ray laser would be of at best marginal use. Critics often cite the X-ray laser system as SDI's primary focus, with its apparent failure warranting opposition to the program. Despite the apparent failure, the legacy of the X-ray laser program is the knowledge gained from the research. A parallel development program advanced laboratory X-ray lasers for biological imaging such as 3D holograms of living organisms. Other spin-offs include research on advanced materials like SEAgel and Aerogel, the Electron-Beam Ion Trap facility for physics research, and techniques for early detection of breast cancer. === Chemical laser === Beginning in 1985, the Air Force tested an SDIO-funded deuterium fluoride laser known as Mid-Infrared Advanced Chemical Laser (MIRACL) at White Sands Missile Range. During a simulation, the laser successfully destroyed a Titan missile booster in 1985. However, the test setup had the booster shell pressurized and under considerable compression loads. These test conditions were used to simulate the loads a booster would be under during launch. The system was later tested for the US Navy on target drones simulating cruise missiles, with some success. After SDIO closed, MIRACL was tested on an old Air Force satellite for potential use as an anti-satellite weapon, with mixed results. The technology was also used to develop the Tactical High Energy Laser (THEL) that was tested against in-flight artillery shells. During the mid-to-late 1980s panel discussions took place at various laser conferences. Proceedings include papers on the status of chemical and other high-power lasers. The Missile Defense Agency's Airborne Laser program used a chemical laser that intercepted a missile taking off, so an offshoot of SDI could be said to have successfully implemented one of the key goals of the program. === Neutral particle beam === In July 1989, the Beam Experiments Aboard a Rocket (BEAR) program launched a sounding rocket containing a neutral particle beam (NPB) accelerator. The experiment successfully demonstrated that a particle beam would operate and propagate as predicted outside the atmosphere and that no unexpected side-effects emerged when firing the beam in space. After the rocket was recovered, the particle beam was still operational. According to BMDO, the research on neutral particle beam accelerators, originally funded by SDIO, could eventually be used to reduce the half-life of nuclear waste products using accelerator-driven transmutation technology. === Laser and mirror experiments === The High Precision Tracking Experiment (HPTE), launched with the Space Shuttle Discovery on STS-51-G, was tested on June 21, 1985, when a Hawaii-based low-power laser successfully tracked the experiment and bounced the laser off of the HPTE mirror. The Relay mirror experiment (RME), launched in February 1990, demonstrated critical technologies for space-based relay mirrors that would be used with an SDI directed-energy weapon system. The experiment validated stabilization, tracking, and pointing concepts and proved that a laser could be relayed from the ground to a 24 in (60 cm) mirror on an orbiting satellite and back to another ground station with a high degree of accuracy and for extended durations. Launched on the same rocket as the RME, the Low-power Atmospheric Compensation Experiment (LACE) satellite was built by the United States Naval Research Laboratory (NRL) to explore atmospheric distortion of lasers and real-time adaptive compensation. The LACE satellite included several other experiments to help develop and improve SDI sensors, including target discrimination using background radiation and tracking ballistic missiles using Ultraviolet Plume Imaging (UVPI). LACE was also used to evaluate ground-based adaptive optics, a technique now used in civilian telescopes to remove atmospheric distortions. === Hypervelocity Railgun (CHECMATE) === Research on hypervelocity railgun technology was conducted to build an information base about railguns. The SDI railgun investigation, called the Compact High Energy Capacitor Module Advanced Technology Experiment, was able to fire two projectiles per day during the initiative. This represented a significant improvement over previous efforts, which were only able to achieve about one shot per month. Hypervelocity railguns are, at least conceptually, an attractive alternative to a space-based defense system because of their envisioned ability to quickly shoot at many targets. Also, since only the projectile leaves the gun, a railgun system can potentially fire many times before needing to be resupplied. A hypervelocity railgun works like a particle accelerator, converting electrical potential energy into kinetic energy for the projectile. A conductive pellet (the projectile) is attracted down the rails by electric current flowing through a rail. Through magnetic forces, a force is exerted on the projectile moving it down the rail. Railguns can generate muzzle-velocities in excess of 1.5 miles per second (2.4 km/s). Railguns face a host of technical challenges to be ready for battlefield deployment. First, the rails guiding the projectile must carry sufficient power. Each firing of the railgun sends tremendous current flow (almost half a million amperes) through the rails, causing rapid erosion of the rail's surfaces (through ohmic heating), and even vaporization of the rail surface. Early prototypes were essentially single-use weapons, requiring complete rail replacement after each firing. Another challenge is projectile survivability. The projectiles experience acceleration force in excess of 100,000 g. To be effective, the fired projectile must first survive the mechanical stress of firing and the thermal effects of a trip through the atmosphere at many times the speed of sound before hitting its target. Any on-board guidance would require the onboard navigation system to be built to the same level of sturdiness as the main mass of the projectile. In addition to destroying ballistic missile threats, railguns were also planned for service in space platform (sensor and battle station) defense. This potential role reflected defense planner expectations that future railguns would be capable of rapid fire and on the order of tens to hundreds of shots. == Space-based programs == === Space-Based Interceptor === The Space-Based Interceptor (SBI) concept involved groups of interceptors housed in orbital modules. Hover testing was completed in 1988 and demonstrated integration of the sensor and propulsion systems. It demonstrated the ability of the seeker to shift its aiming point from a rocket's hot plume to its cool body, a first for infrared ABM seekers. Final hover testing occurred in 1992 using miniaturized components similar to those that would have been used in an operational interceptor. These prototypes eventually evolved into Brilliant Pebbles. === Brilliant Pebbles === Brilliant Pebbles was a non-nuclear system of satellite-based interceptors designed to use high-velocity, watermelon-sized, teardrop-shaped tungsten projectiles as kinetic warheads. It was designed to operate in conjunction with the Brilliant Eyes sensor system. The project was conceived in November 1986 by Lowell Wood at LLNL. Detailed studies were undertaken by several advisory boards, including the Defense Science Board and JASON, in 1989. The Pebbles were designed so that autonomous operation was possible without external guidance from planned SDI sensor systems. This was attractive as a cost saving measure, as it would allow scaling back of those systems, and was estimated to save $7 to $13 billion versus the standard Phase I Architecture. Brilliant Pebbles later became the centerpiece under the Bush Administration. John H. Nuckolls, LLNL director from 1988 to 1994, described the system as "The crowning achievement of the Strategic Defense Initiative". The sensors and cameras developed for Brilliant Pebbles systems became components of the Clementine mission. Though regarded as one of the most capable SDI systems, Brilliant Pebbles was canceled in 1994 by BMDO. == Sensor programs == SDIO sensor research encompassed visible light, ultraviolet, infrared, and radar technologies, and eventually led to the Clementine mission though that mission occurred just after the program transitioned to the BMDO. Like other parts of SDI, the sensor system initially was very large-scale, but after the Soviet threat diminished it was cut back. === Boost Surveillance and Tracking System === Boost Surveillance and Tracking System (BSTS) was part of SDIO in the late 1980s, and was designed to detect missile launches, especially during the boost phase; however, once the SDI program shifted toward theater missile defense in the early 1990s, the system left SDIO control and was transferred to the Air Force. === Space Surveillance and Tracking System === Space Surveillance and Tracking System (SSTS) was a system originally designed for tracking mid-course ballistic missiles. It was designed to work in conjunction with BSTS but was later scaled down in favor of Brilliant Eyes. === Brilliant Eyes === Brilliant Eyes was a simpler derivative of SSTS that focused on theater ballistic missiles rather than ICBMs and was meant to operate in conjunction with Brilliant Pebbles. Brilliant Eyes was renamed Space and Missile Tracking System (SMTS) and scaled back further under BMDO, and in the late 1990s it became the low earth orbit component of the Air Force's Space Based Infrared System (SBIRS). === Other sensor experiments === The Delta 183 program used a satellite known as Delta Star to test sensor-related technologies. Delta Star carried a thermographic camera, a long-wave infrared imager, an ensemble of imagers and photometers covering several visible and ultraviolet bands as well as a laser detector and ranging device. The satellite observed several ballistic missile launches including some releasing liquid propellant as a detection countermeasure. == Countermeasures == In war-fighting, countermeasures encompass multiple meanings: Immediate tactical action to reduce vulnerability, such as chaff, decoys, and maneuvering Counter strategies that exploit a weakness of an opposing system, such as adding more warheads that are less expensive than the interceptors fired against them. Defense suppression - that is, attacking elements of the defensive system. Countermeasures have long been a key part of warfighting strategy; however, with SDI they attained a special prominence due to the system cost, scenario of a massive sophisticated attack, strategic consequences of a less-than-perfect defense, basing many proposed weapons systems in space, and political debate. Whereas the United States national missile defense system targets a relatively limited and unsophisticated attack, SDI planned for a massive attack by a sophisticated opponent. This raised significant issues about economic and technical costs associated with defending against anti-ballistic missile defense countermeasures used by the attacking side. For example, if it had been much cheaper to add attacking warheads than to add defenses, an attacker of similar economic power could have simply outproduced the defender. The "cost effective at the margin" requirement was first formulated by Paul Nitze in November 1985. In addition, SDI envisioned many space-based systems in fixed orbits, ground-based sensors, command, control and communications facilities, etc. In theory, an advanced opponent could have targeted those, in turn requiring self-defense capability or increased numbers to compensate for attrition. A sophisticated attacker having the technology to use decoys, shielding, maneuvering warheads, defense suppression, or other countermeasures would have multiplied the difficulty and cost of intercepting the real warheads. SDI design and operational planning had to factor in these countermeasures and the associated cost. == Response from the Soviet Union == SDI failed to dissuade the USSR from investing in development of ballistic missiles. The Soviet response to SDI from March 1983 through November 1985 provided indications of their view of the program both as a threat and as an opportunity to weaken NATO. SDI was likely seen not only as a threat to the physical security of the Soviet Union, but also as part of a larger effort by the United States to seize the strategic initiative in arms control by neutralizing the military component of Soviet strategy. The Kremlin expressed concerns that space-based missile defenses would make nuclear war inevitable. A major objective of that strategy was the political separation of Western Europe from the United States, which the Soviets sought to facilitate by aggravating allied concern over the SDI's potential implications for European security and economic interests. The Soviet predisposition to see deception behind SDI was reinforced by their assessment of US intentions and capabilities and the utility of military deception in furthering the achievement of political goals. In 1986 Carl Sagan summarized what he heard Soviet commentators saying about SDI. They commonly expressed the notion that SDI was equivalent to starting an economic war through a defensive arms race to further cripple the Soviet economy with extra military spending. Another common Soviet perception suggested that SDI served as a disguise for a US desire to initiate a first strike on the Soviet Union. Though classified at the time, a detailed study on a Soviet space-based LASER system began no later than 1976 as the Skif, a 1 MW carbon dioxide laser along with the anti-satellite Kaskad, an in-orbit missile platform. The devices were reportedly designed to pre-emptively destroy US satellites that might be launched in the future that could otherwise aid US missile defense. Terra-3 was a Soviet laser testing centre, located on the Sary Shagan anti-ballistic missile (ABM) testing range in the Karaganda Region of Kazakhstan. It was originally built to test missile defense concepts. In 1984, officials within the United States Department of Defense (DoD) suggested it was the site of a prototypical anti-satellite weapon system. In 1987 a disguised Mir space station module was lifted on the inaugural flight of the Energia booster as the Polyus. It was later revealed that this craft housed a number of Skif lasers, intended to be clandestinely tested in orbit. However, the spacecraft's attitude control system malfunctioned upon separation from the booster, and it failed to reach orbit. More tentatively, it is also suggested that the Zarya module of the International Space Station, capable of station keeping and providing sizable battery power, was initially developed to power the Skif laser system. The Polyus was a prototype of the Skif orbital weapons platform designed to destroy satellites with a megawatt carbon-dioxide laser. Soviet motivations behind attempting to launch components of the Skif laser in the form of Polyus were, according to interviews conducted years later, more for propaganda purposes in the prevailing climate of focus on US SDI, than as an effective defense technology, as the phrase "Space based laser" has political capital. == Post-Soviet == In 2014, a declassified CIA paper stated that "In response to SDI, Moscow threatened a variety of military countermeasures in lieu of developing a parallel missile defense system". In January 2025 President Donald Trump ordered the building of a national "Iron Dome" missile defense shield. == Controversy and criticism == Jessica Savitch reported on the technology in episode No.111 of Frontline, "Space: The Race for High Ground", on November 4, 1983. The opening sequence shows Jessica Savitch seated next to a laser that she used to destroy a model of a communication satellite. The demonstration was perhaps the first televised use of a weapons-grade laser. No theatrical effects were used. The model was actually destroyed by the heat from the laser. The model and the laser were realized by Marc Palumbo, a High Tech Romantic artist from the Center for Advanced Visual Studies at MIT. Ashton Carter, then a board member at MIT, assessed SDI for Congress in 1984, noting difficulties in creating an adequate missile defense shield, with or without lasers. Carter said X-rays had a limited scope because they become diffused by the atmosphere, much like the beam of a flashlight spreading outward in all directions. This means the X-ray sources needed to be close to the Soviet Union, especially during the boost phase, for the Soviet missiles to be both detectable to radar and targeted by the lasers. Opponents disagreed, saying advances in technology, such as using stronger beams, and by "bleaching" the column of air surrounding the laser beam, could increase the distance that the X-ray could travel to successfully hit its target. Physicists Hans Bethe and Richard Garwin, who worked with Teller on both the atomic bomb and hydrogen bomb at Los Alamos, claimed a laser defense shield was unfeasible. They said that a defensive system was costly and difficult to build yet simple to destroy and claimed that the Soviets could easily use thousands of decoys to overwhelm it during a nuclear attack. They dismissed the idea of a technical solution to the Cold War, saying that a defense shield could be viewed as threatening because it would inhibit Soviet offensive capabilities while leaving America's offense intact. In March 1984, Bethe coauthored a 106-page report for the Union of Concerned Scientists that concluded "the X-ray laser offers no prospect of being a useful component in a system for ballistic missile defense." In response, when Teller testified before Congress he stated that "instead of [Bethe] objecting on scientific and technical grounds, which he thoroughly understands, he now objects on the grounds of politics, on grounds of military feasibility of military deployment, on other grounds of difficult issues which are quite outside the range of his professional cognizance or mine." On June 28, 1985, David Lorge Parnas resigned from SDIO's Panel on Computing in Support of Battle Management, arguing in eight short papers that the SDI software could never be made trustworthy and that such a system would inevitably be unreliable and menace humanity in its own right. Parnas said he joined the panel with the desire to make nuclear weapons "impotent and obsolete" but soon concluded that the concept was "a fraud". === The nickname "Star Wars" === Historians from the Missile Defense Agency attribute the term "Star Wars" to a Washington Post article published March 24, 1983. It quoted a speech delivered by Democratic Senator Ted Kennedy the previous day, describing the proposal as "reckless Star Wars schemes", a reference to the space opera film series Star Wars. Some critics used the term derisively, implying it was an impractical science fiction. In addition, the American media's liberal use of the moniker (despite President Reagan's request) did much to damage the program's credibility. In comments to the media on March 7, 1986, SDIO Acting Deputy Director Dr. Gerold Yonas described "Star Wars" as an important tool for Soviet disinformation and asserted that the nickname gave an entirely wrong impression of SDI. Supporters of the SDI program eventually began to use the nickname as well. George Lucas, the creator of the Star Wars franchise, sued public interest groups High Frontier (a liberal organization that supported the program) and Committee for a Strong, Peaceful America (a conservative organization) in 1985 for trademark infringement. The lawsuit was dismissed by Judge Gerhard Gesell, who ruled that political application of the term was a non-commercial usage outside of the scope of trademark. === Treaty obligations === Another criticism of SDI argued that it would be inconsistent with existing treaties. The Anti-Ballistic Missile Treaty and its subsequent protocol, which limited missile defenses to one location per country at 100 missiles each (which the USSR had and the US did not), would have been violated by SDI ground-based interceptors. The Nuclear Non-Proliferation Treaty requires that "Each of the Parties to the Treaty undertakes to pursue negotiations in good faith on effective measures relating to cessation of the nuclear arms race at an early date and to nuclear disarmament, and on a treaty on general and complete disarmament under strict and effective international control." Many viewed deployment of ABM systems as an escalation, and therefore a violation of this clause, although this view was not universal. The Outer Space Treaty of 1967 required "States Party to the Treaty undertake not to place in orbit around the Earth any objects carrying nuclear weapons or any other kinds of weapons of mass destruction, install such weapons on celestial bodies, or station such weapons in outer space in any other manner." This clause forbade the US from pre-positioning in Earth orbit any devices powered by nuclear weapons and any devices capable of "mass destruction". A space-stationed nuclear-pumped X-ray laser would have violated this treaty, since other SDI systems did not require the pre-positioning of nuclear explosives in space. === Mutual assured destruction === SDI threatened to disrupt the strategic equilibrium ensured by the doctrine of mutual assured destruction (MAD). This doctrine postulated that neither the U.S. nor the USSR could attack the other without considering the strong probability that both sides would be annihilated. A defensive weapon system that could neutralize much of an adversary's nuclear counter-strike force would potentially embolden the possessor to strike first. During the Reykjavík talks with Mikhail Gorbachev in 1986, Reagan addressed Gorbachev's concerns about imbalance by stating that SDI technology could be provided to the entire world – including the Soviet Union – to prevent the imbalance from occurring. Gorbachev answered dismissively. When Reagan proposed technology sharing again, Gorbachev stated "we cannot assume an obligation relative to such a transition", referring to the cost of implementing such a program. === Whistleblower === In 1992, scientist Aldric Saucier was given whistleblower protection after he was fired and complained about "wasteful spending on research and development" at SDI. Saucier lost his security clearance. == Timeline == == See also == == References == === Works cited === == Further reading == Bateman, Aaron (2024). Weapons in Space: Technology, Politics, and the Rise and Fall of the Strategic Defense Initiative. The MIT Press. Broad, William J. (1992). Teller's War: The Top-Secret Story Behind the Star Wars Deception. New York: Simon & Schuster. Guertner, Gary; Snow, Donald (1986). The Last Frontier: An Analysis of the Strategic Defense Initiative. D.C. Heath and Company. ISBN 0-669-12370-6. Linenthal, Edward Tabor (1989). Symbolic Defense: The Cultural Significance of the Strategic Defense Initiative. Urbana, Ill.: University of Illinois Press. Payne, Keith (1986). Strategic Defense: "Star Wars" in Perspective. Hamilton Press. ISBN 0-8191-5109-2. Saltoun-Ebin, Jason. "The Strategic Defense Initiative". The Reagan Files. Archived from the original on January 14, 2024. Retrieved June 5, 2024. Weapons in Space, 2 vols. Daedalus 114, nos. 2 (Spring 1985) & 3 (Summer 1985). == External links == Strategic Defense Initiative – Ronald Reagan Presidential Library	Wikipedia/Strategic_Defense_Initiative
Active thermography is an advanced nondestructive testing procedure, which uses a thermographic measurement of a tested material thermal response after its external excitation. This principle can be used also for non-contact infrared non-destructive testing (IRNDT) of materials. The IRNDT method is based on an excitation of a tested material by an external source, which brings some energy to the material. Halogen lamps, flash-lamps, ultrasonic horn or other sources can be used as the excitation source for the IRNDT. The excitation causes a tested material thermal response, which is measured by an infrared camera. It is possible to obtain information about the tested material surface and sub-surface defects or material inhomogeneities by using a suitable combination of excitation source, excitation procedure, infrared camera and evaluation method. Modern thermographic systems with high-speed and high-sensitivity IR cameras extend the possibilities of the inspection method. Modularity of the systems allows their usage for research and development applications as well as in modern industrial production lines. Thermovision nondestructive testing of components can be carried out on a wide range of various materials. Thermographic inspection of material can be regarded as a method of infrared defectoscopy, that is capable of revealing material imperfections such as cracks, defects, voids, cavities and other inhomogeneities. The thermographic testing can be provided on individual components in a laboratory or directly on technology facilities that are in duty. == Theory == Active thermography uses an external source for measured object excitation, that means introducing an energy into the object. The excitation sources can be classified by the principles: optical radiation or microwaves absorption, electromagnetic induction, elastic waves transformation (e.g. ultrasound), convection (e.g. hot air), plastic deformation transformation (thermoplastic effect during mechanical loading). Various excitation sources can be used for the active thermography and nondestructive testing, for example laser heating, flash lamps, halogen lamps, electrical heating, ultrasonic horn, eddy currents, microwaves, and others. The measured object can be heated by an external source directly, e.g. by halogen lamps or hot air. The material inhomogeneities or defects cause then a distortion of temperature field. This distortion is detected as temperature differences on the material surface. Another possibility is to use thermophysical processes in the material, when mechanical or electrical energy is transformed into thermal energy due to defects and inhomogeneities. It creates local temperature sources, which cause temperature differences detected on the object surface by infrared techniques, such as in the case of ultrasound excitation. == Methods == A lot of methods were developed for active thermography for the nondestructive testing measurement evaluation. The evaluation methods selection depends on application, used excitation source and excitation type (pulse, periodic, continuous). In the simplest case, the response is evident from a thermogram directly. However, it is necessary to use advanced analysis techniques in most cases. The most common methods include Lock-In, Pulse or Transient (Step thermography) evaluation techniques, with continuous excitation used in some cases: Lock-In thermography (periodic excitation method). A modulated periodic source is used for the excitation. The phase and amplitude shift of the measured signal are evaluated and the analysis can be done by various techniques. Halogen lamps, LED lamps, ultrasound, laser or an electric current are suitable excitation sources. It has the advantage that it can be used on large surfaces, and it puts a low thermal energy on the part being inspected. The disadvantage is a longer measurement time and dependence of detection capabilities on a geometrical orientation of defects (except of an indirect excitation such as ultrasound). The Lock-In method is suitable for testing components with a low thermal diffusivity and it has many modifications for various specific applications (such as Lock-In Ref, Lock-In Online, etc.). Pulse thermography (pulse method). A very short pulse – usually in the units of milliseconds – is used to excite the object. The cooling process is then analyzed. A flash lamp is typically used as an excitation source. The advantage of this method is the speed of the analysis and a possibility to estimate the defects depth. The disadvantage is a limited depth of the analysis, a limited area that can be inspected (with regard to a usable power of excitation sources) and a dependence of detection capabilities on geometrical orientation of defects. Transient thermography (step thermography, thermal wave method). In principle, the excitation and evaluation are similar to the pulse thermography, however, the pulse length is much bigger. Less powerful excitation sources are required compared to the pulse thermography. It is therefore possible to analyze larger areas and the measurement time is shorter than in the case of Lock-In thermography. As in the pulse thermography, the sensitivity of the method is limited by the geometrical orientation of defects. Halogen lamps are the suitable excitation source for this type of evaluation. Continual excitation. The simplest method usable only in special applications. A high-speed cooled infrared camera with a high sensitivity is commonly used for IRNDT applications. However, an uncooled bolometric infrared camera can be used for specific applications. It can significantly reduce acquisition costs of the measurement system. The IR nondestructive testing system are usually modular. It means that various excitation sources can be combined with various infrared cameras and various evaluation methods depending on application, tested material, measuring time demands, size of a tested area, etc. The modularity allows universal usage of the system for various industrial, scientific and research applications. == Applications == IRNDT (infra-red nondestructive testing) method is suitable for detection and inspection of cracks, defects, cavities, voids and inhomogeneities in material, it is also possible to use the method for inspection of welded joints of metal and plastic parts, inspection of solar cells and solar panels, determination of internal structure of material etc. The main advantage of IRNDT method is availability for inspection of various materials in wide range of industrial and research applications. IRNDT measurement is fast, nondestructive and noncontact. Restrictive condition for IRNDT method is inspection depth combined with dimension and orientation of defect/crack/inhomogeneity in material. === Inspection of laser welded plastic parts === Laser welding of plastics is a progressive technology of connecting materials with different optical properties. Classical methods for testing of welding performance and weld joints quality – such as the metallographic cut microscopic analysis or X-ray tomography – are not suitable for routine measurements. Pulse IRNDT analysis can be successfully used for weld inspection in many cases. The images show an example of plastic parts inspection with a defective weld and with a correct weld. The gaps in the defective weld and the correct uninterrupted weld line are both well visible in the results of the IRNDT flash-pulse analysis. === Inspection of laser welded joints === Laser beam welding is a modern technology of fusion welding. Currently finds its wide usage not only in the field of scientific research but also establishes itself in a variety of industries. Among the most frequent users belong the automotive industry, which due to its stable continuous innovation enables fast implementation of advanced technologies in their production. It is clear that laser welding significantly enhances engineering designs and thus brings a number of new products which previously could not be made by conventional methods. The laser welding can produce quality welds of different types, both extremely thin and thick blanks. Weldable are common carbon steels, stainless steels, aluminum and its alloys, copper, titanium and last but not least, special materials and its combinations. An integral part of the weldment production is a quality control. Unlike conventional non-destructive test methods, IRNDT is used not only after the laser welding process, but also during it. This makes possible to decide whether or not to the weldment comply with established quality criteria during manufacture process. === Solar cells testing === Active thermography, particularly lock-in thermography, is widely employed for inspecting solar cells. While effective, lock-in thermography often requires physical contact with the solar cell for excitation. However, techniques that involve periodic excitation using light sources allow for non-contact testing of electrode-free cells. Common methods such as Illuminated Lock-In Thermography (ILIT) and Open Circuit Voltage Illuminated Lock-In Thermography (VOC-ILIT) are used to investigate defects or issues like ohmic shunts, cracks, open or short circuits, and degradation in photovoltaic materials. Pulsed thermography, another method under investigation, provides a non-contact alternative with significantly reduced inspection times; however, it usually offers lower detectability than the ILIT method. == References ==	Wikipedia/Infrared_non-destructive_testing_of_materials
Thermographic printing refers to two types of printing, both of which rely on heat to create the letters or images on a sheet of paper. The simplest type of thermography is where the paper has been coated with a material that changes colour on heating. This is called thermal printing and was used in older model fax machines and is used in most shop till receipt printers. This is called direct thermal. More complex is thermal transfer printing that melts print off a ribbon and onto the sheet of paper. == Thermography as raised print process == Thermography is also the name of a post print process that is achieved today using traditional printing methods coupled with thermography machines. Thermography machines consist of three sections with a through conveyor. The first section applies thermographic/embossing powder, made from plastic resins, to the substrate (normally paper). The areas selected for raised printing are printed with slow-drying inks that do not contain dryers or hardeners so that they remain wet during the application of powder. This ink is dried and hardened later during the heating process. The second section of the process is a vacuum system that removes excess powder from areas of the sheet that were not printed. The third section of the process conveys the product through a radiant oven where it is exposed to temperatures of 900 to 1300ºF (500-700ºC). The heating process takes on the order of 2.5 to 3 seconds. The substrate (usually paper) has a peak in IR absorption at the wavelength used. Through conduction from the paper, the powder temperature rapidly increases and starts melting. When the process is correctly adjusted, the center of the largest filmed areas reach sufficient quality level as the product exits the heater. The melted ink then solidifies as the product cools. This process is sometimes produced using manual powdering. The substrate with the wet ink is dipped into the powdered polymer. The sheet is then tilted back and forth, rolling the powder across the image. The excess powder is then removed by raising the substrate to a vertical position and lightly tapping the back side. The powdered sheet is then fed into a radiant heating system (as above) at a speed that achieves a good-quality melted film. In the case of craft applications, the powder is melted using a heatgun that blows hot air. It is commonly used on wedding invitations, letterheads, business cards, greeting cards, gift wrap, packaging, etc. It is sometimes used in diploma printing as a low-cost alternative to engraved embossing. == See also == Dye sublimation List of stationery topics == References == == External links == Simple instructions for using thermographic powders for card making Examples of using raised print or thermography printing on business stationery Video demonstrating thermographic printing Print Invitations	Wikipedia/Thermographic_printing
Fluorescent microthermography (FMT) is a microscopy technique for infrared imaging of temperature distribution in small scale; the achievable spatial resolution is half micrometer and temperature resolution of 0.005 K. Time-dependent measurements are possible, as the fluorescence lifetime is only about 200 microseconds. A thin film of a phosphor, europium thenoyl-trifluoroacetonate, is applied on the surface (e.g. an integrated circuit die) and illuminated by ultraviolet light at 340–380 nm, stimulating fluorescence at mainly 612 nm line. The quantum efficiency of fluorescence decreases exponentially with temperature, differences in emitted light intensity can be therefore used to assess differences on surface temperature, with hot areas showing as darker. == References ==	Wikipedia/Fluorescent_microthermography
Diagnosis (pl.: diagnoses) is the identification of the nature and cause of a certain phenomenon. Diagnosis is used in a lot of different disciplines, with variations in the use of logic, analytics, and experience, to determine "cause and effect". In systems engineering and computer science, it is typically used to determine the causes of symptoms, mitigations, and solutions. == Computer science and networking == Bayesian network Complex event processing Diagnosis (artificial intelligence) Event correlation Fault management Fault tree analysis Grey problem RPR problem diagnosis Remote diagnostics Root cause analysis Troubleshooting Unified Diagnostic Services == Mathematics and logic == Bayesian probability Block Hackam's dictum Occam's razor Regression diagnostics Sutton's law == Medicine == Medical diagnosis Molecular diagnostics === Methods === CDR computerized assessment system Computer-aided diagnosis Differential diagnosis Retrospective diagnosis === Tools === DELTA (taxonomy) DXplain List of diagnostic classification and rating scales used in psychiatry == Organizational development == Organizational diagnostics == Systems engineering == Five whys Eight disciplines problem solving Fault detection and isolation Problem solving == References == == External links == The dictionary definition of diagnosis at Wiktionary	Wikipedia/Fault_diagnosis
Applications of the Stirling engine range from mechanical propulsion to heating and cooling to electrical generation systems. A Stirling engine is a heat engine operating by cyclic compression and expansion of air or other gas, the "working fluid", at different temperature levels such that there is a net conversion of heat to mechanical work. The Stirling cycle heat engine can also be driven in reverse, using a mechanical energy input to drive heat transfer in a reversed direction (i.e. a heat pump, or refrigerator). There are several design configurations for Stirling engines that can be built (many of which require rotary or sliding seals) which can introduce difficult tradeoffs between frictional losses and refrigerant leakage. A free-piston variant of the Stirling engine can be built, which can be completely hermetically sealed, reducing friction losses and completely eliminating refrigerant leakage. For example, a free-piston Stirling cooler (FPSC) can convert an electrical energy input into a practical heat pump effect, used for high-efficiency portable refrigerators and freezers. Conversely, a free-piston electrical generator could be built, converting a heat flow into mechanical energy, and then into electricity. In both cases, energy is usually converted from/to electrical energy using magnetic fields in a way that avoids compromising the hermetic seal. == Mechanical output and propulsion == === Automotive engines === It is often claimed that the Stirling engine has too low a power/weight ratio, too high a cost, and too long a starting time for automotive applications. They also have complex and expensive heat exchangers. A Stirling cooler must reject twice as much heat as an Otto engine or diesel engine radiator. The heater must be made of stainless steel, exotic alloy, or ceramic to support high heating temperatures needed for high power density, and to contain hydrogen gas that is often used in automotive Stirlings to maximize power. The main difficulties involved in using the Stirling engine in an automotive application are startup time, acceleration response, shutdown time, and weight, not all of which have ready-made solutions. However, a modified Stirling engine has been introduced that uses concepts taken from a patented internal-combustion engine with a sidewall combustion chamber (US patent 7,387,093) that promises to overcome the deficient power-density and specific-power problems, as well as the slow acceleration-response problem inherent in all Stirling engines. It could be possible to use these in co-generation systems that use waste heat from a conventional piston or gas turbine engine's exhaust and use this either to power the ancillaries (e.g.: the alternator) or even as a turbo-compound system that adds power and torque to the crankshaft. Automobiles exclusively powered by Stirling engines were developed in test projects by NASA, as well as earlier projects by the Ford Motor Company using engines provided by Philips, and by American Motors Corporation (AMC) with several cars equipped with units from Sweden's United Stirling built under a license from Philips. The NASA vehicle test projects were designed by contractors and designated MOD I and MOD II. NASA's Stirling MOD 1 powered engineering vehicles were built in partnership with the United States Department of Energy (DOE) and NASA, under contract by AMC's AM General to develop and demonstrate practical alternatives for standard engines. The United Stirling AB's P-40 powered AMC Spirit was tested extensively for over 50,000 miles (80,467 km) and achieved average fuel efficiency up to 28.5 mpg‑US (8.3 L/100 km; 34.2 mpg‑imp). A 1980 4-door liftback VAM Lerma was also converted to United Stirling P-40 power to demonstrate the Stirling engine to the public and to promote the U.S. government's alternative engine program. Tests conducted with the 1979 AMC Spirit, as well as a 1977 Opel and a 1980 AMC Concord, revealed the Stirling engines "could be developed into an automotive power train for passenger vehicles and that it could produce favorable results." However, progress was achieved with equal-power spark-ignition engines since 1977, and the Corporate Average Fuel Economy (CAFE) requirements that were to be achieved by automobiles sold in the U.S. were being increased. Moreover, the Stirling engine design continued to exhibit a shortfall in fuel efficiency There were also two major drawbacks for consumers using the Stirling engines: first was the time needed to warm up – because most drivers do not like to wait to start driving; and second was the difficulty in changing the engine's speed – thus limiting driving flexibility on the road and traffic. The process of auto manufacturers converting their existing facilities and tooling for the mass production of a completely new design and type of powerplant was also questioned. The MOD II project in 1980 produced one of the most efficient automotive engines ever made. The engine reached a peak thermal efficiency of 38.5%, compared to a modern spark-ignition (gasoline) engine, which has a peak efficiency of 20–25%. The Mod II project replaced the normal spark-ignition engine in a 1985 4-door Chevrolet Celebrity notchback. In the 1986 MOD II Design Report (Appendix A) the results showed that highway gas mileage was increased from 40 to 58 mpg‑US (5.9 to 4.1 L/100 km; 48 to 70 mpg‑imp) and achieved an urban range of 26 to 33 mpg‑US (9.0–7.1 L/100 km; 31–40 mpg‑imp) with no change in vehicle gross weight. Startup time in the NASA vehicle was a maximum of 30 seconds, while Ford's research vehicle used an internal electric heater to quickly start the engine, giving a start time of only a few seconds. The high torque output of the Stirling engine at low speed eliminated the need for a torque converter in the transmission resulting in decreased weight and transmission drivetrain losses negating somewhat the weight disadvantage of the Stirling in auto use. This resulted in increased efficiencies being mentioned in the test results. The experiments indicated that the Stirling engine could improve vehicle operational efficiency by ideally detaching the Stirling from direct power demands, eliminating a direct mechanical linkage as used in most current vehicles. Its prime function used in an extended-range series electric hybrid vehicle would be as a generator providing electricity to drive the electric vehicle traction motors and charging a buffer battery set. In a petro-hydraulic hybrid the Stirling would perform a similar function as in a petro-electric series-hybrid turning a pump charging a hydraulic buffer tank. Although successful in the MOD 1 and MOD 2 phases of the experiments, cutbacks in funding further research and lack of interest by automakers ended possible commercialization of the Automotive Stirling Engine Program. === Electric vehicles === Stirling engines as part of a hybrid electric drive system may be able to bypass the design challenges or disadvantages of a non-hybrid Stirling automobile. In November 2007, a prototype hybrid car using solid biofuel and a Stirling engine was announced by the Precer project in Sweden. The New Hampshire Union Leader reported that Dean Kamen developed a series plug-in hybrid car using a Ford Think. Called the DEKA Revolt, the car can reach approximately 60 miles (97 km) on a single charge of its lithium battery. === Aircraft engines === Robert McConaghy created the first flying Stirling engine-powered aircraft in August 1986. The Beta type engine weighed 360 grams, and produced only 20 watts of power. The engine was attached to the front of a modified Super Malibu radio control glider with a gross takeoff weight of 1 kg. The best-published test flight lasted 6 minutes and exhibited "barely enough power to make the occasional gentle turn and maintain altitude". === Marine engines === The Stirling engine could be well suited for underwater power systems where electrical work or mechanical power is required on an intermittent or continuous level. General Motors has undertaken work on advanced Stirling cycle engines which include thermal storage for underwater applications. United Stirling, in Malmö, Sweden, are developing an experimental four–cylinder engine using hydrogen peroxide as an oxidant in underwater power systems. The SAGA (Submarine Assistance Great Autonomy) submarine became operational in the 1990s and is driven by two Stirling engines supplied with diesel fuel and liquid oxygen. This system also has potential for surface-ship propulsion, as the engine's size is less of a concern, and placing the radiator section in seawater rather than open air (as a land-based engine would be) allows for it to be smaller. Swedish shipbuilder Kockums has built eight successful Stirling-powered submarines since the late 1980s. They carry compressed oxygen to allow fuel combustion submerged, providing heat for the Stirling engine. They are currently used on submarines of the Gotland and Södermanland classes. They are the first submarines in the world to feature Stirling air-independent propulsion (AIP), which extends their underwater endurance from a few days to several weeks. The Kockums engine also powers the Japanese Sōryū-class submarine. This capability has previously only been available with nuclear-powered submarines. === Pump engines === Stirling engines can power pumps to move fluids like water, air and gasses. For instance the ST-5 from Stirling Technology Inc. power output of 5 horsepower (3.7 kW) that can run a 3 kW generator or a centrifugal water pump. == Electrical power generation == === Combined heat and power === In a combined heat and power (CHP) system, mechanical or electrical power is generated in the usual way, however, the waste heat given off by the engine is used to supply a secondary heating application. This can be virtually anything that uses low-temperature heat. It is often a pre-existing energy use, such as commercial space heating, residential water heating, or an industrial process. Thermal power stations on the electric grid use fuel to produce electricity. However, there are large quantities of waste heat produced which often go unused. In other situations, high-grade fuel is burned at high temperatures for a low-temperature application. According to the second law of thermodynamics, a heat engine can generate power from this temperature difference. In a CHP system, the high-temperature primary heat enters the Stirling engine heater, then some of the energy is converted to mechanical power in the engine, and the rest passes through to the cooler, where it exits at a low temperature. The "waste" heat actually comes from the engine's main cooler, and possibly from other sources such as the exhaust of the burner, if there is one. The power produced by the engine can be used to run an industrial or agricultural process, which in turn creates biomass waste refuse that can be used as free fuel for the engine, thus reducing waste removal costs. The overall process can be efficient and cost-effective. Inspirit Energy, a UK-based company have a gas fired CHP unit called the Inspirit Charger which is on sale in 2016. The floor standing unit generates 3 kW of electrical and 15 kW of thermal energy. WhisperGen, a New Zealand firm with offices in Christchurch, has developed an "AC Micro Combined Heat and Power" Stirling cycle engine. These microCHP units are gas-fired central heating boilers that sell unused power back into the electricity grid. WhisperGen announced in 2004 that they were producing 80,000 units for the residential market in the United Kingdom. A 20 unit trial in Germany was conducted in 2006. === Solar power generation === Placed at the focus of a parabolic mirror, a Stirling engine can convert solar energy to electricity with an efficiency better than non-concentrated photovoltaic cells, and comparable to concentrated photovoltaics. On August 11, 2005, Southern California Edison announced an agreement with Stirling Energy Systems (SES) to purchase electricity created using over 30,000 Solar Powered Stirling Engines over a twenty-year period sufficient to generate 850 MW of electricity. These systems, on an 8,000 acre (19 km2) solar farm will use mirrors to direct and concentrate sunlight onto the engines which will in turn drive generators. "In January, 2010, four months after breaking ground, Stirling Energy partner company Tessara Solar completed the 1.5 MW Maricopa Solar power plant in Peoria, Arizona, just outside Phoenix. The power plant is composed of 60 SES SunCatchers." The SunCatcher is described as "a large, tracking, concentrating solar power (CSP) dish collector that generates 25 kilowatts (kW) of electricity in full sun. Each of the 38-foot-diameter collectors contains over 300 curved mirrors (heliostats) that focus sunlight onto a power conversion unit, which contains the Stirling engine. The dish uses dual-axis tracking to follow the sun precisely as it moves across the sky." There have been disputes over the project due to concerns of environmental impact on animals living on the site. The Maricopa Solar Plant has been closed. === Nuclear power === There is a potential for nuclear-powered Stirling engines in electric power generation plants. Replacing the steam turbines of nuclear power plants with Stirling engines might simplify the plant, yield greater efficiency, and reduce the radioactive byproducts. A number of breeder reactor designs use liquid sodium as a coolant. If the heat is to be employed in a steam plant, a water/sodium heat exchanger is required, which raises some concern if a leak were to occur, as sodium reacts violently with water. A Stirling engine eliminates the need for water anywhere in the cycle. This would have advantages for nuclear installations in dry regions. United States government labs have developed a modern Stirling engine design known as the Stirling radioisotope generator for use in space exploration. It is designed to generate electricity for deep space probes on missions lasting decades. The engine uses a single displacer to reduce moving parts and uses high energy acoustics to transfer energy. The heat source is a dry solid nuclear fuel slug, and the heat sink is radiation into free space itself. == Heating and cooling == If supplied with mechanical power, a Stirling engine can function in reverse as a heat pump for heating or cooling. In the late 1930s, the Philips Corporation of the Netherlands successfully utilized the Stirling cycle in cryogenic applications. During the Space Shuttle program, NASA successfully lofted a Stirling cycle cooler in a form "similar in size and shape to the small domestic units often used in college dormitories" for use in the Life Science Laboratory. Further research on this unit for domestic use led to a Carnot coefficient-of-performance gain by a factor of three and a weight reduction of 1kg for the unit. Experiments have been performed using wind power driving a Stirling cycle heat pump for domestic heating and air conditioning. === Stirling cryocoolers === Any Stirling engine will also work in reverse as a heat pump: when mechanical energy is applied to the shaft, a temperature difference appears between the reservoirs. The essential mechanical components of a Stirling cryocooler are identical to a Stirling engine. In both the engine and the heat pump, heat flows from the expansion space to the compression space; however, input work is required in order for heat to flow "uphill" against a thermal gradient, specifically when the compression space is hotter than the expansion space. The external side of the expansion-space heat exchanger may be placed inside a thermally insulated compartment such as a vacuum flask. Heat is in effect pumped out of this compartment, through the working gas of the cryocooler and into the compression space. The compression space will be above ambient temperature, and so heat will flow out into the environment. One of their modern uses is in cryogenics and, to a lesser extent, refrigeration. At typical refrigeration temperatures, Stirling coolers are generally not economically competitive with the less expensive mainstream Rankine cooling systems, because they are less energy-efficient. However, below about −40...−30 °C, Rankine cooling is not effective because there are no suitable refrigerants with boiling points this low. Stirling cryocoolers are able to "lift" heat down to −200 °C (73 K), which is sufficient to liquefy air (specifically the primary constituent gases oxygen, nitrogen and argon). They can go as low as 40–60 K for single-stage machines, depending on the particular design. Two-stage Stirling cryocoolers can reach temperatures of 20 K, sufficient to liquify hydrogen and neon. Cryocoolers for this purpose are more or less competitive with other cryocooler technologies. The coefficient of performance at cryogenic temperatures is typically 0.04–0.05 (corresponding to a 4–5% efficiency). Empirically, the devices show a linear trend, typically with the COP = 0.0015 Tc − 0.065, where Tc is the cryogenic temperature. At these temperatures, solid materials have lower specific heat values, so the regenerator must be made from unexpected materials, such as cotton. The first Stirling-cycle cryocooler was developed at Philips in the 1950s and commercialized in such places as liquid air production plants. The Philips Cryogenics business evolved until it was split off in 1990 to form the Stirling Cryogenics BV, The Netherlands. This company is still active in the development and manufacturing of Stirling cryocoolers and cryogenic cooling systems. A wide variety of smaller Stirling cryocoolers are commercially available for tasks such as the cooling of electronic sensors and sometimes microprocessors. For this application, Stirling cryocoolers are the highest-performance technology available, due to their ability to lift heat efficiently at very low temperatures. They are silent, vibration-free, can be scaled down to small sizes, and have very high reliability and low maintenance. As of 2009, cryocoolers were considered to be the only widely deployed commercially successful Stirling devices. === Heat pumps === A Stirling heat pump is very similar to a Stirling cryocooler, the main difference being that it usually operates at room temperature. At present, its principal application is to pump heat from the outside of a building to the inside, thus heating it at lowered energy costs. As with any other Stirling device, heat flow is from the expansion space to the compression space. However, in contrast to the Stirling engine, the expansion space is at a lower temperature than the compression space, so instead of producing work, an input of mechanical work is required by the system (in order to satisfy the second law of thermodynamics). The mechanical energy input can be supplied by an electrical motor, or an internal combustion engine, for example. When the mechanical work for the heat pump is provided by a second Stirling engine, then the overall system is called a "heat-driven heatpump". The expansion side of the heat pump is thermally coupled to the heat source, which is often the external environment. The compression side of the Stirling device is placed in the environment to be heated, for example, a building, and heat is "pumped" into it. Typically there will be thermal insulation between the two sides so there will be a temperature rise inside the insulated space. Heat pumps are by far the most energy-efficient types of heating systems, since they "harvest" heat from the environment, rather than only turning their input energy into heat. In accordance with the second law of thermodynamics, heat pumps always require the additional input of some external energy to "pump" the collected heat "uphill" against a temperature differential. Compared to conventional heat pumps, Stirling heat pumps often have a higher coefficient of performance. Stirling systems have seen limited commercial use; however, use is expected to increase along with market demand for energy conservation, and adoption will likely be accelerated by technological refinements. === Portable refrigeration === The free-piston Stirling cooler (FPSC) is a completely sealed heat transfer system that has only two moving parts (a piston and a displacer), and which can use helium as the working fluid. The piston is typically driven by an oscillating magnetic field that is the source of the power needed to drive the refrigeration cycle. The magnetic drive allows the piston to be driven without requiring any seals, gaskets, O-rings, or other compromises to the hermetically sealed system. Claimed advantages for the system include improved efficiency and cooling capacity, lighter weight, smaller size and better controllability. The FPSC was invented in 1964 by William Beale (1928–2016), a professor of mechanical engineering at Ohio University in Athens, Ohio. He founded Sunpower Inc., which researches and develops FPSC systems for military, aerospace, industrial, and commercial applications. A FPSC cooler made by Sunpower was used by NASA to cool instrumentation in satellites. The firm was sold by the Beale family in 2015 to become a unit of Ametek. Other suppliers of FPSC technology include the Twinbird Corporation of Japan and Global Cooling of the Netherlands, which (like Sunpower) has a research center in Athens, Ohio. For several years starting around 2004, the Coleman Company sold a version of the Twinbird "SC-C925 Portable Freezer Cooler 25L" under its own brand name, but it has since discontinued offering the product. The portable cooler can be operated more than a day, maintaining sub-freezing temperatures while powered by an automotive battery. This cooler is still being manufactured, with Global Cooling now coordinating distribution to North America and Europe. Other variants offered by Twinbird include a portable deep freezer (to −80 °C), collapsible coolers, and a model for transporting blood and vaccine. == Low temperature difference engines == A low temperature difference (LTD, or Low Delta T (LDT)) Stirling engine will run on any low-temperature differential, for example, the difference between the palm of a hand and room temperature, or room temperature and an ice cube. A record of only 0.5 °C temperature differential was achieved in 1990. Usually they are designed in a gamma configuration for simplicity, and without a regenerator, although some have slits in the displacer typically made of foam for partial regeneration. They are typically unpressurized, running at pressure close to 1 atmosphere. The power produced is less than 1 W, and they are intended for demonstration purposes only. They are sold as toys and educational models. However, larger (typically 1 m square) low temperature engines have been built for pumping water using direct sunlight with minimal or no magnification. == Other applications == === Acoustic Stirling Heat Engine === Los Alamos National Laboratory has developed an "Acoustic Stirling Heat Engine" with no moving parts. It converts heat into intense acoustic power which (quoted from given source) "can be used directly in acoustic refrigerators or pulse-tube refrigerators to provide heat-driven refrigeration with no moving parts, or ... to generate electricity via a linear alternator or other electro-acoustic power transducer". === MicroCHP === WhisperGen, (bankruptcy 2012) a New Zealand-based company has developed Stirling engines that can be powered by natural gas or diesel. An agreement has been signed with Mondragon Corporación Cooperativa, a Spanish firm, to produce WhisperGen's microCHP (Combined Heat and Power) and make them available for the domestic market in Europe. Some time ago E.ON UK announced a similar initiative for the UK. Domestic Stirling engines would supply the client with hot water, space heating, and a surplus electric power that could be fed back into the electric grid. Based on the companies' published performance specifications, the off-grid diesel-fueled unit produces combined heat (5.5 kW heat) and electric (800W electric) output, from a unit being fed 0.75 liters of automotive-grade diesel fuel per hour. Whispergen units are claimed to operate as a combined co-generation unit reaching as high as ~80% operating efficiency. However the preliminary results of an Energy Saving Trust review of the performance of the WhisperGen microCHP units suggested that their advantages were marginal at best in most homes. However another author shows that Stirling engine microgeneration is the most cost effective of various microgeneration technologies in terms of reducing CO2. === Chip cooling === MSI (Taiwan) developed a miniature Stirling engine cooling system for personal computer chips that uses the waste heat from the chip to drive a fan. === Desalination === In all thermal power plants there has to be an exhaust of waste heat. However, there's no reason that the waste heat cannot be diverted to run Stirling engines to pump seawater through reverse osmosis assemblies except that any additional use of the heat raises the effective heat sink temperature for the thermal power plant resulting in some loss of energy conversion efficiency. In a typical nuclear power plant, two-thirds of the thermal energy produced by the reactor is waste heat. In a Stirling assembly the waste heat has the potential to be used as an additional source of electricity. == References ==	Wikipedia/Applications_of_the_Stirling_engine
The science of epidemiology has matured significantly from the times of Hippocrates, Semmelweis and John Snow. The techniques for gathering and analyzing epidemiological data vary depending on the type of disease being monitored but each study will have overarching similarities. == Outline of the process of an epidemiological study == Establish that a problem exists Full epidemiological studies are expensive and laborious undertakings. Before any study is started, a case must be made for the importance of the research. Confirm the homogeneity of the events Any conclusions drawn from inhomogeneous cases will be suspicious. All events or occurrences of the disease must be true cases of the disease. Collect all the events It is important to collect as much information as possible about each event in order to inspect a large number of possible risk factors. The events may be collected from varied methods of epidemiological study or from censuses or hospital records. The events can be characterized by Incidence rates and prevalence rates. Often, occurrence of a single disease entity is set as an event. Given inherent heterogeneous nature of any given disease (i.e., the unique disease principle), a single disease entity may be treated as disease subtypes. This framework is well conceptualized in the interdisciplinary field of molecular pathological epidemiology (MPE). Characterize the events as to epidemiological factors Predisposing factors Non-environmental factors that increase the likelihood of getting a disease. Genetic history, age, and gender are examples. Enabling/disabling factors Factors relating to the environment that either increase or decrease the likelihood of disease. Exercise and good diet are examples of disabling factors. A weakened immune system and poor nutrition are examples of enabling factors. Precipitation factors This factor is the most important in that it identifies the source of exposure. It may be a germ, toxin or gene. Reinforcing factors These are factors that compound the likelihood of getting a disease. They may include repeated exposure or excessive environmental stresses. Look for patterns and trends Here one looks for similarities in the cases which may identify major risk factors for contracting the disease. Epidemic curves may be used to identify such risk factors. Formulate a hypothesis If a trend has been observed in the cases, the researcher may postulate as to the nature of the relationship between the potential disease-causing agent and the disease. Test the hypothesis Because epidemiological studies can rarely be conducted in a laboratory the results are often polluted by uncontrollable variations in the cases. This often makes the results difficult to interpret. Two methods have evolved to assess the strength of the relationship between the disease causing agent and the disease. Koch's postulates were the first criteria developed for epidemiological relationships. Because they only work well for highly contagious bacteria and toxins, this method is largely out of favor. Bradford-Hill Criteria are the current standards for epidemiological relationships. A relationship may fill all, some, or none of the criteria and still be true. Publish the results. == Measures == Epidemiologists are famous for their use of rates. Each measure serves to characterize the disease giving valuable information about contagiousness, incubation period, duration, and mortality of the disease. === Measures of occurrence === Incidence measures Incidence rate, where cases included are defined using a case definition Hazard rate Cumulative incidence Prevalence measures Point prevalence Period prevalence === Measures of association === Relative measures Risk ratio Rate ratio Odds ratio Hazard ratio Absolute measures Absolute risk reduction Attributable risk Attributable risk in exposed Percent attributable risk Levin's attributable risk === Other measures === Virulence and Infectivity Mortality rate and Morbidity rate Case fatality Sensitivity (tests) and Specificity (tests) == Limitations == Epidemiological (and other observational) studies typically highlight associations between exposures and outcomes, rather than causation. While some consider this a limitation of observational research, epidemiological models of causation (e.g. Bradford Hill criteria) contend that an entire body of evidence is needed before determining if an association is truly causal. Moreover, many research questions are impossible to study in experimental settings, due to concerns around ethics and study validity. For example, the link between cigarette smoke and lung cancer was uncovered largely through observational research; however research ethics would certainly prohibit conducting a randomized trial of cigarette smoking once it had already been identified as a potential health threat. == See also == Clinical study design – Plan for research in clinical medicine Epi Info – Statistical software from the CDC Epidemiology – Study of health and disease within a population Molecular pathological epidemiology – Discipline combining epidemiology and pathology OpenEpi – SoftwarePages displaying wikidata descriptions as a fallbackPages displaying short descriptions with no spaces Sanitary epidemiological reconnaissance == References == == External links == Epidemiologic.org Epidemiologic Inquiry online weblog for epidemiology researchers Epidemiology Forum A discussion and forum community for epi analysis support and fostering questions, debates, and collaborations in epidemiology The Centre for Evidence Based Medicine at Oxford maintains an on-line "Toolbox" of evidence-based medicine methods. Epimonitor has a comprehensive list of links to associations, agencies, bulletins, etc. Epidemiology for the Uninitiated On line text, with easy explanations. North Carolina Center for Public Health Preparedness Training On line training classes for epidemiology and related topics. People's Epidemiology Library	Wikipedia/Epidemiological_method
In the field of epidemiology, the causal pie model can be used to explain the causal mechanisms responsible for diseases. It was introduced as a conceptual model by Ken Rothman to communicate how constellations of component causes can lead to a sufficient cause to lead to a condition of interest and that reflection on these sets could improve epidemiological study design. A set of proposed causal mechanisms are represented as pie charts where each pie in the diagram represent a theoretical causal mechanism for a given disease, which is also called a sufficient cause. Each pie is made up of many component factors, otherwise known as component causes represented by sectors in the diagram. In this framework, each component cause represents an event or condition required for a given disease or outcome. A component cause that appears in every pie is called a necessary cause as the outcome cannot occur without it. == References ==	Wikipedia/Causal_pie_model
Transfer entropy is a non-parametric statistic measuring the amount of directed (time-asymmetric) transfer of information between two random processes. Transfer entropy from a process X to another process Y is the amount of uncertainty reduced in future values of Y by knowing the past values of X given past values of Y. More specifically, if X t {\displaystyle X_{t}} and Y t {\displaystyle Y_{t}} for t ∈ N {\displaystyle t\in \mathbb {N} } denote two random processes and the amount of information is measured using Shannon's entropy, the transfer entropy can be written as: T X → Y = H ( Y t ∣ Y t − 1 : t − L ) − H ( Y t ∣ Y t − 1 : t − L , X t − 1 : t − L ) , {\displaystyle T_{X\rightarrow Y}=H\left(Y_{t}\mid Y_{t-1:t-L}\right)-H\left(Y_{t}\mid Y_{t-1:t-L},X_{t-1:t-L}\right),} where H(X) is Shannon's entropy of X. The above definition of transfer entropy has been extended by other types of entropy measures such as Rényi entropy. Transfer entropy is conditional mutual information, with the history of the influenced variable Y t − 1 : t − L {\displaystyle Y_{t-1:t-L}} in the condition: T X → Y = I ( Y t ; X t − 1 : t − L ∣ Y t − 1 : t − L ) . {\displaystyle T_{X\rightarrow Y}=I(Y_{t};X_{t-1:t-L}\mid Y_{t-1:t-L}).} Transfer entropy reduces to Granger causality for vector auto-regressive processes. Hence, it is advantageous when the model assumption of Granger causality doesn't hold, for example, analysis of non-linear signals. However, it usually requires more samples for accurate estimation. The probabilities in the entropy formula can be estimated using different approaches (binning, nearest neighbors) or, in order to reduce complexity, using a non-uniform embedding. While it was originally defined for bivariate analysis, transfer entropy has been extended to multivariate forms, either conditioning on other potential source variables or considering transfer from a collection of sources, although these forms require more samples again. Transfer entropy has been used for estimation of functional connectivity of neurons, social influence in social networks and statistical causality between armed conflict events. Transfer entropy is a finite version of the directed information which was defined in 1990 by James Massey as I ( X n → Y n ) = ∑ i = 1 n I ( X i ; Y i \| Y i − 1 ) {\displaystyle I(X^{n}\to Y^{n})=\sum _{i=1}^{n}I(X^{i};Y_{i}\|Y^{i-1})} , where X n {\displaystyle X^{n}} denotes the vector X 1 , X 2 , . . . , X n {\displaystyle X_{1},X_{2},...,X_{n}} and Y n {\displaystyle Y^{n}} denotes Y 1 , Y 2 , . . . , Y n {\displaystyle Y_{1},Y_{2},...,Y_{n}} . The directed information places an important role in characterizing the fundamental limits (channel capacity) of communication channels with or without feedback and gambling with causal side information. == See also == Directed information Mutual information Conditional mutual information Causality Causality (physics) Structural equation modeling Rubin causal model == References == == External links == "Transfer Entropy Toolbox". Google Code., a toolbox, developed in C++ and MATLAB, for computation of transfer entropy between spike trains. "Java Information Dynamics Toolkit (JIDT)". GitHub. 2019-01-16., a toolbox, developed in Java and usable in MATLAB, GNU Octave and Python, for computation of transfer entropy and related information-theoretic measures in both discrete and continuous-valued data. "Multivariate Transfer Entropy (MuTE) toolbox". GitHub. 2019-01-09., a toolbox, developed in MATLAB, for computation of transfer entropy with different estimators.	Wikipedia/Transfer_entropy
In chemistry, the term substrate is highly context-dependent. Broadly speaking, it can refer either to a chemical species being observed in a chemical reaction, or to a surface on which other chemical reactions or microscopy are performed. In the former sense, a reagent is added to the substrate to generate a product through a chemical reaction. The term is used in a similar sense in synthetic and organic chemistry, where the substrate is the chemical of interest that is being modified. In biochemistry, an enzyme substrate is the material upon which an enzyme acts. When referring to Le Chatelier's principle, the substrate is the reagent whose concentration is changed. In the latter sense, it may refer to a surface on which other chemical reactions are performed or play a supporting role in a variety of spectroscopic and microscopic techniques, as discussed in the first few subsections below. == Microscopy == In three of the most common nano-scale microscopy techniques, atomic force microscopy (AFM), scanning tunneling microscopy (STM), and transmission electron microscopy (TEM), a substrate is required for sample mounting. Substrates are often thin and relatively free of chemical features or defects. Typically silver, gold, or silicon wafers are used due to their ease of manufacturing and lack of interference in the microscopy data. Samples are deposited onto the substrate in fine layers where it can act as a solid support of reliable thickness and malleability. Smoothness of the substrate is especially important for these types of microscopy because they are sensitive to very small changes in sample height. Various other substrates are used in specific cases to accommodate a wide variety of samples. Thermally-insulating substrates are required for AFM of graphite flakes for instance, and conductive substrates are required for TEM. In some contexts, the word substrate can be used to refer to the sample itself, rather than the solid support on which it is placed. == Spectroscopy == Various spectroscopic techniques also require samples to be mounted on substrates, such as powder diffraction. This type of diffraction, which involves directing high-powered X-rays at powder samples to deduce crystal structures, is often performed with an amorphous substrate such that it does not interfere with the resulting data collection. Silicon substrates are also commonly used because of their cost-effective nature and relatively little data interference in X-ray collection. Single-crystal substrates are useful in powder diffraction because they are distinguishable from the sample of interest in diffraction patterns by differentiating by phase. == Atomic layer deposition == In atomic layer deposition, the substrate acts as an initial surface on which reagents can combine to precisely build up chemical structures. A wide variety of substrates are used depending on the reaction of interest, but they frequently bind the reagents with some affinity to allow sticking to the substrate. The substrate is exposed to different reagents sequentially and washed in between to remove excess. A substrate is critical in this technique because the first layer needs a place to bind to such that it is not lost when exposed to the second or third set of reagents. == Biochemistry == In biochemistry, the substrate is a molecule upon which an enzyme acts. Enzymes catalyze chemical reactions involving the substrate(s). In the case of a single substrate, the substrate bonds with the enzyme active site, and an enzyme-substrate complex is formed. The substrate is transformed into one or more products, which are then released from the active site. The active site is then free to accept another substrate molecule. In the case of more than one substrate, these may bind in a particular order to the active site, before reacting together to produce products. A substrate is called 'chromogenic' if it gives rise to a coloured product when acted on by an enzyme. In histological enzyme localization studies, the colored product of enzyme action can be viewed under a microscope, in thin sections of biological tissues. Similarly, a substrate is called 'fluorogenic' if it gives rise to a fluorescent product when acted on by an enzyme. For example, curd formation (rennet coagulation) is a reaction that occurs upon adding the enzyme rennin to milk. In this reaction, the substrate is a milk protein (e.g., casein) and the enzyme is rennin. The products are two polypeptides that have been formed by the cleavage of the larger peptide substrate. Another example is the chemical decomposition of hydrogen peroxide carried out by the enzyme catalase. As enzymes are catalysts, they are not changed by the reactions they carry out. The substrate(s), however, is/are converted to product(s). Here, hydrogen peroxide is converted to water and oxygen gas. E + S ⇌ ES → EP ⇌ E + P Where E is enzyme, S is substrate, and P is product While the first (binding) and third (unbinding) steps are, in general, reversible, the middle step may be irreversible (as in the rennin and catalase reactions just mentioned) or reversible (e.g. many reactions in the glycolysis metabolic pathway). By increasing the substrate concentration, the rate of reaction will increase due to the likelihood that the number of enzyme-substrate complexes will increase; this occurs until the enzyme concentration becomes the limiting factor. === Substrate promiscuity === Although enzymes are typically highly specific, some are able to perform catalysis on more than one substrate, a property termed enzyme promiscuity. An enzyme may have many native substrates and broad specificity (e.g. oxidation by cytochrome p450s) or it may have a single native substrate with a set of similar non-native substrates that it can catalyse at some lower rate. The substrates that a given enzyme may react with in vitro, in a laboratory setting, may not necessarily reflect the physiological, endogenous substrates of the enzyme's reactions in vivo. That is to say that enzymes do not necessarily perform all the reactions in the body that may be possible in the laboratory. For example, while fatty acid amide hydrolase (FAAH) can hydrolyze the endocannabinoids 2-arachidonoylglycerol (2-AG) and anandamide at comparable rates in vitro, genetic or pharmacological disruption of FAAH elevates anandamide but not 2-AG, suggesting that 2-AG is not an endogenous, in vivo substrate for FAAH. In another example, the N-acyl taurines (NATs) are observed to increase dramatically in FAAH-disrupted animals, but are actually poor in vitro FAAH substrates. === Sensitivity === Sensitive substrates, also known as sensitive index substrates, are drugs that demonstrate an increase in AUC of ≥5-fold with strong index inhibitors of a given metabolic pathway in clinical drug-drug interaction (DDI) studies. Moderate sensitive substrates are drugs that demonstrate an increase in AUC of ≥2 to <5-fold with strong index inhibitors of a given metabolic pathway in clinical DDI studies. ==== Interaction between substrates ==== Metabolism by the same cytochrome P450 isozyme can result in several clinically significant drug-drug interactions. == See also == Limiting reagent Reaction progress kinetic analysis Solvent == References ==	Wikipedia/Enzyme_substrate
Cardiovascular disease (CVD) is any disease involving the heart or blood vessels. CVDs constitute a class of diseases that includes: coronary artery diseases (e.g. angina, heart attack), heart failure, hypertensive heart disease, rheumatic heart disease, cardiomyopathy, arrhythmia, congenital heart disease, valvular heart disease, carditis, aortic aneurysms, peripheral artery disease, thromboembolic disease, and venous thrombosis. The underlying mechanisms vary depending on the disease. It is estimated that dietary risk factors are associated with 53% of CVD deaths. Coronary artery disease, stroke, and peripheral artery disease involve atherosclerosis. This may be caused by high blood pressure, smoking, diabetes mellitus, lack of exercise, obesity, high blood cholesterol, poor diet, excessive alcohol consumption, and poor sleep, among other things. High blood pressure is estimated to account for approximately 13% of CVD deaths, while tobacco accounts for 9%, diabetes 6%, lack of exercise 6%, and obesity 5%. Rheumatic heart disease may follow untreated strep throat. It is estimated that up to 90% of CVD may be preventable. Prevention of CVD involves improving risk factors through: healthy eating, exercise, avoidance of tobacco smoke and limiting alcohol intake. Treating risk factors, such as high blood pressure, blood lipids and diabetes is also beneficial. Treating people who have strep throat with antibiotics can decrease the risk of rheumatic heart disease. The use of aspirin in people who are otherwise healthy is of unclear benefit. Cardiovascular diseases are the leading cause of death worldwide except Africa. Together CVD resulted in 17.9 million deaths (32.1%) in 2015, up from 12.3 million (25.8%) in 1990. Deaths, at a given age, from CVD are more common and have been increasing in much of the developing world, while rates have declined in most of the developed world since the 1970s. Coronary artery disease and stroke account for 80% of CVD deaths in males and 75% of CVD deaths in females. Most cardiovascular disease affects older adults. In the United States 11% of people between 20 and 40 have CVD, while 37% between 40 and 60, 71% of people between 60 and 80, and 85% of people over 80 have CVD. The average age of death from coronary artery disease in the developed world is around 80, while it is around 68 in the developing world. CVD is typically diagnosed seven to ten years earlier in men than in women.: 48 == Types == There are many cardiovascular diseases involving the blood vessels. They are known as vascular diseases. Coronary artery disease (coronary heart disease or ischemic heart disease) Peripheral arterial disease – a disease of blood vessels that supply blood to the arms and legs Cerebrovascular disease – a disease of blood vessels that supply blood to the brain (includes stroke) Renal artery stenosis Aortic aneurysm There are also many cardiovascular diseases that involve the heart. Cardiomyopathy – diseases of cardiac muscle Hypertensive heart disease – diseases of the heart secondary to high blood pressure or hypertension Heart failure – a clinical syndrome caused by the inability of the heart to supply sufficient blood to the tissues to meet their metabolic requirements Pulmonary heart disease – a failure at the right side of the heart with respiratory system involvement Cardiac dysrhythmias – abnormalities of heart rhythm Inflammatory heart diseases Endocarditis – inflammation of the inner layer of the heart, the endocardium. The structures most commonly involved are the heart valves. Inflammatory cardiomegaly Myocarditis – inflammation of the myocardium, the muscular part of the heart, caused most often by viral infection and less often by bacterial infections, certain medications, toxins, and autoimmune disorders. It is characterized in part by infiltration of the heart by lymphocyte and monocyte types of white blood cells. Eosinophilic myocarditis – inflammation of the myocardium caused by pathologically activated eosinophilic white blood cells. This disorder differs from myocarditis in its causes and treatments. Valvular heart disease Congenital heart disease – heart structure malformations existing at birth Rheumatic heart disease – heart muscles and valves damage due to rheumatic fever caused by Streptococcus pyogenes a group A streptococcal infection. == Risk factors == There are many risk factors for heart diseases: age, sex, tobacco use, physical inactivity, non-alcoholic fatty liver disease, excessive alcohol consumption, unhealthy diet, obesity, genetic predisposition and family history of cardiovascular disease, raised blood pressure (hypertension), raised blood sugar (diabetes mellitus), raised blood cholesterol (hyperlipidemia), undiagnosed celiac disease, psychosocial factors, poverty and low educational status, air pollution, and poor sleep. While the individual contribution of each risk factor varies between different communities or ethnic groups the overall contribution of these risk factors is very consistent. Some of these risk factors, such as age, sex or family history/genetic predisposition, are immutable; however, many important cardiovascular risk factors are modifiable by lifestyle change, social change, drug treatment (for example prevention of hypertension, hyperlipidemia, and diabetes). People with obesity are at increased risk of atherosclerosis of the coronary arteries. === Genetics === Cardiovascular disease in a person's parents increases their risk by ~3 fold, and genetics is an important risk factor for cardiovascular diseases. Genetic cardiovascular disease can occur either as a consequence of single variant (Mendelian) or polygenic influences. There are more than 40 inherited cardiovascular disease that can be traced to a single disease-causing DNA variant, although these conditions are rare. Most common cardiovascular diseases are non-Mendelian and are thought to be due to hundreds or thousands of genetic variants (known as single nucleotide polymorphisms), each associated with a small effect. === Age === Age is the most important risk factor in developing cardiovascular or heart diseases, with approximately a tripling of risk with each decade of life. Coronary fatty streaks can begin to form in adolescence. It is estimated that 82 percent of people who die of coronary heart disease are 65 and older. Simultaneously, the risk of stroke doubles every decade after age 55. Multiple explanations are proposed to explain why age increases the risk of cardiovascular/heart diseases. One of them relates to serum cholesterol level. In most populations, the serum total cholesterol level increases as age increases. In men, this increase levels off around age 45 to 50 years. In women, the increase continues sharply until age 60 to 65 years. Aging is also associated with changes in the mechanical and structural properties of the vascular wall, which leads to the loss of arterial elasticity and reduced arterial compliance and may subsequently lead to coronary artery disease. === Sex === Men are at greater risk of heart disease than pre-menopausal women. Once past menopause, it has been argued that a woman's risk is similar to a man's although more recent data from the WHO and UN disputes this. If a female has diabetes, she is more likely to develop heart disease than a male with diabetes. Women who have high blood pressure and had complications in their pregnancy have three times the risk of developing cardiovascular disease compared to women with normal blood pressure who had no complications in pregnancy. Coronary heart diseases are 2 to 5 times more common among middle-aged men than women. In a study done by the World Health Organization, sex contributes to approximately 40% of the variation in sex ratios of coronary heart disease mortality. Another study reports similar results finding that sex differences explains nearly half the risk associated with cardiovascular diseases One of the proposed explanations for sex differences in cardiovascular diseases is hormonal difference. Among women, estrogen is the predominant sex hormone. Estrogen may have protective effects on glucose metabolism and hemostatic system, and may have direct effect in improving endothelial cell function. The production of estrogen decreases after menopause, and this may change the female lipid metabolism toward a more atherogenic form by decreasing the HDL cholesterol level while increasing LDL and total cholesterol levels. Among men and women, there are differences in body weight, height, body fat distribution, heart rate, stroke volume, and arterial compliance. In the very elderly, age-related large artery pulsatility and stiffness are more pronounced among women than men. This may be caused by the women's smaller body size and arterial dimensions which are independent of menopause. === Tobacco === Cigarettes are the major form of smoked tobacco. Risks to health from tobacco use result not only from direct consumption of tobacco, but also from exposure to second-hand smoke. Approximately 10% of cardiovascular disease is attributed to smoking; however, people who quit smoking by age 30 have almost as low a risk of death as never smokers. === Physical inactivity === Insufficient physical activity (defined as less than 5 x 30 minutes of moderate activity per week, or less than 3 x 20 minutes of vigorous activity per week) is currently the fourth leading risk factor for mortality worldwide. In 2008, 31.3% of adults aged 15 or older (28.2% men and 34.4% women) were insufficiently physically active. The risk of ischemic heart disease and diabetes mellitus is reduced by almost a third in adults who participate in 150 minutes of moderate physical activity each week (or equivalent). In addition, physical activity assists weight loss and improves blood glucose control, blood pressure, lipid profile and insulin sensitivity. These effects may, at least in part, explain its cardiovascular benefits. === Diet === High dietary intakes of saturated fat, trans-fats and salt, and low intake of fruits, vegetables and fish are linked to cardiovascular risk, although whether all these associations indicate causes is disputed. The World Health Organization attributes approximately 1.7 million deaths worldwide to low fruit and vegetable consumption. Frequent consumption of high-energy foods, such as processed foods that are high in fats and sugars, promotes obesity and may increase cardiovascular risk. The amount of dietary salt consumed may also be an important determinant of blood pressure levels and overall cardiovascular risk. There is moderate quality evidence that reducing saturated fat intake for at least two years reduces the risk of cardiovascular disease. High trans-fat intake has adverse effects on blood lipids and circulating inflammatory markers, and elimination of trans-fat from diets has been widely advocated. In 2018 the World Health Organization estimated that trans fats were the cause of more than half a million deaths per year. There is evidence that higher consumption of sugar is associated with higher blood pressure and unfavorable blood lipids, and sugar intake also increases the risk of diabetes mellitus. High consumption of processed meats is associated with an increased risk of cardiovascular disease, possibly in part due to increased dietary salt intake. === Alcohol === The relationship between alcohol consumption and cardiovascular disease is complex, and may depend on the amount of alcohol consumed. There is a direct relationship between high levels of drinking alcohol and cardiovascular disease. Drinking at low levels without episodes of heavy drinking may be associated with a reduced risk of cardiovascular disease, but there is evidence that associations between moderate alcohol consumption and protection from stroke are non-causal. Moderate drinking is defined as one drink per day for women or two drinks a day for men. At the population level, the health risks of drinking alcohol exceed any potential benefits. Exercising regularly can provide the same benefits as potentially consuming small amounts of alcohol and is a much safer alternative. Consuming too much alcohol can cause a high blood pressure, heart failure, and cardiomyopathy. Drinking alcohol can also cause obesity, which can contribute to cardiovascular issues as well. === Celiac disease === Untreated celiac disease can cause the development of many types of cardiovascular diseases, most of which improve or resolve with a gluten-free diet and intestinal healing. However, delays in recognition and diagnosis of celiac disease can cause irreversible heart damage. === Sleep === A lack of good sleep, in amount or quality, is documented as increasing cardiovascular risk in both adults and teens. Recommendations suggest that infants typically need 12 or more hours of sleep per day, adolescents at least eight or nine hours, and adults seven or eight. About one-third of adult Americans get less than the recommended seven hours of sleep per night, and in a study of teenagers, just 2.2 percent of those studied got enough sleep, many of whom did not get good quality sleep. Studies have shown that short sleepers getting less than seven hours sleep per night have a 10 percent to 30 percent higher risk of cardiovascular disease. Sleep disorders such as sleep-disordered breathing and insomnia, are also associated with a higher cardiometabolic risk. An estimated 50 to 70 million Americans have insomnia, sleep apnea or other chronic sleep disorders. In addition, sleep research displays differences in race and class. Short sleep and poor sleep tend to be more frequently reported in ethnic minorities than in whites. African-Americans report experiencing short durations of sleep five times more often than whites, possibly as a result of social and environmental factors. Black children and children living in disadvantaged neighborhoods have much higher rates of sleep apnea. One study found that of adults who are 45 and older, subjects that fell asleep at different times each night and slept inconsistent numbers of hours each night were more likely to develop atherosclerosis. Poor sleep habits, such as too little sleep, too much sleep, or fragmented sleep, were associated with cardiovascular disease, obesity, and high blood pressure. Another study noted that participants whose sleep duration varied by more than two hours within the course of a week were 1.4 times more likely to have elevated levels of coronary artery calcium, a predictor of cardiovascular events. === Socioeconomic disadvantage === Cardiovascular disease has a greater impact on low- and middle-income countries compared to those with higher income. Although data on the social patterns of cardiovascular disease in low- and middle-income countries is limited, reports from high-income countries consistently demonstrate that low educational status or income are associated with a greater risk of cardiovascular disease. Policies that have resulted in increased socio-economic inequalities have been associated with greater subsequent socio-economic differences in cardiovascular disease implying a cause and effect relationship. Psychosocial factors, environmental exposures, health behaviours, and health-care access and quality contribute to socio-economic differentials in cardiovascular disease. The Commission on Social Determinants of Health recommended that more equal distributions of power, wealth, education, housing, environmental factors, nutrition, and health care were needed to address inequalities in cardiovascular disease and non-communicable diseases. === Air pollution === Particulate matter has been studied for its short- and long-term exposure effects on cardiovascular disease. Currently, airborne particles under 2.5 micrometers in diameter (PM2.5) are the major focus, in which gradients are used to determine CVD risk. Overall, long-term PM exposure increased rate of atherosclerosis and inflammation. In regards to short-term exposure (2 hours), every 25 μg/m3 of PM2.5 resulted in a 48% increase of CVD mortality risk. In addition, after only 5 days of exposure, a rise in systolic (2.8 mmHg) and diastolic (2.7 mmHg) blood pressure occurred for every 10.5 μg/m3 of PM2.5. Other research has implicated PM2.5 in irregular heart rhythm, reduced heart rate variability (decreased vagal tone), and most notably heart failure. PM2.5 is also linked to carotid artery thickening and increased risk of acute myocardial infarction. === Cardiovascular risk assessment === Existing cardiovascular disease or a previous cardiovascular event, such as a heart attack or stroke, is the strongest predictor of a future cardiovascular event. Age, sex, smoking, blood pressure, blood lipids and diabetes are important predictors of future cardiovascular disease in people who are not known to have cardiovascular disease. These measures, and sometimes others, may be combined into composite risk scores to estimate an individual's future risk of cardiovascular disease. Numerous risk scores exist although their respective merits are debated. Other diagnostic tests and biomarkers remain under evaluation but currently these lack clear-cut evidence to support their routine use. They include family history, coronary artery calcification score, high sensitivity C-reactive protein (hs-CRP), ankle–brachial pressure index, lipoprotein subclasses and particle concentration, lipoprotein(a), apolipoproteins A-I and B, fibrinogen, white blood cell count, homocysteine, N-terminal pro B-type natriuretic peptide (NT-proBNP), and markers of kidney function. High blood phosphorus is also linked to an increased risk. === Psychological stress === There is evidence that mental health problems, in particular depression and traumatic stress, is linked to cardiovascular diseases. Whereas mental health problems are known to be associated with risk factors for cardiovascular diseases such as smoking, poor diet, and a sedentary lifestyle, these factors alone do not explain the increased risk of cardiovascular diseases seen in depression, stress, and anxiety. Moreover, posttraumatic stress disorder is independently associated with increased risk for incident coronary heart disease, even after adjusting for depression and other covariates. Many studies recognize depression and anxiety as two important disorders that can cause an increase in the risk of developing cardiovascular disease. Only half of the instances of cardiovascular disease are explained by factors such as age and gender that cannot be changed. The other half of instances are due to other sources, including psychological stress. Studies have shown that the prevalence of depression in patients with heart failure is higher than 20%. Another study assessed the link between men and women who had been divorced and instance of cardiovascular disease. The study found that women who had gone through at least two divorces were just as likely to experience cardiovascular disease as a smoker or diabetic. Men, on the other hand, also had a higher risk of cardiovascular disease, however, their health improved upon remarriage while women did not. This study also found that during a World Cup soccer event in Germany, heart attacks more than doubled during the days when the nation's team was playing. Researchers assume this link is due to the fact that stress can increase inflammation in the body, which can cause high blood pressure and low HDL cholesterol. Chronic stress can also affect sleep, exercise, and food choices. === Anxiety === Patients who suffer from generalized anxiety disorder are more likely to develop some form of cardiovascular disease. It is hypothesized that anxiety makes one more likely to develop cardiovascular disease due to the fact that it can change the body's stress response through hormonal and physiological reactions. People with anxiety often experience high blood pressure, arrhythmias, and heart attacks. The stress response caused by anxiety can increase inflammation in the body. It was also discovered that patients with anxiety had lower levels of omega-3-fatty acids which is linked to an increased risk of developing cardiovascular disease. === Occupational exposure === Little is known about the relationship between work and cardiovascular disease, but links have been established between certain toxins, extreme heat and cold, exposure to tobacco smoke, and mental health concerns such as stress and depression. ==== Non-chemical risk factors ==== A 2015 SBU-report looking at non-chemical factors found an association for those: with mentally stressful work with a lack of control over their working situation — with an effort-reward imbalance who experience low social support at work; who experience injustice or experience insufficient opportunities for personal development; or those who experience job insecurity those who work night schedules; or have long working weeks those who are exposed to noise Specifically the risk of stroke was also increased by exposure to ionizing radiation. Hypertension develops more often in those who experience job strain and who have shift-work. Differences between women and men in risk are small, however men risk having and dying of heart attacks or stroke twice as often as women during working life. ==== Chemical risk factors ==== A 2017 SBU report found evidence that workplace exposure to silica dust, engine exhaust or welding fumes is associated with heart disease. Associations also exist for exposure to arsenic, benzopyrenes, lead, dynamite, carbon disulphide, carbon monoxide, metalworking fluids and occupational exposure to tobacco smoke. Working with the electrolytic production of aluminium or the production of paper when the sulphate pulping process is used is associated with heart disease. An association was also found between heart disease and exposure to compounds which are no longer permitted in certain work environments, such as phenoxy acids containing TCDD(dioxin) or asbestos. Workplace exposure to silica dust or asbestos is also associated with pulmonary heart disease. There is evidence that workplace exposure to lead, carbon disulphide, phenoxyacids containing TCDD, as well as working in an environment where aluminum is being electrolytically produced, is associated with stroke. === Somatic mutations === As of 2017, evidence suggests that certain leukemia-associated mutations in blood cells may also lead to increased risk of cardiovascular disease. Several large-scale research projects looking at human genetic data have found a robust link between the presence of these mutations, a condition known as clonal hematopoiesis, and cardiovascular disease-related incidents and mortality. === Radiation therapy === Radiation treatments (RT) for cancer can increase the risk of heart disease and death, as observed in breast cancer therapy. Therapeutic radiation increases the risk of a subsequent heart attack or stroke by 1.5 to 4 times; the increase depends on the dose strength, volume, and location. Use of concomitant chemotherapy, e.g. anthracyclines, is an aggravating risk factor. The occurrence rate of RT induced cardiovascular disease is estimated between 10% and 30%. Side-effects from radiation therapy for cardiovascular diseases have been termed radiation-induced heart disease or radiation-induced cardiovascular disease. Symptoms are dose-dependent and include cardiomyopathy, myocardial fibrosis, valvular heart disease, coronary artery disease, heart arrhythmia and peripheral artery disease. Radiation-induced fibrosis, vascular cell damage and oxidative stress can lead to these and other late side-effect symptoms. == Pathophysiology == Population-based studies show that atherosclerosis, the major precursor of cardiovascular disease, begins in childhood. The Pathobiological Determinants of Atherosclerosis in Youth (PDAY) study demonstrated that intimal lesions appear in all the aortas and more than half of the right coronary arteries of youths aged 7–9 years. Obesity and diabetes mellitus are linked to cardiovascular disease, as are a history of chronic kidney disease and hypercholesterolaemia. In fact, cardiovascular disease is the most life-threatening of the diabetic complications and diabetics are two- to four-fold more likely to die of cardiovascular-related causes than nondiabetics. == Screening == Screening ECGs (either at rest or with exercise) are not recommended in those without symptoms who are at low risk. This includes those who are young without risk factors. In those at higher risk the evidence for screening with ECGs is inconclusive. Additionally echocardiography, myocardial perfusion imaging, and cardiac stress testing is not recommended in those at low risk who do not have symptoms. Some biomarkers may add to conventional cardiovascular risk factors in predicting the risk of future cardiovascular disease; however, the value of some biomarkers is questionable. Ankle-brachial index (ABI), high-sensitivity C-reactive protein (hsCRP), and coronary artery calcium, are also of unclear benefit in those without symptoms as of 2018. The NIH recommends lipid testing in children beginning at the age of 2 if there is a family history of heart disease or lipid problems. It is hoped that early testing will improve lifestyle factors in those at risk such as diet and exercise. Screening and selection for primary prevention interventions has traditionally been done through absolute risk using a variety of scores (ex. Framingham or Reynolds risk scores). This stratification has separated people who receive the lifestyle interventions (generally lower and intermediate risk) from the medication (higher risk). The number and variety of risk scores available for use has multiplied, but their efficacy according to a 2016 review was unclear due to lack of external validation or impact analysis. Risk stratification models often lack sensitivity for population groups and do not account for the large number of negative events among the intermediate and low risk groups. As a result, future preventative screening appears to shift toward applying prevention according to randomized trial results of each intervention rather than large-scale risk assessment. == Prevention == Up to 90% of cardiovascular disease may be preventable if established risk factors are avoided. Currently practised measures to prevent cardiovascular disease include: Maintaining a healthy diet, such as the Mediterranean diet, a vegetarian, vegan or another plant-based diet. Replacing saturated fat with healthier choices: Clinical trials show that replacing saturated fat with polyunsaturated vegetable oil reduced CVD by 30%. Prospective observational studies show that in many populations lower intake of saturated fat coupled with higher intake of polyunsaturated and monounsaturated fat is associated with lower rates of CVD. Decrease body fat if overweight or obese. The effect of weight loss is often difficult to distinguish from dietary change, and evidence on weight reducing diets is limited. In observational studies of people with severe obesity, weight loss following bariatric surgery is associated with a 46% reduction in cardiovascular risk. Limit alcohol consumption to the recommended daily limits. People who moderately consume alcoholic drinks have a 25–30% lower risk of cardiovascular disease. However, people who are genetically predisposed to consume less alcohol have lower rates of cardiovascular disease suggesting that alcohol itself may not be protective. Excessive alcohol intake increases the risk of cardiovascular disease and consumption of alcohol is associated with increased risk of a cardiovascular event in the day following consumption. Decrease non-HDL cholesterol. Statin treatment reduces cardiovascular mortality by about 31%. Stopping smoking and avoidance of second-hand smoke. Stopping smoking reduces risk by about 35%. At least 150 minutes (2 hours and 30 minutes) of moderate exercise per week. Lower blood pressure, if elevated. A 10 mmHg reduction in blood pressure reduces risk by about 20%. Lowering blood pressure appears to be effective even at normal blood pressure ranges. Not enough sleep also raises the risk of high blood pressure. Adults need about 7–9 hours of sleep. Sleep apnea is also a major risk as it causes breathing to stop briefly, which can put stress on the body which can raise the risk of heart disease. Most guidelines recommend combining preventive strategies. There is some evidence that interventions aiming to reduce more than one cardiovascular risk factor may have beneficial effects on blood pressure, body mass index and waist circumference; however, evidence was limited and the authors were unable to draw firm conclusions on the effects on cardiovascular events and mortality. There is additional evidence to suggest that providing people with a cardiovascular disease risk score may reduce risk factors by a small amount compared to usual care. However, there was some uncertainty as to whether providing these scores had any effect on cardiovascular disease events. It is unclear whether or not dental care in those with periodontitis affects their risk of cardiovascular disease. According to a 2021 WHO study, working 55+ hours a week raises the risk of stroke by 35% and the risk of dying from heart conditions by 17%, when compared to a 35-40 hours week. === Psychological prevention === Decrease psychosocial stress. This measure may be complicated by imprecise definitions of what constitute psychosocial interventions. Mental stress–induced myocardial ischemia is associated with an increased risk of heart problems in those with previous heart disease. Severe emotional and physical stress leads to a form of heart dysfunction known as Takotsubo syndrome in some people. Specific relaxation therapies are of unclear benefit. Decreasing psychological stress can be accomplished by receiving access to services and support, recognizing signs and symptoms of mental health disorders, awareness of family history, and understanding which mental health disorders increase the risk of cardiovascular disease. Psychosocial intervention programs have been shown to improve risk of developing cardiovascular disease in the high-risk population. === Diet === A diet high in fruits and vegetables decreases the risk of cardiovascular disease and death. A 2021 review found that plant-based diets can provide a risk reduction for CVD if a healthy plant-based diet is consumed. Unhealthy plant-based diets do not provide benefits over diets including meat. A similar meta-analysis and systematic review also looked into dietary patterns and found "that diets lower in animal foods and unhealthy plant foods, and higher in healthy plant foods are beneficial for CVD prevention". A 2018 meta-analysis of observational studies concluded that "In most countries, a vegan diet is associated with a more favourable cardio-metabolic profile compared to an omnivorous diet." Evidence suggests that the Mediterranean diet may improve cardiovascular outcomes. There is also evidence that a Mediterranean diet may be more effective than a low-fat diet in bringing about long-term changes to cardiovascular risk factors (e.g., lower cholesterol level and blood pressure). The DASH diet (high in nuts, fish, fruits and vegetables, and low in sweets, red meat and fat) has been shown to reduce blood pressure, lower total and low density lipoprotein cholesterol and improve metabolic syndrome; but the long-term benefits have been questioned. A high-fiber diet is associated with lower risks of cardiovascular disease. Worldwide, dietary guidelines recommend a reduction in saturated fat, and although the role of dietary fat in cardiovascular disease is complex and controversial there is a long-standing consensus that replacing saturated fat with unsaturated fat in the diet is sound medical advice. Total fat intake has not been found to be associated with cardiovascular risk. A 2020 systematic review found moderate quality evidence that reducing saturated fat intake for at least 2 years caused a reduction in cardiovascular events. A 2015 meta-analysis of observational studies however did not find a convincing association between saturated fat intake and cardiovascular disease. Variation in what is used as a substitute for saturated fat may explain some differences in findings. The benefit from replacement with polyunsaturated fats appears greatest, while replacement of saturated fats with carbohydrates does not appear to have a beneficial effect. A diet high in trans fatty acids is associated with higher rates of cardiovascular disease, and in 2015 the Food and Drug Administration (FDA) determined that there was 'no longer a consensus among qualified experts that partially hydrogenated oils (PHOs), which are the primary dietary source of industrially produced trans fatty acids (IP-TFA), are generally recognized as safe (GRAS) for any use in human food'. There is conflicting evidence concerning whether dietary supplements of omega-3 fatty acids (a type of polyunsaturated essential fatty acid) added to diet improve cardiovascular risk. The benefits of recommending a low-salt diet in people with high or normal blood pressure are not clear. In those with heart failure, after one study was left out, the rest of the trials show a trend to benefit. Another review of dietary salt concluded that there is strong evidence that high dietary salt intake increases blood pressure and worsens hypertension, and that it increases the number of cardiovascular disease events; both as a result of the increased blood pressure and probably through other mechanisms. Moderate evidence was found that high salt intake increases cardiovascular mortality; and some evidence was found for an increase in overall mortality, strokes, and left ventricular hypertrophy. ==== Intermittent fasting ==== Overall, the current body of scientific evidence is uncertain on whether intermittent fasting could prevent cardiovascular disease. Intermittent fasting may help people lose more weight than regular eating patterns, but was not different from energy restriction diets. === Medication === Blood pressure medication reduces cardiovascular disease in people at risk, irrespective of age, the baseline level of cardiovascular risk, or baseline blood pressure. The commonly-used drug regimens have similar efficacy in reducing the risk of all major cardiovascular events, although there may be differences between drugs in their ability to prevent specific outcomes. Larger reductions in blood pressure produce larger reductions in risk, and most people with high blood pressure require more than one drug to achieve adequate reduction in blood pressure. Adherence to medications is often poor, and while mobile phone text messaging has been tried to improve adherence, there is insufficient evidence that it alters secondary prevention of cardiovascular disease. Statins are effective in preventing further cardiovascular disease in people with a history of cardiovascular disease. As the event rate is higher in men than in women, the decrease in events is more easily seen in men than women. In those at risk, but without a history of cardiovascular disease (primary prevention), statins decrease the risk of death and combined fatal and non-fatal cardiovascular disease. The benefit, however, is small. A United States guideline recommends statins in those who have a 12% or greater risk of cardiovascular disease over the next ten years. Niacin, fibrates and CETP Inhibitors, while they may increase HDL cholesterol do not affect the risk of cardiovascular disease in those who are already on statins. Fibrates lower the risk of cardiovascular and coronary events, but there is no evidence to suggest that they reduce all-cause mortality. Anti-diabetic medication may reduce cardiovascular risk in people with Type 2 diabetes, although evidence is not conclusive. A meta-analysis in 2009 including 27,049 participants and 2,370 major vascular events showed a 15% relative risk reduction in cardiovascular disease with more-intensive glucose lowering over an average follow-up period of 4.4 years, but an increased risk of major hypoglycemia. Aspirin has been found to be of only modest benefit in those at low risk of heart disease, as the risk of serious bleeding is almost equal to the protection against cardiovascular problems. In those at very low risk, including those over the age of 70, it is not recommended. The United States Preventive Services Task Force recommends against use of aspirin for prevention in women less than 55 and men less than 45 years old; however, it is recommended for some older people. The use of vasoactive agents for people with pulmonary hypertension with left heart disease or hypoxemic lung diseases may cause harm and unnecessary expense. Antibiotics for secondary prevention of coronary heart disease Antibiotics may help patients with coronary disease to reduce the risk of heart attacks and strokes. However, evidence in 2021 suggests that antibiotics for secondary prevention of coronary heart disease are harmful, with increased mortality and occurrence of stroke; the use of antibiotics is not supported for preventing secondary coronary heart disease. === Physical activity === Exercise-based cardiac rehabilitation following a heart attack reduces the risk of death from cardiovascular disease and leads to less hospitalizations. There have been few high-quality studies of the benefits of exercise training in people with increased cardiovascular risk but no history of cardiovascular disease. A systematic review estimated that inactivity is responsible for 6% of the burden of disease from coronary heart disease worldwide. The authors estimated that 121,000 deaths from coronary heart disease could have been averted in Europe in 2008 if people had not been physically inactive. Low-quality evidence from a limited number of studies suggest that yoga has beneficial effects on blood pressure and cholesterol. Tentative evidence suggests that home-based exercise programs may be more efficient at improving exercise adherence. === Dietary supplements === While a healthy diet is beneficial, the effect of antioxidant supplementation (vitamin E, vitamin C, etc.) or vitamins has not been shown to protect against cardiovascular disease and in some cases may possibly result in harm. Mineral supplements have also not been found to be useful. Niacin, a type of vitamin B3, may be an exception with a modest decrease in the risk of cardiovascular events in those at high risk. Magnesium supplementation lowers high blood pressure in a dose-dependent manner. Magnesium therapy is recommended for people with ventricular arrhythmia associated with torsades de pointes who present with long QT syndrome, and for the treatment of people with digoxin intoxication-induced arrhythmias. There is no evidence that omega-3 fatty acid supplementation is beneficial. A 2022 review found that some dietary supplements, including micronutrients, may reduce risk factors for cardiovascular disease. == Management == Cardiovascular disease is treatable with initial treatment primarily focused on diet and lifestyle interventions. Influenza may make heart attacks and strokes more likely and therefore influenza vaccination may decrease the chance of cardiovascular events and death in people with heart disease. Proper CVD management necessitates a focus on MI and stroke cases due to their combined high mortality rate, keeping in mind the cost-effectiveness of any intervention, especially in developing countries with low or middle-income levels. Regarding MI, strategies using aspirin, atenolol, streptokinase or tissue plasminogen activator have been compared for quality-adjusted life-year (QALY) in regions of low and middle income. The costs for a single QALY for aspirin and atenolol were less than US$25, streptokinase was about $680, and t-PA was $16,000. Aspirin, ACE inhibitors, beta-blockers, and statins used together for secondary CVD prevention in the same regions showed single QALY costs of $350. There are also surgical or procedural interventions that can save someone's life or prolong it. For heart valve problems, a person could have surgery to replace the valve. For arrhythmias, a pacemaker can be put in place to help reduce abnormal heart rhythms and for a heart attack, there are multiple options two of these are a coronary angioplasty and a coronary artery bypass surgery. There is probably no additional benefit in terms of mortality and serious adverse events when blood pressure targets were lowered to ≤ 135/85 mmHg from ≤ 140 to 160/90 to 100 mmHg. == Epidemiology == Cardiovascular diseases are the leading cause of death worldwide and in all regions except Africa. In 2008, 30% of all global death was attributed to cardiovascular diseases. Death caused by cardiovascular diseases are also higher in low- and middle-income countries as over 80% of all global deaths caused by cardiovascular diseases occurred in those countries. It is also estimated that by 2030, over 23 million people will die from cardiovascular diseases each year. It is estimated that 60% of the world's cardiovascular disease burden will occur in the South Asian subcontinent despite only accounting for 20% of the world's population. This may be secondary to a combination of genetic predisposition and environmental factors. Organizations such as the Indian Heart Association are working with the World Heart Federation to raise awareness about this issue. == Research == There is evidence that cardiovascular disease existed in pre-history, and research into cardiovascular disease dates from at least the 18th century. The causes, prevention, and/or treatment of all forms of cardiovascular disease remain active fields of biomedical research, with hundreds of scientific studies being published on a weekly basis. Recent areas of research include the link between inflammation and atherosclerosis the potential for novel therapeutic interventions, and the genetics of coronary heart disease. == References == == External links == WHO fact sheet on cardiovascular diseases 2021 ESC Guidelines on cardiovascular disease prevention in clinical practice Heart Disease MedicineNet Slides, photos, descriptions Risk calculator Interactive CV Risk Calculator	Wikipedia/Cardiovascular_diseases
In cardiology, ventricular remodeling (or cardiac remodeling) refers to changes in the size, shape, structure, and function of the heart. This can happen as a result of exercise (physiological remodeling) or after injury to the heart muscle (pathological remodeling). The injury is typically due to acute myocardial infarction (usually transmural or ST segment elevation infarction), but may be from a number of causes that result in increased pressure or volume, causing pressure overload or volume overload (forms of strain) on the heart. Chronic hypertension, congenital heart disease with intracardiac shunting, and valvular heart disease may also lead to remodeling. After the insult occurs, a series of histopathological and structural changes occur in the left ventricular myocardium that lead to progressive decline in left ventricular performance. Ultimately, ventricular remodeling may result in diminished contractile (systolic) function and reduced stroke volume. Physiological remodeling is reversible while pathological remodeling is mostly irreversible. Remodeling of the ventricles under left/right pressure demand make mismatches inevitable. Pathologic pressure mismatches between the pulmonary and systemic circulation guide compensatory remodeling of the left and right ventricles. The term "reverse remodeling" in cardiology implies an improvement in ventricular mechanics and function following a remote injury or pathological process. Ventricular remodeling may include ventricular hypertrophy, ventricular dilation, cardiomegaly, and other changes. It is an aspect of cardiomyopathy, of which there are many types. Concentric hypertrophy is due to pressure overload, while eccentric hypertrophy is due to volume overload. == Pathophysiology == The cardiac myocyte is the major cell involved in remodeling. Fibroblasts, collagen, the interstitium, and the coronary vessels to a lesser extent, also play a role. A common scenario for remodeling is after myocardial infarction. There is myocardial necrosis (cell death) and disproportionate thinning of the heart. This thin, weakened area is unable to withstand the pressure and volume load on the heart in the same manner as the other healthy tissue. As a result, there is dilatation of the chamber arising from the infarct region. The initial remodeling phase after a myocardial infarction results in repair of the necrotic area and myocardial scarring that may, to some extent, be considered beneficial since there is an improvement in or maintenance of LV function and cardiac output. Over time, however, as the heart undergoes ongoing remodeling, it becomes less elliptical and more spherical. Ventricular mass and volume increase, which together adversely affect cardiac function. Eventually, diastolic function, or the heart's ability to relax between contractions may become impaired, further causing decline. After a myocardial infarction (MI), cardiac myocyte death can be triggered by necrosis, apoptosis, or autophagy, leading to thinning of the cardiac wall. The surviving cardiac myocytes either arrange in parallel or in series to each other, contributing to ventricular dilatation or ventricular hypertrophy, depending on the loading stress on the ventricular wall. Besides, reduced expression of V1 myosin and L-type calcium channels on cardiac myocytes are also thought to cause cardiac remodeling. Under normal body conditions, fatty acid accounts for 60 to 90% of the energy supply of the heart. Post MI, as fatty acid oxidation decreases, it leads to reduced energy supply for the cardiac myocytes, accumulation of fatty acids to toxic levels, and dysfunction of mitochondria. These consequences also led to the increase in oxidative stress on the heart, causing the proliferation of fibroblasts, activation of metalloproteinases, and induction of apoptosis, which would be explained below. Besides, inflammatory immune response after MI also contributes to the above changes. Besides, the cardiac interstitium which consisted of largely Type I and Type III collagen fibres are also involved in cardiac remodeling. Cardiac collagen is synthesized by fibroblasts and degraded by metalloproteinases. Fibroblasts are activated post MI, leading to increased collagen synthesis and fibrosis of the heart. Increase expression of MMP1 and MMP9 led to degradation of collagen fibres, and subsequently dilatation of the heart. Several signal pathways such as Angiotensin II, Transforming growth factor beta (TGF-beta), and Endothelin 1 are known to trigger synthesis and degradation of collagen fibres in the heart. Other factors such as high blood pressure, activation of sympathetic system which releases norepinephrine, activation of renin–angiotensin system which releases renin and anti-diuretic hormones are important contributors of cardiac remodelling. However, atrial natriuretic peptide is thought to be cardio-protective. == Evaluation == Remodeling of the heart is evaluated by performing an echocardiogram. The size and function of the atria and ventricles can be characterized using this test. == Treatment == Many factors influence the time course and extent of remodeling, including the severity of the injury, secondary events (recurrent ischemia or infarction), neurohormonal activation, genetic factors and gene expression, and treatment. Medications may attenuate remodeling. Angiotensin-converting enzyme (ACE) inhibitors have been consistently shown to decrease remodeling in animal models or transmural infarction and chronic pressure overload. Clinical trials have shown that ACE inhibitor therapy after myocardial infarction leads to improved myocardial performance, improved ejection fraction, and decreased mortality compared to patients treated with placebo. Likewise, inhibition of aldosterone, either directly or indirectly, leads to improvement in remodeling. Carvedilol, a 3rd generation beta blocker, may actually reverse the remodeling process by reducing left ventricular volumes and improving systolic function. Cardiac resynchronization therapy (CRT) has shown the ability to reverse left ventricular remodeling in some patients. Early correction of congenital heart defects, if appropriate, may prevent remodeling, as will treatment of chronic hypertension or valvular heart disease. Often, reverse remodeling, or improvement in left ventricular function, will also be seen. == See also == Dor procedure Athlete's heart == References == == Further reading == "Left Ventricular Remodeling in Heart Failure: Current Concepts in Clinical Significance and Assessment". imaging.onlinejacc.org. Retrieved 2016-02-12.	Wikipedia/Ventricular_remodeling
Digital holography is the acquisition and processing of holograms with a digital sensor array, typically a CCD camera or a similar device. Image rendering, or reconstruction of object data is performed numerically from digitized interferograms. Digital holography offers a means of measuring optical phase data and typically delivers three-dimensional surface or optical thickness images. Several recording and processing schemes have been developed to assess optical wave characteristics such as amplitude, phase, and polarization state, which make digital holography a very powerful method for metrology applications . == Digital recording and processing of holograms == === Off-axis configuration === In the off-axis configuration, a small angle between the reference and the object beams is used to prevent overlapping of the cross-beating contributions between the object and reference optical fields with the self-beating contributions of these fields. These discoveries were made by Emmett Leith and Juris Upatnieks for analog holography, and subsequently adapted to digital holography. In this configuration, only a single recorded digital interferogram is required for image reconstruction. Yet, this configuration can also be used in conjunction with temporal modulation methods, such as phase-shifting and frequency-shifting for high sensitivity measurements in low light. === Phase-shifting holography === The phase-shifting (or phase-stepped) digital holography process entails capturing multiple interferograms that each indicate the optical phase relationships between light returned from all points on the illuminated object and a controlled reference beam of light. The optical phase of the reference beam is shifted from one sampled interferogram to the next. From a linear combination of these interferograms, complex-valued holograms are formed. These holograms contain amplitude and phase information of the optical radiation diffracted by the object, in the sensor plane. === Frequency-shifting holography === Through the use of electro-optic modulators (Pockel cells) or acousto-optic modulators (Bragg cells), the reference laser beam can be frequency-shifted by a tunable quantity. This enables optical heterodyne detection, a frequency-conversion process aimed at shifting a given radiofrequency optical signal component in the sensor's temporal bandwidth. Frequency-shifted holograms can be used for narrowband laser Doppler imaging. === Multiplexing of holograms === Addressing simultaneously distinct domains of the temporal and spatial bandwidth of holograms was performed with success for angular, wavelength, space-division, polarization, and sideband multiplexing schemes. Digital holograms can be numerically multiplexed and demultiplexed for efficient storage and transmission. Amplitude and phase can be correctly recovered. === Super-resolution in Digital Holography === Super-resolution is possible by means of a dynamic phase diffraction grating for increasing synthetically the aperture of the CCD array. Super-localization of particles can be achieved by adopting an optics/data-processing co-design scheme. === Optical Sectioning in Digital Holography === Optical sectioning, also known as sectional image reconstruction, is the process of recovering a planar image at a particular axial depth from a three-dimensional digital hologram. Various mathematical techniques have been used to solve this problem, with inverse imaging among the most versatile. === Extending Depth-of-Focus by Digital Holography in Microscopy === By using the 3D imaging capability of Digital Holography in amplitude and phase it is possible to extend the depth of focus in microscopy. === Combining of holograms and interferometric microscopy === The digital analysis of a set of holograms recorded from different directions or with different direction of the reference wave allows the numerical emulation of an objective with large numerical aperture, leading to corresponding enhancement of the resolution. This technique is called interferometric microscopy. == See also == Computer generated holography Digital holographic microscopy Holographic interferometry Holography == References == == Further reading == Grilli, S.; Ferraro, P.; Nicola, S. De; Finizio, A.; Pierattini, G.; Meucci, R. (2001). "Whole optical wavefields reconstruction by digital holography". Optics Express. 9 (6): 294–302. Bibcode:2001OExpr...9..294G. doi:10.1364/OE.9.000294. PMID 19421300.	Wikipedia/Digital_holography
Right atrial pressure (RAP) is the blood pressure in the right atrium of the heart. RAP reflects the amount of blood returning to the heart and the ability of the heart to pump the blood into the arterial system. RAP is often nearly identical to central venous pressure (CVP), although the two terms are not identical, as a pressure differential can sometimes exist between the venae cavae and the right atrium. CVP and RAP can differ when venous tone (i.e the degree of venous constriction) is altered. This can be graphically depicted as changes in the slope of the venous return plotted against right atrial pressure (where central venous pressure increases, but right atrial pressure stays the same; VR = CVP − RAP). == Factors affecting RAP == Factors that increase RAP include: Hypervolemia Forced exhalation Tension pneumothorax Heart failure Pleural effusion Decreased cardiac output Cardiac tamponade Mechanical ventilation and the application of positive end-expiratory pressure (PEEP) Pulmonary Hypertension Pulmonary Embolism Left to right shunted Atrial Septal Defect Factors that decrease RAP include: Hypovolemia Deep inhalation Distributive shock == See also == Pulmonary capillary wedge pressure Jugular venous pressure Central venous pressure == References == == External links == Cardiovascular Physiology Concepts Cardiovascular Physiology Right+Atrial+Pressure at the U.S. National Library of Medicine Medical Subject Headings (MeSH)	Wikipedia/Right_atrial_pressure
In physics, the Young–Laplace equation () is an equation that describes the capillary pressure difference sustained across the interface between two static fluids, such as water and air, due to the phenomenon of surface tension or wall tension, although use of the latter is only applicable if assuming that the wall is very thin. The Young–Laplace equation relates the pressure difference to the shape of the surface or wall and it is fundamentally important in the study of static capillary surfaces. It is a statement of normal stress balance for static fluids meeting at an interface, where the interface is treated as a surface (zero thickness): Δ p = − γ ∇ ⋅ n ^ = − 2 γ H f = − γ ( 1 R 1 + 1 R 2 ) {\displaystyle {\begin{aligned}\Delta p&=-\gamma \nabla \cdot {\hat {n}}\\&=-2\gamma H_{f}\\&=-\gamma \left({\frac {1}{R_{1}}}+{\frac {1}{R_{2}}}\right)\end{aligned}}} where Δ p {\displaystyle \Delta p} is the Laplace pressure, the pressure difference across the fluid interface (the exterior pressure minus the interior pressure), γ {\displaystyle \gamma } is the surface tension (or wall tension), n ^ {\displaystyle {\hat {n}}} is the unit normal pointing out of the surface, H f {\displaystyle H_{f}} is the mean curvature, and R 1 {\displaystyle R_{1}} and R 2 {\displaystyle R_{2}} are the principal radii of curvature. Note that only normal stress is considered, because a static interface is possible only in the absence of tangential stress. The equation is named after Thomas Young, who developed the qualitative theory of surface tension in 1805, and Pierre-Simon Laplace who completed the mathematical description in the following year. It is sometimes also called the Young–Laplace–Gauss equation, as Carl Friedrich Gauss unified the work of Young and Laplace in 1830, deriving both the differential equation and boundary conditions using Johann Bernoulli's virtual work principles. == Soap films == If the pressure difference is zero, as in a soap film without gravity, the interface will assume the shape of a minimal surface. == Emulsions == The equation also explains the energy required to create an emulsion. To form the small, highly curved droplets of an emulsion, extra energy is required to overcome the large pressure that results from their small radius. The Laplace pressure, which is greater for smaller droplets, causes the diffusion of molecules out of the smallest droplets in an emulsion and drives emulsion coarsening via Ostwald ripening. == Capillary pressure in a tube == In a sufficiently narrow (i.e., low Bond number) tube of circular cross-section (radius a), the interface between two fluids forms a meniscus that is a portion of the surface of a sphere with radius R. The pressure jump across this surface is related to the radius and the surface tension γ by Δ p = 2 γ R . {\displaystyle \Delta p={\frac {2\gamma }{R}}.} This may be shown by writing the Young–Laplace equation in spherical form with a contact angle boundary condition and also a prescribed height boundary condition at, say, the bottom of the meniscus. The solution is a portion of a sphere, and the solution will exist only for the pressure difference shown above. This is significant because there isn't another equation or law to specify the pressure difference; existence of solution for one specific value of the pressure difference prescribes it. The radius of the sphere will be a function only of the contact angle, θ, which in turn depends on the exact properties of the fluids and the container material with which the fluids in question are contacting/interfacing: R = a cos ⁡ θ {\displaystyle R={\frac {a}{\cos \theta }}} so that the pressure difference may be written as: Δ p = 2 γ cos ⁡ θ a . {\displaystyle \Delta p={\frac {2\gamma \cos \theta }{a}}.} In order to maintain hydrostatic equilibrium, the induced capillary pressure is balanced by a change in height, h, which can be positive or negative, depending on whether the wetting angle is less than or greater than 90°. For a fluid of density ρ: ρ g h = 2 γ cos ⁡ θ a . {\displaystyle \rho gh={\frac {2\gamma \cos \theta }{a}}.} where g is the gravitational acceleration. This is sometimes known as the Jurin's law or Jurin height after James Jurin who studied the effect in 1718. For a water-filled glass tube in air at sea level: γ = 0.0728 J/m2 at 20 °C θ = 20° (0.35 rad) ρ = 1000 kg/m3 g = 9.8 m/s2 and so the height of the water column is given by: h ≈ 1.4 × 10 − 5 m 2 a . {\displaystyle h\approx {{1.4\times 10^{-5}}\mathrm {m} ^{2} \over a}.} Thus for a 2 mm wide (1 mm radius) tube, the water would rise 14 mm. However, for a capillary tube with radius 0.1 mm, the water would rise 14 cm (about 6 inches). == Capillary action and gravity == When including also the effects of gravity, for a free surface and for a pressure difference between the fluids equal to Δp at the level h=0, there is a balance, when the interface is in equilibrium, between Δp, the hydrostatic pressure and the effects of surface tension. The Young–Laplace equation becomes: Δ p = ρ g h − γ [ 1 R 1 ( h ) + 1 R 2 ( h ) ] {\displaystyle \Delta p=\rho gh-\gamma \left[{\frac {1}{R_{1}(h)}}+{\frac {1}{R_{2}(h)}}\right]} Note that the mean curvature of the fluid-fluid interface now depends on h. The equation can be non-dimensionalised in terms of its characteristic length-scale, the capillary length: L c = γ ρ g , {\displaystyle L_{c}={\sqrt {\frac {\gamma }{\rho g}}},} and characteristic pressure p c = γ L c = γ ρ g . {\displaystyle p_{c}={\frac {\gamma }{L_{c}}}={\sqrt {\gamma \rho g}}.} For clean water at standard temperature and pressure, the capillary length is ~2 mm. The non-dimensional equation then becomes: h ∗ − Δ p ∗ = [ 1 R 1 ∗ ( h ) + 1 R 2 ∗ ( h ) ] . {\displaystyle h^{}-\Delta p^{}=\left[{\frac {1}{{R_{1}}^{}(h)}}+{\frac {1}{{R_{2}}^{}(h)}}\right].} Thus, the surface shape is determined by only one parameter, the over pressure of the fluid, Δp* and the scale of the surface is given by the capillary length. The solution of the equation requires an initial condition for position, and the gradient of the surface at the start point. === Axisymmetric equations === The (nondimensional) shape, r(z) of an axisymmetric surface can be found by substituting general expressions for principal curvatures to give the hydrostatic Young–Laplace equations: r ″ ( 1 + r ′ 2 ) 3 / 2 − 1 r ( z ) 1 + r ′ 2 = z − Δ p ∗ {\displaystyle {\frac {r''}{(1+r'^{2})^{{3}/{2}}}}-{\frac {1}{r(z){\sqrt {1+r'^{2}}}}}=z-\Delta p^{}} z ″ ( 1 + z ′ 2 ) 3 / 2 + z ′ r ( 1 + z ′ 2 ) 1 / 2 = Δ p ∗ − z ( r ) . {\displaystyle {\frac {z''}{(1+z'^{2})^{3/2}}}+{\frac {z'}{r(1+z'^{2})^{{1}/{2}}}}=\Delta p^{}-z(r).} == Application in medicine == In medicine it is often referred to as the Law of Laplace, used in the context of cardiovascular physiology, and also respiratory physiology, though the latter use is often erroneous. == History == Francis Hauksbee performed some of the earliest observations and experiments in 1709 and these were repeated in 1718 by James Jurin who observed that the height of fluid in a capillary column was a function only of the cross-sectional area at the surface, not of any other dimensions of the column. Thomas Young laid the foundations of the equation in his 1804 paper An Essay on the Cohesion of Fluids where he set out in descriptive terms the principles governing contact between fluids (along with many other aspects of fluid behaviour). Pierre Simon Laplace followed this up in Mécanique Céleste with the formal mathematical description given above, which reproduced in symbolic terms the relationship described earlier by Young. Laplace accepted the idea propounded by Hauksbee in his book Physico-mechanical Experiments (1709), that the phenomenon was due to a force of attraction that was insensible at sensible distances. The part which deals with the action of a solid on a liquid and the mutual action of two liquids was not worked out thoroughly, but ultimately was completed by Carl Friedrich Gauss. Franz Ernst Neumann (1798-1895) later filled in a few details. == References == == Further reading == Maxwell, James Clerk; Strutt, John William (1911). "Capillary Action" . In Chisholm, Hugh (ed.). Encyclopædia Britannica. Vol. 5 (11th ed.). Cambridge University Press. pp. 256–275. Batchelor, G. K. (1967) An Introduction To Fluid Dynamics, Cambridge University Press Jurin, J. (1716). "An account of some experiments shown before the Royal Society; with an enquiry into the cause of the ascent and suspension of water in capillary tubes". Philosophical Transactions of the Royal Society. 30 (351–363): 739–747. doi:10.1098/rstl.1717.0026. S2CID 186211806. Tadros T. F. (1995) Surfactants in Agrochemicals, Surfactant Science series, vol.54, Dekker	Wikipedia/Young–Laplace_equation
The volume of the heart's left atrium (left atrial volume) is an important biomarker for cardiovascular physiology and clinical cardiology. It is usually calculated as left atrial volume index in terms of body surface area. == Measurement == The left atrial volume is commonly measured by echocardiography or magnetic resonance tomography. It is calculated from biplane recordings with the equation: A L = 8 3 π A 4 c ⋅ A 2 c L {\displaystyle {A}_{L}={\frac {8}{3\pi }}{\frac {A4c\cdot A2c}{L}}} where A4c and A2c denote LA areas in 4- and 2-chamber views respectively, and L corresponds to the shortest long-axis length measured in either views. Usually, the volume of the left atrium is divided by the body surface area in order to provide an extensive property, which is independent from body size. The resulting index is referred to as left atrial volume index (LAVI): L A V I = A L B S A {\displaystyle LAVI={\frac {{A}_{L}}{BSA}}} == Physiology == LAVI between 16 and 34 ml/m2 is regarded as normal. 2015 ASE guidelines. == Pathophysiologiy and clinical implications == Enlargement of the left atrium is a form of cardiomegaly. Moderately increased LAVI (63 to 73 mL/m2) is associated with slightly elevated mortality hazard and severely increased LAVI (>73 mL/m2) with significantly higher hazard ratio of mortality. LAVI predicts survival after acute myocardial infarction, postoperative atrial fibrillation in subjects undergoing heart surgery, atrial fibrillation and stroke as well as hospital admission in ambulatory patients. == References ==	Wikipedia/Left_atrial_volume
A cardiac function curve is a graph showing the relationship between right atrial pressure (x-axis) and cardiac output (y-axis). Superimposition of the cardiac function curve and venous return curve is used in one hemodynamic model. == Shape of curve == It shows a steep relationship at relatively low filling pressures and a plateau, where further stretch is not possible and so increases in pressure have little effect on output. The pressures where there is a steep relationship lie within the normal range of right atrial pressure (RAP) found in the healthy human during life. This range is about -1 to +2 mmHg. The higher pressures normally occur only in disease, in conditions such as heart failure, where the heart is unable to pump forward all the blood returning to it and so the pressure builds up in the right atrium and the great veins. Swollen neck veins are often an indicator of this type of heart failure. At low right atrial pressures this graph serves as a graphic demonstration of the Frank–Starling mechanism, that is as more blood is returned to the heart, more blood is pumped from it without extrinsic signals. == Changes in the cardiac function curve == In vivo however, extrinsic factors such as an increase in activity of the sympathetic nerves, and a decrease in vagal tone cause the heart to beat more frequently and more forcefully. This alters the cardiac function curve, shifting it upwards. This allows the heart to cope with the required cardiac output at a relatively low right atrial pressure. We get what is known as a family of cardiac function curves, as the heart rate increases before the plateau is reached, and without the RAP having to rise dramatically to stretch the heart more and get the Starling effect. In vivo sympathetic outflow within the myocardium is probably best described by the time honored description of the sinoatrial tree branching out to Purkinges fibers. Parasympathetic inflow within the myocardium is probably best described by influence of the vagus nerve and spinal accessory ganglia. == See also == Right atrial pressure Central venous pressure == References ==	Wikipedia/Cardiac_function_curve
In cardiology, the P wave on an electrocardiogram (ECG) represents atrial depolarization, which results in atrial contraction, or atrial systole. == Physiology == The P wave is a summation wave generated by the depolarization front as it transits the atria. Normally the right atrium depolarizes slightly earlier than left atrium since the depolarization wave originates in the sinoatrial node, in the high right atrium and then travels to and through the left atrium. The depolarization front is carried through the atria along semi-specialized conduction pathways including Bachmann's bundle resulting in uniform shaped waves. Depolarization originating elsewhere in the atria (atrial ectopics) result in P waves with a different morphology from normal. == Pathology == Peaked P waves (> 0.25 mV) suggest right atrial enlargement, cor pulmonale, (P pulmonale rhythm), but have a low predictive value (~20%). A P wave with increased amplitude can indicate hypokalemia. It can also indicate right atrial enlargement. A P wave with decreased amplitude can indicate hyperkalemia. Bifid P waves (known as P mitrale) indicate left-atrial abnormality - e.g. dilatation or hypertrophy. If at least three different shaped P waves can be seen in a given ECG lead tracing, this implies that even if one of them arises from the SA node, at least two others are arising elsewhere. This is taken as evidence of multiple (i.e. at least two) ectopic foci, and is called multifocal (or more correctly, multiform) atrial rhythm if the rate is ≤100) or multifocal atrial tachycardia if the rate is over 100. This appears particularly commonly in exacerbations of chronic obstructive lung disease. If the baseline has a totally irregular form, this suggests fibrillatory waves of atrial fibrillation or possibly artefact; a saw tooth shaped baseline suggests the flutter waves of atrial flutter. With either of these rhythms, if the ventricular rate is fast, the fibrillatory or flutter waves can easily be misinterpreted as P waves. Absence of the P wave with a flat baseline may indicate: Fine atrial fibrillation Sinoatrial arrest (with a secondary escape rhythm) If P waves are not clearly delineated in the surface ECG, a Lewis lead may be used to better visualize P waves. == Atrial repolarization == This occurs a mean of 320 ms after the end of the P wave, with a duration of 2-3 times that of the P wave and a polarity always opposite to that of the P wave. It is represented on the surface ECG by a so-called Ta wave. The clinical relevance of this is that, although a normal phenomenon, the nadir of the Ta wave can occur just after the QRS complex and cause ST depression similar to (and easily mistaken with) that occurring with disease states such as cardiac ischaemia. == Related pages == Electrocardiography PR interval QRS complex QT interval ST segment T wave U wave == References ==	Wikipedia/P_wave_(electrocardiography)
The hemodynamics of the aorta is an ongoing field of research in which the goal is to identify what flow patterns and subsequent forces occur within the thoracic aorta. These patterns and forces are used to identify the presence and severity of cardiovascular diseases such as aortic aneurysm and atherosclerosis. Some of the methods used to study the hemodynamics of aortic flow are patient scans, computational fluid dynamics models, and particle tracking velocimetry (PTV). The information gathered through these studies can be used for surgery planning and the development of implants. Greater understanding of this topic reduces mortality rates associated with cardiovascular disease. == General flow patterns == The mean velocity in the aorta varies over the cardiac cycle. During systole the mean velocity rises to a peak, then it falls during diastole. This pattern is repeated with each squeezing pulse of the heart. The highest velocities are found at the exit of the valve during systole. At this stage the majority of the flow can be described with velocity vectors normal to the entrance, but in plane velocities tangent to the flow are present. As the path starts to curve in the ascending aorta, the blood towards the outside of the arch tends to rotate towards the inner wall, causing a helical pattern that is observed in most individuals. As the blood moves into the aortic arch, the area with the highest velocity tends to be on the inner wall. Helical flow within the ascending aorta and aortic arch help to reduce flow stagnation and increase oxygen transport. As the blood moves into the descending aorta, rotations in the flow are less present. Physiological abnormalities due to plague formation or aneurysm lead to helical flows and high velocity flows in locations where they would not normally be present or as prominent. The abnormal high velocity areas generate a higher amount of wall shear stress than normal and contribute to stenosis and further plaque formation. Abnormal helical structures expose tissue to low wall shear stresses that it would not normally experience. Simulations of these flow patterns seek to identify what normal wall shear stress conditions and helical flows are present at specific location within the aorta. == Effect of age and sex == When evaluating the significance of the hemodynamics of a patient their age and gender play a role. Each individual will have specific aortic geometries but trends can be identified when observed as a group. As age increases the aortic diameter tends to increase and the peak velocity of systolic flow tends to decrease until patients reach an age greater than 60 years old. Patients over the age of 60 tend to have an increase of peak systolic velocity. While both sexes experience the same pattern of velocity change with age, men tend to experience a wider range and higher peak velocity with age. == Effect of diabetes == Diabetes mellitus (diabetes) is a significant risk factor for cardiovascular diseases. The presence of diabetes affects the dynamic viscosity of blood and the compliance of the aortic walls. The dynamic viscosity of blood where diabetes is present is higher than that of healthy blood making it slightly less resistive to flow. The Young's modulus of the aortic walls where diabetes is present is higher than that of a healthy patient making it more stiff. When comparing CFD models of normal blood and wall properties with CFD models where the blood and wall properties to replicate that of an individual with diabetes, it is found that the models with diabetes have a lower mean velocity. It is also observed that the outlet velocity of the descending aorta is lower in the diabetes model. The blood pressure in the diabetes model is lower than that of the control model, but the mean pressures of the entire aorta are similar between both models. == Modeling of aortic flow == === CFD modeling of the aorta === CFD models allow for researchers to recreate flows happening within the aorta and evaluate factors that cannot be obtained through normal patient scans. These factors include wall shear stress and helicity. These factors are then used to evaluate the progression and severity of cardiovascular diseases. ==== Patient specific information ==== In order to replicate patient-specific geometries a CT scan or an MRI is taken. From this scan the inlet, various outlets, and walls can be digitally reconstructed to create the control volume. A common software used to construct the geometry and discretize the mesh is ANSYS. The inlet is identified as the cross section directly above the aortic valve. The outlets are identified as the brachiocephalic artery, left and right common carotid artery, subclavian artery, and the descending aorta. In order to replicate the flow velocities that occur in individual patients a PC-MRI is taken. The PC-MRI can be taken be 1D, 3D, or 4D. 1D PC-MRIs only capture the velocity in one direction, typically axially with the inlet. A 4D PC-MRI can capture the axial through plane velocity, as well as orthogonal in plane velocities. Although 4D PC-MRIs provide more accurate and useful information on the flow, 1D PC-MRIs are more commonly taken and used in CFD modeling of the aorta. Wall shear stress and helicity of the flow tend to be influenced by which type of velocity information is used in the model. ==== Boundary conditions ==== There are a variety of flows that have been modeled and studied as the inlet boundary condition. Some simplified flows include plug flow, parabolic flow, linear shear flow, and skewed cubic flow. 1D and 3D flows generated from patient scans can be used as more accurate inlet conditions. 1D flows include the patient-specific variation of velocity normal to inlet. 3D flows include patient-specific velocities in the inlet plane in addition to the velocities normal to the inlet. The more accurate inlet conditions are oftentimes not used because the high acquisition time and low spatial resolution of the PC-MRIs needed. In each patient-specific model there are multiple outlets. The most common outlet boundary conditions used are the two and three-element Windkessel models. The two-element Windkessel model replicates viscous resistance immediately downstream from the outlet and the three-element Windkessel model accounts for the resistance of capillaries and venous circulation. Comparing the results of the two outlet conditions there is no significant difference in wall shear stress. It has been found that the outlet boundary condition has an effect on less of the total flow than the inlet boundary condition. Because of this, the inlet boundary condition has been of higher focus in most CFD studies. ==== Limitations in modeling ==== Because there is no standard for setting inlet boundary condition in CFD models, they have to be verified with experimental results. Those results can be obtained either through in vivo measurements using 4D PC-MRIs. 4D PC-MRI's are also limited because the acquisition time is high, the spatial and temporal resolution is low, and the signal to noise ratio is also low. === Particle tracking velocimetry === Particle tracking velocimetry (PTV) allows for researchers to create an experimental setup to evaluate aortic flow patterns. ==== Methods ==== A CT scan or MRI is taken of a patient to obtain the geometry of the aorta. The information from that scan is then used to create a physical model made from a transparent silicone material. The material used can either be compliant, in order to replicate the dilation of the valve, or rigid. The working fluid within the model should have a refractive index to match that of the material used to create the model. Fluorescent tracers in the working fluid are illuminated by a laser in the volume of interest. A single high speed camera can be used to capture four separate images of the same illuminated volume using and image splitter and four mirrors. The pulsating flow of the aorta is replicated by a ventricular assist device (VAD). The VAD is driven by a pump with a waveform to replicate the systole and diastole of the flow. When the pump is running, the high speed camera collects images of the tracers within the volume under investigation. A 3D velocity profile of the volume under investigation can be created from the particle movement from frame to frame. Focusing on different control volumes within the model allow for the creation of velocity profiles at different locations within the aorta. ==== Application of results ==== PTV velocity information can be used in place of 4D PC-MRI information in a CFD model. The 3D velocity information from the inlet of the PTV model can be applied as the inlet boundary condition in a CFD model. That CFD model can then solve for wall shear stresses. The velocity information from PTV can also be used to create an MRI simulation. The MRI simulation can then be used to assess progression of cardiovascular diseases. == References ==	Wikipedia/Hemodynamics_of_the_aorta
Micrography (from Greek, literally small-writing – "Μικρογραφία"), also called microcalligraphy, is a Jewish form of calligrams developed in the 9th century, with parallels in Christianity and Islam, utilizing minute Hebrew letters to form representational, geometric and abstract designs. Colored micrography is especially distinctive because these rare artworks are customarily rendered in black and white. == Description == The artwork is created from text that forms an image when viewed at a distance, creating an interplay between the text and image. The photomosaic, whose tiny individual images form a mosaic when viewed from a distance, is a modern analogue. Another modern analogue is ASCII art, where ASCII or extended ASCII characters are arranged to form an image on a computer screen and/or printout. == Motivation == There is a relationship between this form of art, employing both digital and analogic symbols, and the restrictions on images found in the second commandment. Micrography provides a unique solution to the visual artist who wishes to remain devout in observation of Jewish law, by using only text, not images per se. As similar restrictions exist in certain Muslim societies, this solution has been adapted in Islamic calligraphy to the Arabic alphabet as well. == See also == Matthias Buchinger Los Angeles Pop Art == References == == External links == Micrography: Text Art and Typography Leila Avrin, Interlaces and Grotesques: the Art of Hebrew Micrography, Jewish Heritage Online Magazine A 13th Century Pentateuch British Library, BL Add. MS 21160 A German Pentateuch, c. 1300 British Library, BL Add. MS 15282 Jewish Theological Seminary exhibit on Micrography Judaic Treasures of the Library of Congress, from the Jewish Virtual Library Dalia-Ruth Halperin, Micrography - a Jewish art, British Library Hebrew manuscripts project. Accessed 2016-05-25.	Wikipedia/Micrography
Microphotographs are photographs shrunk to microscopic scale. Microphotography is the art of making such images. Applications of microphotography include espionage such as in the Hollow Nickel Case, where they are known as microfilm. Using the daguerreotype process, John Benjamin Dancer was one of the first to produce microphotographs, in 1839. He achieved a reduction ratio of 160:1. Dancer perfected his reduction procedures with Frederick Scott Archer's wet collodion process, developed in 1850–51, but he dismissed his decades-long work on microphotographs as a personal hobby, and did not document his procedures. The idea that microphotography could be no more than a novelty was an opinion shared by the 1858 Dictionary of Photography, which called the process "somewhat trifling and childish." Novelty viewing devices such as Stanhopes were once a popular way to carry and view microphotographs. == See also == Macro photography Microprinting == References ==	Wikipedia/Microphotograph
A macrograph or photomacrograph is an image taken at a scale that is visible to the naked eye, as opposed to a micrographic image, taken with a microscope. It is sometimes defined more precisely as an image at a scale of less than ten times magnification. == Materials science == This term is often applied to a three-dimensional image taken of a material using a low-power stereomicroscope. These images are used in materials science, particularly in the study of stress fractures in metals. This method can also be used to assay the fine structure of steel, in a standardized test called the Baumann method that creates a sulfur print showing the amount and distribution of sulfur inclusions through the metal structure. == References ==	Wikipedia/Macrograph
QT prolongation is a measure of delayed ventricular repolarisation, which means the heart muscle takes longer than normal to recharge between beats. It is an electrical disturbance which can be seen on an electrocardiogram (EKG). Excessive QT prolongation can trigger tachycardias such as torsades de pointes (TdP). QT prolongation is an established side effect of antiarrhythmics, but can also be caused by a wide range of non-cardiac medicines, including antibiotics, antidepressants, antihistamines, opioids, and complementary medicines. On an EKG, the QT interval represents the summation of action potentials in cardiac muscle cells, which can be caused by an increase in inward current through sodium or calcium channels, or a decrease in outward current through potassium channels. By binding to and inhibiting the “rapid” delayed rectifier potassium current protein, certain drugs are able to decrease the outward flow of potassium ions and extend the length of phase 3 myocardial repolarization, resulting in QT prolongation. == Background == A QT interval is a value that is measured on an electrocardiogram. Measurements begin from the start of the Q wave to the end of the T wave. The value is an indication of the time it takes for a ventricle from the beginning of a contraction to the end of relaxation. The value for a normal QT interval is similar in males and females from birth up to adolescence. During infancy, a normal QTc is defined as 400±20 milliseconds. Before puberty, the 99th percentile of QTc values is 460 milliseconds. After puberty, this value increases to 470 milliseconds in males and 480 milliseconds in females. Torsades de pointes (TdP) is an arrhythmia. More specifically, it is one form of a polymorphic ventricular tachycardia that presents with a long QT interval. Diagnosis is made by electrocardiogram (EKG), which shows rapid irregular QRS complexes. The term "torsades de pointes" is translated from French as "twisting of the peaks" because the complexes appear to undulate, or twist around, the EKG baseline. TdP can be acquired by inheritance of a congenital long QT syndrome, or more commonly from the ingestion of a pharmacologic drug. During TdP episodes, patients have a heart rate of 200 to 250 beats/minute, which may present as palpitations or syncope. TdP often self-resolves, however, it may lead to ventricular fibrillation and cause sudden cardiac death. == Risk factors == Although it is difficult to predict which individuals will be affected from drug-induced long QT syndrome, there are general risk factors that can be associated with the use of certain medications. Generally, as the dose of a drug increases, the risk of QT prolongation increases as well. In addition, factors such as rapid infusion, concurrent use of more than one drug known to prolong QT interval, diuretic treatment, electrolyte derangements (hypokalemia, hypomagnesemia, or hypocalcemia), advanced age, bradyarrhythmias, and female sex have all been shown to be risk factors for developing drug-induced QT prolongation. TdP has been shown to occur up to three times more often in female patients compared with males, likely as a result of post-pubertal hormonal influence on cardiac ion channels. The QTc interval is longer in females, as well as having a stronger response to IKr-blocking agents. In males, the presence of testosterone upregulates IKr channels and therefore decreases QT interval. Stated otherwise, estrogens prolong the QT interval, while androgens shorten it and decrease the response to IKr-blocking agents. Structural heart disease, such as heart failure, myocardial infarction, and left ventricular hypertrophy, are also risk factors. Diuretic-induced hypokalemia and/or hypomagnesemia taken for heart failure can induce proarrthymia. The ischemia that results from myocardial infarctions also induce QT prolongation. === Drugs that cause QT prolongation === The main groups of drugs that can cause QT prolongation are antiarrhythmic medications, psychiatric medications, and antibiotics. Other drugs include antivirals and antifungals. ==== Antiarrhythmic agents ==== Source: Class IA Class IA antiarrhythmic drugs work by blocking sodium and potassium channels. Blocking sodium channels tend to shorten the action potential duration, while blocking potassium channels prolongs the action potential. When the drug concentration is at a low to normal concentration, the potassium channel blocking activity takes precedence over the sodium channel blocking activity Disopyramide Procainamide Propafenone Quinidine Because of the predominance of the potassium blocking activity, TdP is seen more frequently with therapeutic levels of quinidine. Sodium blocking activity is dominant with subtherapeutic levels, which does not lead to QT prolongation and TdP. Class III Class III antiarrhythmic drugs are potassium channel blockers that cause QT prolongation and are associated with TdP. Amiodarone Amiodarone works in many ways. It blocks sodium, potassium, and calcium channels, as well as alpha and beta adrenergic receptors. Because of its multiple actions, amiodarone causes QT prolongation but TdP is rarely observed. Dofetilide Ibutilide Ibutilide differs from other class III antiarrhythmic agents in that it activates the slow, delayed inward sodium channels rather than inhibiting outward potassium channels. Sotalol Sotalol has beta-blocking activity. Approximately 2 to 7 percent of patients taking at least 320 mg/day experience proarrhythmia, most often in the form of TdP. The risks and effects are dose-dependent. ==== Psychiatric medications ==== Psychiatric medications include antipsychotics and antidepressants that have been shown to lengthen the QT interval and induce TdP, especially when given intravenously or in higher concentrations. Typical antipsychotics Chlorpromazine Haloperidol Haloperidol functions by blocking the KCNH2 channel, the same pathway that other drug-inducing LQTS block. Patients taking haloperidol are at a higher risk if they also have electrolyte abnormalities (such as hypokalemia and/or hypomagnesemia), congenital LQTS, cardiac abnormalities, hypothyroidism, or if they are concurrently taking other medications known to lengthen the QT interval. Sulpiride Thioridazine (especially high risk; withdrawn by the manufacturer for this precise reason) Atypical antipsychotics Amisulpride Quetiapine Overdoses on quetiapine cause QT prolongation in patients with cardiac risks. Risperidone Mild QT prolongation can be caused by risperidone but there are no specific drug warnings associated with this. Sertindole Ziprasidone SSRIs An EKG is recommended before patients are prescribed SSRI agents citalopram and escitalopram if the prescribed dose is above 40 mg or 20 mg per day, respectively. Fluoxetine Paroxetine Sertraline SNRIs Venlafaxine Tricyclic antidepressants Amitriptyline Desipramine Doxepin Imipramine ==== Antibiotics ==== Source: Macrolides Azithromycin Clarithromycin Erythromycin When taken independently, erythromycin has been shown to cause both QT prolongation and TdP. Erythromycin works inhibiting the CYP3A protein. Patients who have low CYP3A activity and are also concurrently taking other medications such as disopyramide, which can lead to QT prolongation and TdP. Fluoroquinolones Ciprofloxacin Levofloxacin Moxifloxacin ==== Other agents ==== Sources: Buprenorphine Chloroquine Cisapride Domperidone Famotidine Foscarnet Hydroxychloroquine Ibogaine Ketoconazole Methadone Octreotide Ondansetron Oxycodone Tramadol Tacrolimus Tamoxifen == Pathophysiology == IKr (hERG) blockade On EKG, the QT interval represents the summation of action potentials in cardiac muscle cells. QT prolongation therefore results from action potential prolongation, which can be caused by an increase in inward current through sodium or calcium channels, or a decrease in outward current through potassium channels. By binding to and inhibiting the “rapid” delayed rectifier potassium current protein, IKr, which is encoded by the hERG gene, certain drugs are able to decrease the outward flow of potassium ions and extend the length of phase 3 myocardial repolarization, which is reflected as QT prolongation. hERG trafficking inhibition A number of drugs that cause QT prolongation does not directly block hERG, but reduces the trafficking of the mature protein to the surface of the cell. This includes probucol, which appears to enhance the intercellular degradation of hERG; and several cardiac glycosides, which reduces trafficking due to decreased intracellular potassium. Some drugs such as ketoconazole both directly disrupt the Ikr channel and reduce its trafficking. Growth factors A number of antineoplastic drugs inhibit VEGF or PDGF signaling. As those growth factors are also important for the survival and renewal of cardiomyocytes, they exhibit toxicity to these cells. With some such agents, the result is QT prongation. == Diagnosis == Most patients with drug-induced QT prolongation are asymptomatic and are diagnosed solely by EKG in association with a history of using medications known to cause QT prolongation. A minority of patients are symptomatic and typically present with one or more signs of arrhythmia, such as lightheadedness, syncope, or palpitations. If the arrhythmia persists, patients may experience sudden cardiac arrest. == Management == Treatment requires identifying and removing any causative medications and correcting any underlying electrolyte abnormalities. While TdP often self-resolves, cardioversion may be indicated if patients become hemodynamically unstable, as evidenced by signs such as hypotension, altered mental status, chest pain, or heart failure. Intravenous magnesium sulfate has been proven to be highly effective for both the treatment and prevention of TdP. Managing patients with TdP is dependent on the patient's stability. Vital signs, level of consciousness, and current symptoms are used to assess stability. Patients who are stable should be managed by removing the underlying cause and correcting electrolyte abnormalities, especially hypokalemia. An EKG should be obtained, a cardiac monitor should be attached, IV access should be established, supplemental oxygen should be given, and blood samples should be sent for appropriate studies. Patients should be continually re-evaluated for signs of deterioration until the TdP resolves. In addition to correcting the electrolyte abnormalities, magnesium given intravenously has also been shown to be helpful. Magnesium sulfate given as a 2 g IV bolus mixed with D5W can be given over a period of 15 minutes in patients without cardiac arrest Atrial pacing or administering isoproterenol can normalize the heart rate. Unstable patients exhibit signs of chest pain, hypotension, elevated heart rate, and/or heart failure. Patients who develop cardiac arrest will be pulseless and unconscious. Defibrillation and resuscitation is indicated in these cases. Patients with cardiac arrest should be given IV magnesium sulfate over a period of two minutes.After diagnosing and treating the cause of LQTS, it is also important to perform a thorough history and EKG screening. Immediate family members should also be screened for inherited and congenital causes of drug-induced QT syndrome. == Incidence == Unfortunately, there is no absolute definition that describes the incidence of drug-induced QT prolongation, as most data is obtained from case reports or small observational studies. Although QT interval prolongation is one of the most common reasons for drug withdrawal from the market, the overall incidence of drug-induced QT prolongation is difficult to estimate. One study in France estimated that between 5-7% of reports of ventricular tachycardia, ventricular fibrillation, or sudden cardiac death were in fact due to drug-induced QT prolongation and torsades de pointes. An observational study from the Netherlands showed that 3.1% of patients who experienced sudden cardiac death were also using a QT-prolonging drug. == See also == Long QT syndrome Torsades de pointes == References == == Further reading ==	Wikipedia/Drug-induced_QT_prolongation
Electrocardiography in suspected myocardial infarction has the main purpose of detecting ischemia or acute coronary injury in emergency department populations coming for symptoms of myocardial infarction (MI). Also, it can distinguish clinically different types of myocardial infarction. == Technical issues == The standard 12 lead electrocardiogram (ECG) has several limitations. An ECG represents a brief sample in time. Because unstable ischemic syndromes have rapidly changing supply versus demand characteristics, a single ECG may not accurately represent the entire picture. It is therefore desirable to obtain serial 12 lead ECGs, particularly if the first ECG is obtained during a pain-free episode. Alternatively, many emergency departments and chest pain centers use computers capable of continuous ST segment monitoring. The standard 12 lead ECG also does not directly examine the right ventricle, and is relatively poor at examining the posterior basal and lateral walls of the left ventricle. In particular, acute myocardial infarction in the distribution of the circumflex artery is likely to produce a nondiagnostic ECG. The use of additional ECG leads like right-sided leads V3R and V4R and posterior leads V7, V8, and V9 may improve sensitivity for right ventricular and posterior myocardial infarction. In spite of these limitations, the 12 lead ECG stands at the center of risk stratification for the patient with suspected acute myocardial infarction. Mistakes in interpretation are relatively common, and the failure to identify high risk features has a negative effect on the quality of patient care. == Main patterns == The 12 lead ECG is used to classify MI patients into one of three groups: those with ST segment elevation or new bundle branch block (suspicious for acute injury and a possible candidate for acute reperfusion therapy with thrombolytics or primary PCI), those with ST segment depression or T wave inversion (suspicious for ischemia), and those with a so-called non-diagnostic or normal ECG. However, a normal ECG does not rule out acute myocardial infarction. === ST elevation MI === The 2018 European Society of Cardiology/American College of Cardiology Foundation/American Heart Association/World Health Federation Universal Definition of Myocardial Infarction for the ECG diagnosis of the ST segment elevation type of acute myocardial infarction require new ST elevation at J point of at least 1mm (0.1 mV) in two contiguous leads with the cut-points: ≥1 mm in all leads other than leads V2-V3. For leads V2-V3: ≥2 mm in men ≥40 years, ≥2.5 mm in men <40 years, or ≥1.5 mm in women regardless of age. This assumes usual calibration of 1mV/10mm. These elevations must be present in anatomically contiguous leads. (I, aVL, V5, V6 correspond to the lateral wall; V3-V4 correspond to the anterior wall ; V1-V2 correspond to the septal wall; II, III, aVF correspond to the inferior wall.) This criterion is problematic, however, as acute myocardial infarction is not the most common cause of ST segment elevation in chest pain patients. Over 90% of healthy men have at least 1 mm (0.1 mV) of ST segment elevation in at least one precordial lead. The clinician must therefore be well versed in recognizing the so-called ECG mimics of acute myocardial infarction, which include left ventricular hypertrophy, left bundle branch block, paced rhythm, early repolarization, pericarditis, hyperkalemia, and ventricular aneurysm. There are heavily researched clinical decision tools such as the TIMI Scores which help prognose and diagnose STEMI based on clinical data. For example, TIMI scores are frequently used to take advantage of EKG findings to prognose patients with MI symptoms. Based on symptoms and electrocardiographic findings, practitioners can differentiate between unstable angina, NSTEMI and STEMI, normally in the emergency room setting. Other calculators such as the GRACE and HEART scores, assess other major cardiac events using electrocardiogram findings, both predicting mortality rates for 6 months and 6 weeks, respectively. == Typical progression == Sometimes the earliest presentation of acute myocardial infarction is the hyperacute T wave, which is treated the same as ST segment elevation. In practice this is rarely seen, because it only exists for 2–30 minutes after the onset of infarction. Hyperacute T waves need to be distinguished from the peaked T waves associated with hyperkalemia. In the first few hours the ST segments usually begin to rise. Pathological Q waves may appear within hours or may take greater than 24 hr. The T wave will generally become inverted in the first 24 hours, as the ST elevation begins to resolve. Long term changes of ECG include persistent Q waves (in 90% of cases) and persistent inverted T waves. Persistent ST elevation is rare except in the presence of a ventricular aneurysm. == See also == Sgarbossa's criteria == References == == External links == TIMI Risk Score for UA/NSTEMI and STEMI Heart Risk Scores Print out by American Heart Association Archived 2015-09-20 at the Wayback Machine	Wikipedia/Electrocardiography_in_myocardial_infarction
Multifocal (or multiform) atrial tachycardia (MAT) is an abnormal heart rhythm, specifically a type of supraventricular tachycardia, that is particularly common in older people and is associated with exacerbations of chronic obstructive pulmonary disease (COPD). Normally, the heart rate is controlled by a cluster of pacemaker cells called the sinoatrial node (SA node). When different clusters of cells known as ectopic pacemakers, that are outside the SA node take over control of the heart rate, and the rate exceeds 100 beats per minute, this is called multifocal atrial tachycardia. A fast heart rate below 100, is technically not a tachycardia and is then termed multifocal atrial rhythm, also known as wandering atrial tachycardia. "Multiform" refers to the observation of variable P wave shapes, while "multifocal" refers to the underlying cause. Although these terms are used interchangeably, some sources prefer "multiform" since it does not presume any underlying mechanism. == Causes == MAT usually arises because of an underlying medical condition. Its prevalence has been estimated at 3 per 1000 in adult hospital inpatients and is much rarer in paediatric practice; it is more common in the elderly, and its management and prognosis are both those of the underlying diagnosis. It is mostly common in patients with lung disorders, but it can occur after acute myocardial infarction and can also occur in the setting of low blood potassium or low blood magnesium. It is sometimes associated with digitalis toxicity in patients with heart disease. It is most commonly associated with hypoxia and COPD. Additionally, it can be caused by theophylline toxicity, a drug with a narrow therapeutic index commonly used to treat COPD. Theophylline can cause a number of different abnormal heart rhythms when in excess, and thus further predisposes COPD patients to MAT. Theophylline toxicity often occurs following acute or chronic overtreatment or factors lowering its clearance from the body. == Pathophysiology == The P-waves and P–R intervals are variable due to a phenomenon called wandering atrial pacemaker (WAP). The electrical impulse is generated at a different focus within the atria of the heart each time. WAP is positive once the heart generates at least three different P-wave formations from the same ECG lead. Then, if the heart rate exceeds 100 beats per minute, the phenomenon is called multifocal atrial tachycardia. == Diagnosis == Multifocal atrial tachycardia is characterized by an electrocardiogram (ECG) strip with three or more discrete P wave morphologies in the same lead, not including that originating from the sinoatrial node, plus tachycardia, which is a heart rate exceeding 100 beats per minute (although some suggest using a threshold of 90 beats per minute). Furthermore, there should be irregular PP intervals, and the baseline should be isoelectric between P waves. Other findings that are commonly seen, but are not diagnostic include irregular PR and RR intervals. Variation in PR intervals has not been included in the diagnostic criteria because the PR interval varies with the length of the preceding RP interval. Other diagnoses that may present with similar findings on electrocardiogram that should be included in the differential diagnosis include sinus tachycardia with frequent premature atrial contractions (this would have regular PP intervals), atrial flutter with variable AV node conduction (this would have regular PP intervals and flutter waves), atrial fibrillation (this would not have discrete P-wave morphologies), and wandering atrial pacemaker which would have a heart rate less than 100 beats per minute). === Additional workup === If arrhythmia persists despite the treatment of underlying medical conditions it may be worth checking a complete blood count and serum chemistry for signs of infection, anemia, or electrolyte abnormalities such as hypokalemia and hypomagnesemia. == Treatment == Management of multifocal atrial tachycardia consists mainly of the treatment of the underlying cause. If treatment is indicated, therapy should begin with first correcting underlying electrolyte abnormalities with the repletion of potassium to maintain greater than 4 mEq/L and magnesium greater than 2 mEq/L. Studies have shown magnesium suppresses ectopic atrial activity and can be beneficial even if magnesium levels are within the normal range. Once electrolyte abnormalities have been corrected, possible treatment options include non-dihydropyridine calcium channel blockers, beta-blockers, and atrioventricular (AV) node ablation. Studies have found no role for antiarrhythmic agents, cardioversion, or anticoagulation. In the absence of underlying pulmonary disease, the first-line agent is beta-blockers. A beta-blockers act to suppress ectopic foci by reducing sympathetic stimulation and decreasing conduction through the atrioventricular node, thereby slowing the ventricular response. Studies have found an average decrease in heart rate of 51 beats per minute and 79% of patients reverted to sinus rhythm. Most patients did not need beta-blocker therapy long term as studies found long-term therapy was needed in only 25% of patients. Caution should be used in patients with an underlying pulmonary disease such as COPD and patients with decompensated heart failure due to the increased risk for bronchospasms and decreased cardiac output. Furthermore, beta-blockers should be avoided in patients with atrioventricular blocks unless a pacemaker has been implanted. In the presence of underlying pulmonary disease, the first-line agent is a non-dihydropyridine calcium channel blocker such as verapamil or diltiazem. These agents act to suppress atrial rate and decrease conduction through the atrioventricular node, thereby slowing the ventricular rate. Studies have found an average reduction in the ventricular rate of 31 beats per minute and 43% of patients reverted to sinus rhythm. Caution should be used in patients with preexisting heart failure or hypotension due to negative inotropic effects and peripheral vasodilation. Similarly, calcium channel blockers should also be avoided in patients with atrioventricular blocks unless a pacemaker has been implanted. In select cases of refractory multifocal atrial tachycardia, AV node ablation has been performed. Studies have found an average reduction in the ventricular rate of 56 beats per minute with adequate control of ventricular response in 84% of patients. However, AV node ablation creates a complete heart block and requires the placement of a permanent pacemaker. Administration of oxygen may play a role in the treatment of some patients. == References == == External links ==	Wikipedia/Multifocal_atrial_tachycardia
Atrial tachycardia is a type of heart rhythm problem in which the heart's electrical impulse comes from an ectopic pacemaker (that is, an abnormally located cardiac pacemaker) in the upper chambers (atria) of the heart, rather than from the sinoatrial node, the normal origin of the heart's electrical activity. As with any other form of tachycardia (rapid heart beat), the underlying mechanism can be either the rapid discharge of an abnormal focus, the presence of a ring of cardiac tissue that gives rise to a circle movement (reentry), or a triggered rapid rhythm due to other pathological circumstances (as would be the case with some drug toxicities, such as digoxin toxicity). == Classification == Forms of atrial tachycardia (ATach) include multifocal atrial tachycardia (MAT), focal atrial tachycardia and atrial flutter. Paroxysmal atrial tachycardia (PAT) is an episode of arrhythmia that begins and ends abruptly. == Etiology == Atrial tachycardia tends to occur in individuals with structural heart disease, with or without heart failure, and ischemic coronary artery disease. However, focal atrial tachycardia often occurs in healthy individuals without structural heart disease. Other possible etiologies are listed below: Hypoxia Pulmonary disease Ischemic heart disease Stimulants: cocaine, caffeine, chocolate, ephedra Alcohol Metabolic disturbances Digoxin toxicity Heightened sympathetic tone A study noted 10 to 15% of patients presenting for supraventricular tachycardia (SVT) ablation had atrial tachycardia. == Diagnosis == Electrocardiographic features include: Atrial rate: 100 to 250 BPM Ventricular conduction can be variable Irregular or irregularly irregular in the setting of variable AV block Regular if 1 to 1, 2 to 1, or 4 to 1 AV block P wave morphology Unifocal, but similar in morphology to each other Might be inverted Differs from normal sinus P wave May exhibit either long RP or short PR intervals Rhythm may be paroxysmal or sustained May demonstrate an increase in the rate at initiation (e.g., "warm up," or "rev up") May demonstrate a decrease in the rate at termination (e.g., "cool down") == Treatment == Initial management of focal atrial tachycardia should focus on addressing underlying causes: treating acute illness, cessation of stimulants, stress reduction, appropriately managing digoxin toxicity, or chronic disease management. The ventricular rate is controllable with the use of beta blockers or calcium channel blockers. If atrial tachyarrhythmia persists and the patient is symptomatic, the patient may benefit from class IA, IC, or class III antiarrhythmics. Catheter ablation of focal atrial tachycardia may be appropriate in patients failing medical therapy. == Epidemiology == A European study of young males applying for pilot licenses demonstrated that 0.34% had asymptomatic atrial tachycardia and 0.46% had symptomatic atrial tachycardia. == References == == External links ==	Wikipedia/Atrial_tachycardia
Electropalatography (EPG) is a technique used to monitor contacts between the tongue and hard palate, particularly during articulation and speech. A custom-made artificial palate is moulded to fit against a speaker's hard palate. The artificial palate contains electrodes exposed to the lingual surface. When contact occurs between the tongue surface and any of the electrodes, particularly between the lateral margins of the tongue and the borders of the hard palate, electronic signals are sent to an external processing unit. EPG provides dynamic real-time visual feedback of the location and timing of tongue contacts with the hard palate. The details of tongue activity during speech are recorded, providing direct articulatory information that a person can use in therapy to monitor and improve their articulation patterns. Visual feedback is very important in the success of treating deaf children. == History == Electropalatography was originally conceptualized and developed as a tool for phonetics research to improve upon traditional palatography methods. Both military and academic language researchers used early electropalatography tools to obtain accurate information regarding tongue-to-palate contact in a number of foreign languages. Early EPG devices used direct current electricity to power the sensors, which were activated by moisture sensors on mouthpieces. Mouthpieces (electropalates) originally closely resembled modern dental impression plates. Mouthpieces became more customized over time, which allowed for more accurate research. Fig. 1 shows a typical electropalate from the Reading system. EPG added significant insight into academic understanding of articulatory phonetics. In the 1960s and 1970s a number of independent individuals and companies recognized EPG's potential for pedagogical and therapeutic applications. Despite the multiple attempts to reverse engineer EPG tools for speech therapy, most companies failed to commercialize EPG effectively. EPG tools remain fairly expensive tools for speech therapy and phonetics research, though the information they provide are difficult to obtain using other methods of visual feedback of articulation. == In phonetic research == Although much of the development of EPG has been dedicated to clinical applications, it has been used in a number of laboratory phonetic investigations. Stone (1997) lists three main areas of research: study of the physiology of consonant articulations involving lingual-palatal contact study of the size and shape of oral constrictions in the production of fricative consonants the effect of neighbouring vowels on consonants production (coarticulation) When electropalatography is used for speech research, the data from tongue-palate contact is sampled by the controlling computer at up to 100 frames per second. In the early days (when digital displays were less ubiquitous and more limited), the data was printed out on paper for analysis. An example of the printout can be seen in Fig.2, where the sequence runs from top to bottom, and where the 'O' symbol indicates contact and '.' indicates no contact. The utterance shown is 'catkin' /kæt.kɪn/; the sample numbered 344 shows when the /t/ closure is complete, and at frame 350 there is a complete velar closure. The alveolar closure is released at 351. The articulatory overlap (which is inaudible) is thus clearly shown. Individual frames of EPG contact data may be used to illustrate descriptions of consonant articulations, and this is done by Cruttenden for all the English (RP) consonants. In some research, multiple repetitions may be summed to produce graphical representations of tongue-palate contact in a way that minimizes effects of random variation on single tokens. This was done by Farnetani in studies of Italian and French coarticulation. == Providers == Three primary manufacturers of EPG tools exist: CompleteSpeech in the United States, Articulate Instruments, and icSpeech in Great Britain. Completespeech is a private company that specializes in speech therapy oriented EPG tools, branded as The SmartPalate System. The SmartPalate System uses a standard size sensor sheet with 126 sensors that is fitted to individual mouthpiece molds. Articulate Instruments provides both speech therapy and research oriented EPG mouthpieces, branded as The Reading Palate and The Articulate Palate. Articulate Instrument EPG sensors are places by hand for individual users' mouthpieces. The icSpeech, branded as LinguaGraph, also uses the Reading Palate. == In therapy == Electropalatography has been studied in a variety of populations, including children with cleft palate, children with Down syndrome, children who are deaf, children with cochlear implants, children with cerebral palsy and adults with Parkinson's disease. Therapy has proved to be successful in tested populations. Longitudinal studies with large sample sizes are needed to determine the long-term success of therapy. == References ==	Wikipedia/Electropalatography
The QT interval is a measurement made on an electrocardiogram used to assess some of the electrical properties of the heart. It is calculated as the time from the start of the Q wave to the end of the T wave, and approximates to the time taken from when the cardiac ventricles start to contract to when they finish relaxing. An abnormally long or abnormally short QT interval is associated with an increased risk of developing abnormal heart rhythms and sudden cardiac death. Abnormalities in the QT interval can be caused by genetic conditions such as long QT syndrome, by certain medications such as fluconazole, sotalol or pitolisant, by disturbances in the concentrations of certain salts within the blood such as hypokalaemia, or by hormonal imbalances such as hypothyroidism. == Measurement == The QT interval is most commonly measured in lead II for evaluation of serial ECGs, with leads I and V5 being comparable alternatives to lead II. Leads III, aVL and V1 are generally avoided for measurement of QT interval. The accurate measurement of the QT interval is subjective because the end of the T wave is not always clearly defined and usually merges gradually with the baseline. QT interval in an ECG complex can be measured manually by different methods, such as the threshold method, in which the end of the T wave is determined by the point at which the component of the T wave merges with the isoelectric baseline, or the tangent method, in which the end of the T wave is determined by the intersection of a tangent line extrapolated from the T wave at the point of maximum downslope to the isoelectric baseline. With the increased availability of digital ECGs with simultaneous 12-channel recording, QT measurement may also be done by the 'superimposed median beat' method. In the superimposed median beat method, a median ECG complex is constructed for each of the 12 leads. The 12 median beats are superimposed on each other and the QT interval is measured either from the earliest onset of the Q wave to the latest offset of the T wave or from the point of maximum convergence for the Q wave onset to the T wave offset. == Correction for heart rate == The QT interval changes in response to the heart rate - as heart rate increase the QT interval shortens. These changes make it harder to compare QT intervals measured at different heart rates. To account for this, and thereby improve the reliability of QT measurement, the QT interval can be corrected for heart rate (QTc) using a variety of mathematical formulae, a process often performed automatically by modern ECG recorders. === Bazett's formula === The most commonly used QT correction formula is the Bazett's formula, named after physiologist Henry Cuthbert Bazett (1885–1950), calculating the heart rate-corrected QT interval (QTcB). Bazett's formula is based on observations from a study in 1920. Bazett's formula is often given in a form that returns QTc in dimensionally suspect units, square root of seconds. The dimensionally correct form of Bazett's formula is: Q T c B = Q T R R 1 s {\displaystyle QTc_{B}={QT \over {\sqrt {RR \over 1{\text{ s}}}}}} where QTcB is the QT interval corrected for heart rate, and RR is the interval from the onset of one QRS complex to the onset of the next QRS complex. This dimensionally correct formula returns the QTc in the same units as QT, generally milliseconds. In some popular forms of this formula, it is assumed that QT is measured in milliseconds and that RR is measured in seconds, often derived from the heart rate (HR) as 60/HR. Therefore, the result will be given in seconds per square root of milliseconds. However, reporting QTc using this formula creates a "requirement regarding the units in which the original QT and RR are measured." In either form, Bazett's non-linear QT correction formula is generally not considered accurate, as it over-corrects at high heart rates and under-corrects at low heart rates. Bazett's correction formula is one of the most suitable QT correction formulae for neonates. === Fridericia's formula === Fridericia had proposed an alternative correction formula (QTcF) using the cube-root of RR. Q T c F = Q T R R 1 s 3 {\displaystyle QTc_{F}={QT \over {\sqrt[{3}]{RR \over 1{\text{ s}}}}}} === Sagie's formula === The Framingham correction, also called as Sagie's formula based on the Framingham Heart Study, which used long-term cohort data of over 5,000 subjects, is considered a better method. Q T l c = 1000 ( Q T 1000 + 0.154 ( 1 − R R ) ) {\displaystyle QTlc=1000\left({\frac {QT}{1000}}+0.154(1-RR)\right)} Again, here QT and QTlc are in milliseconds and RR is measured in seconds. === Comparison of corrections === A retrospective study suggests that Fridericia's method and the Framingham method may produce results most useful for stratifying the 30-day and 1-year risks of mortality. Definitions of normal QTc vary from being equal to or less than 0.40 s (≤ 400 ms), 0.41 s (≤ 410 ms), 0.42 s (≤ 420 ms) or 0.44 s (≤ 440 ms). For risk of sudden cardiac death, "borderline QTc" in males is 431–450 ms; and, in females, 451–470 ms. An "abnormal" QTc in males is a QTc above 450 ms; and, in females, above 470 ms. If there is not a very high or low heart rate, the upper limits of QT can roughly be estimated by taking QT = QTc at a heart rate of 60 beats per minute (bpm), and subtracting 0.02 s from QT for every 10 bpm increase in heart rate. For example, taking normal QTc ≤ 0.42 s, QT would be expected to be 0.42 s or less at a heart rate of 60 bpm. For a heart rate of 70 bpm, QT would roughly be expected to be equal to or below 0.40 s. Likewise, for 80 bpm, QT would roughly be expected to be equal to or below 0.38 s. == Abnormal intervals == Prolonged QTc causes premature action potentials during the late phases of depolarization. This increases the risk of developing ventricular arrhythmias, including fatal ventricular fibrillation. Higher rates of prolonged QTc are seen in females, older patients, high systolic blood pressure or heart rate, and short stature. Prolonged QTc is also associated with ECG findings called Torsades de Pointes, which are known to degenerate into ventricular fibrillation, associated with higher mortality rates. There are many causes of prolonged QT intervals, acquired causes being more common than genetic. === Genetic causes === An abnormally prolonged QT interval could be due to long QT syndrome, whereas an abnormally shortened QT interval could be due to short QT syndrome. The QTc length is associated with variations in the NOS1AP gene. The autosomal recessive syndrome of Jervell and Lange-Nielsen is characterized by a prolonged QTc interval in conjunction with sensorineural hearing loss. === Due to adverse drug reactions === Prolongation of the QT interval may be due to an adverse drug reaction. Antipsychotics (especially first generation/"typical") haloperidol thioridazine mesoridazine chlorpromazine sertindole DMARDs and antimalarial drugs hydroxychloroquine chloroquine quinine Antibiotics macrolides fluoroquinolones Other drugs methadone vemurafenib pitolisant fluconazole Some second-generation antihistamines, such as astemizole, have this effect. The mechanism of action of certain antiarrhythmic drugs, like amiodarone or sotalol, involve intentional pharmacological QT prolongation. In addition, high blood alcohol concentrations prolong the QT interval. A possible interaction between selective serotonin reuptake inhibitors and thiazide diuretics is associated with QT prolongation. === Due to pathological conditions === Hypothyroidism, a condition of low function of the thyroid gland, can cause QT prolongation at the electrocardiogram. Acute hypocalcemia causes prolongation of the QT interval, which may lead to ventricular dysrhythmias. A shortened QT can be associated with hypercalcemia. === Use in drug approval studies === Since 2005, the FDA and European regulators have required that nearly all new molecular entities be evaluated in a Thorough QT (TQT) or similar study to determine a drug's effect on the QT interval. The TQT study serves to assess the potential arrhythmia liability of a drug. Traditionally, the QT interval had been evaluated by having an individual human reader measure approximately nine cardiac beats per clinical timepoint. However, a substantial portion of drug approvals after 2010 have incorporated a partially automated approach, blending automated software algorithms with expert human readers reviewing a portion of the cardiac beats, to enable the assessment of significantly more beats in order to improve precision and reduce cost. In 2014, an industrywide consortium consisting of the FDA, iCardiac Technologies and other organizations released the results of a seminal study indicating how waivers from TQT studies can be obtained by the assessment of early phase data. As the pharmaceutical industry has gained experience in performing TQT studies, it has also become evident that traditional QT correction formulas such as QTcF, QTcB, and QTcLC may not always be suitable for evaluation of drugs impacting autonomic tone. === As a predictor of mortality === Electrocardiography is a safe and noninvasive tool that can be used to identify those with a higher risk of mortality. In the general population, there has been no consistent evidence that prolonged QTc interval in isolation is associated with an increase in mortality from cardiovascular disease. However, several studies have examined prolonged QT interval as a predictor of mortality for diseased subsets of the population. === Rheumatoid arthritis === Rheumatoid arthritis is the most common inflammatory arthritis. Studies have linked rheumatoid arthritis with increased death from cardiovascular disease. In a 2014 study, Panoulas et al. found a 50 ms increase in QTc interval increased the odds of all-cause mortality by 2.17 in patients with rheumatoid arthritis. Patients with the highest QTc interval (> 424 ms) had higher mortality than those with a lower QTc interval. The association was lost when calculations were adjusted for C-reactive protein levels. The researchers proposed that inflammation prolonged the QTc interval and created arrhythmias that were associated with higher mortality rates. However, the mechanism by which C-reactive protein is associated with the QTc interval is still not understood. === Type 1 diabetes === Compared to the general population, type 1 diabetes may increase the risk of mortality, due largely to an increased risk of cardiovascular disease. Almost half of patients with type 1 diabetes have a prolonged QTc interval (> 440 ms). Diabetes with a prolonged QTc interval was associated with a 29% mortality over 10 years in comparison to 19% with a normal QTc interval. Anti-hypertensive drugs increased the QTc interval, but were not an independent predictor of mortality. === Type 2 diabetes === QT interval dispersion (QTd) is the maximum QT interval minus the minimum QT interval, and is linked with ventricular repolarization. A QTd over 80 ms is considered abnormally prolonged. Increased QTd is associated with mortality in type 2 diabetes. QTd is a better predictor of cardiovascular death than QTc, which was unassociated with mortality in type 2 diabetes. QTd higher than 80 ms had a relative risk of 1.26 of dying from cardiovascular disease compared to a normal QTd. == See also == Electrocardiogram Long QT syndrome Short QT syndrome QT interval variability Drug-induced QT prolongation == References == == External links == Cardiac safety section in the Biopharmaceutical network Corrected QT interval calculation Comprehensive QTc Calculator with 5 formulas at TheCalculator.co	Wikipedia/Correction_for_heart_rate
The Hilbert–Huang transform (HHT) is a way to decompose a signal into so-called intrinsic mode functions (IMF) along with a trend, and obtain instantaneous frequency data. It is designed to work well for data that is nonstationary and nonlinear. The Hilbert–Huang transform (HHT), a NASA designated name, was proposed by Norden E. Huang. It is the result of the empirical mode decomposition (EMD) and the Hilbert spectral analysis (HSA). The HHT uses the EMD method to decompose a signal into so-called intrinsic mode functions (IMF) with a trend, and applies the HSA method to the IMFs to obtain instantaneous frequency data. Since the signal is decomposed in time domain and the length of the IMFs is the same as the original signal, HHT preserves the characteristics of the varying frequency. This is an important advantage of HHT since a real-world signal usually has multiple causes happening in different time intervals. The HHT provides a new method of analyzing nonstationary and nonlinear time series data. == Definition == === Empirical mode decomposition === The fundamental part of the HHT is the empirical mode decomposition (EMD) method. Breaking down signals into various components, EMD can be compared with other analysis methods such as Fourier transform and Wavelet transform. Using the EMD method, any complicated data set can be decomposed into a finite and often small number of components. These components form a complete and nearly orthogonal basis for the original signal. In addition, they can be described as intrinsic mode functions (IMF). Because the first IMF usually carries the most oscillating (high-frequency) components, it can be rejected to remove high-frequency components (e.g., random noise). EMD based smoothing algorithms have been widely used in seismic data processing, where high-quality seismic records are highly demanded. Without leaving the time domain, EMD is adaptive and highly efficient. Since the decomposition is based on the local characteristic time scale of the data, it can be applied to nonlinear and nonstationary processes. === Intrinsic mode functions === An intrinsic mode function (IMF) is defined as a function that satisfies the following requirements: In the whole data set, the number of extrema and the number of zero-crossings must either be equal or differ at most by one. At any point, the mean value of the envelope defined by the local maxima and the envelope defined by the local minima is zero. It represents a generally simple oscillatory mode as a counterpart to the simple harmonic function. By definition, an IMF is any function with the same number of extrema and zero crossings, whose envelopes are symmetric with respect to zero. This definition guarantees a well-behaved Hilbert transform of the IMF. === Hilbert spectral analysis === Hilbert spectral analysis (HSA) is a method for examining each IMF's instantaneous frequency as functions of time. The final result is a frequency-time distribution of signal amplitude (or energy), designated as the Hilbert spectrum, which permits the identification of localized features. == Techniques == The Intrinsic Mode Function (IMF) amplitude and frequency can vary with time and it must satisfy the rule below: The number of extremes(local maximums & local minimums) and the number of zero-crossings must either equal or differ at most by one. At any point, the mean value of the envelope defined by the local maxima and the envelope defined by the local minima is near zero. === Empirical mode decomposition === The empirical mode decomposition (EMD) method is a necessary step to reduce any given data into a collection of intrinsic mode functions (IMF) to which the Hilbert spectral analysis can be applied. IMF represents a simple oscillatory mode as a counterpart to the simple harmonic function, but it is much more general: instead of constant amplitude and frequency in a simple harmonic component, an IMF can have variable amplitude and frequency along the time axis. The procedure of extracting an IMF is called sifting. The sifting process is as follows: Identify all the local extrema in the test data. Connect all the local maxima by a cubic spline line as the upper envelope. Repeat the procedure for the local minima to produce the lower envelope. The upper and lower envelopes should cover all the data between them. Their mean is m1. The difference between the data and m1 is the first component h1: X ( t ) − m 1 = h 1 . {\displaystyle X(t)-m_{1}=h_{1}.\,} Ideally, h1 should satisfy the definition of an IMF, since the construction of h1 described above should have made it symmetric and having all maxima positive and all minima negative. After the first round of sifting, a crest may become a local maximum. New extrema generated in this way actually reveal the proper modes lost in the initial examination. In the subsequent sifting process, h1 can only be treated as a proto-IMF. In the next step, h1 is treated as data: h 1 − m 11 = h 11 . {\displaystyle h_{1}-m_{11}=h_{11}.\,} After repeated sifting up to k times, h1 becomes an IMF, that is h 1 ( k − 1 ) − m 1 k = h 1 k . {\displaystyle h_{1(k-1)}-m_{1k}=h_{1k}.\,} Then, h1k is designated as the first IMF component of the data: c 1 = h 1 k . {\displaystyle c_{1}=h_{1k}.\,} === Stoppage criteria of the sifting process === The stoppage criterion determines the number of sifting steps to produce an IMF. Following are the four existing stoppage criterion: ==== Standard deviation ==== This criterion is proposed by Huang et al. (1998). It is similar to the Cauchy convergence test, and we define a sum of the difference, SD, as S D k = ∑ t = 0 T \| h k − 1 ( t ) − h k ( t ) \| 2 h k − 1 2 ( t ) . {\displaystyle SD_{k}=\sum _{t=0}^{T}{\frac {\|h_{k-1}(t)-h_{k}(t)\|^{2}}{h_{k-1}^{2}(t)}}.\,} Then the sifting process stops when SD is smaller than a pre-given value. ==== S Number criterion ==== This criterion is based on the so-called S-number, which is defined as the number of consecutive siftings for which the number of zero-crossings and extrema are equal or at most differing by one. Specifically, an S-number is pre-selected. The sifting process will stop only if, for S consecutive siftings, the numbers of zero-crossings and extrema stay the same, and are equal or at most differ by one. ==== Threshold method ==== Proposed by Rilling, Flandrin and Gonçalvés, threshold method set two threshold values to guaranteeing globally small fluctuations in the meanwhile taking in account locally large excursions. ==== Energy difference tracking ==== Proposed by Cheng, Yu and Yang, energy different tracking method utilized the assumption that the original signal is a composition of orthogonal signals, and calculate the energy based on the assumption. If the result of EMD is not an orthogonal basis of the original signal, the amount of energy will be different from the original energy. Once a stoppage criterion is selected, the first IMF, c1, can be obtained. Overall, c1 should contain the finest scale or the shortest period component of the signal. We can, then, separate c1 from the rest of the data by X ( t ) − c 1 = r 1 . {\displaystyle X(t)-c_{1}=r_{1}.\,} Since the residue, r1, still contains longer period variations in the data, it is treated as the new data and subjected to the same sifting process as described above. This procedure can be repeated for all the subsequent rj's, and the result is r n − 1 − c n = r n . {\displaystyle r_{n-1}-c_{n}=r_{n}.\,} The sifting process finally stops when the residue, rn, becomes a monotonic function from which no more IMF can be extracted. From the above equations, we can induce that X ( t ) = ∑ j = 1 n c j + r n . {\displaystyle X(t)=\sum _{j=1}^{n}c_{j}+r_{n}.\,} Thus, a decomposition of the data into n-empirical modes is achieved. The components of the EMD are usually physically meaningful, for the characteristic scales are defined by the physical data. Flandrin et al. (2003) and Wu and Huang (2004) have shown that the EMD is equivalent to a dyadic filter bank. === Hilbert spectral analysis === Having obtained the intrinsic mode function components, the instantaneous frequency can be computed using the Hilbert transform. After performing the Hilbert transform on each IMF component, the original data can be expressed as the real part, Real, in the following form: X ( t ) = Real ∑ j = 1 n a j ( t ) e i ∫ ω j ( t ) d t . {\displaystyle X(t)={\text{Real}}{\sum _{j=1}^{n}a_{j}(t)e^{i\int \omega _{j}(t)dt}}.\,} == Current applications == === Two-Dimensional EMD === In the above examples, all signals are one-dimensional signals, and in the case of two-dimensional signals, the Hilbert-Huang Transform can be applied for image and video processing in the following ways: Pseudo-Two-Dimensional EMD (Pseudo-two-dimensional Empirical Mode Decomposition): Directly splitting the two-dimensional signal into two sets of one-dimensional signals and applying the Hilbert-Huang Transform separately. After that, rearrange the two signals back into a two-dimensional signal. The result can produce excellent patterns, and display local rapid oscillations in long-wavelength waves. However, this method has many drawbacks. The most significant one is the discontinuities, occurring when the two sets of processed Intrinsic Mode Functions (IMFs) are recombined into the original two-dimensional signal. The following methods can be used to address this issue. Pseudo-Two-Dimensional EEMD (Pseudo-two-dimensional Ensemble Empirical Mode Decomposition): Compared to Pseudo-Two-Dimensional EMD, using EEMD instead of EMD can effectively improve the issue of discontinuity. However, this method has limitations and it's only effective when the time scale is very clear, such as in the case of temperature detection in the North Atlantic. It is not suitable for situations where the time scale of the signal is unclear. Genuine Two-Dimensional EMD (Genuine two-dimensional Empirical Mode Decomposition): As Genuine Two-Dimensional EMD directly processes two-dimensional signals, it poses some definitional challenges. How to determine the maximum value—should the edges of the image be considered, or should another method be used to define the maximum value? How to choose the progressive manner after identifying the maximum value. While Bézier curves may be effective in one-dimensional signals, they may not be directly applicable to two-dimensional signals. Therefore, Nunes et al. used radial basis functions and the Riesz transform to handle Genuine Two-Dimensional EMD. The following is the form of the Riesz transform. For a complex function f on R d {\displaystyle R^{d}} . for j = 1,2,...,d. The constant C d {\displaystyle C_{d}} is a dimension-normalized constant. c d = 1 π ω d − 1 = Γ [ ( d + 1 ) / 2 ] π ( d + 1 ) / 2 . {\displaystyle c_{d}={\frac {1}{\pi \omega _{d-1}}}={\frac {\Gamma [(d+1)/2]}{\pi ^{(d+1)/2}}}.} Linderhed used Genuine Two-Dimensional EMD for image compression. Compared to other compression methods, this approach provides a lower distortion rate. Song and Zhang [2001], Damerval et al. [2005], and Yuan et al. [2008] used Delaunay triangulation to find the upper and lower bounds of the image. Depending on the requirements for defining maxima and selecting different progressive methods, different effects can be obtained. === Other application === Improved EMD on ECG signals: Ahmadi et al.[2019] presented an Improved EMD and compared with other types of EMD. Results show the proposed algorithm provides no spurious IMF for these functions and is not placed in an infinite loop. EMD types comparison on ECG(Electrocardiography) signals reveal the improved EMD was an appropriate algorithm to be used for analyzing biological signals. Biomedical applications: Huang et al. [1999b] analyzed the pulmonary arterial pressure on conscious and unrestrained rats. Neuroscience: Pigorini et al. [2011] analyzed Human EEG response to Transcranial Magnetic Stimulation; Liang et al. [2005] analyzed the visual evoked potentials of macaque performing visual spatial attention task. Epidemiology: Cummings et al. [2004] applied the EMD method to extract a 3-year-periodic mode embedded in Dengue Fever outbreak time series recorded in Thailand and assessed the travelling speed of Dengue Fever outbreaks. Yang et al. [2010] applied the EMD method to delineate sub-components of a variety of neuropsychiatric epidemiological time series, including the association between seasonal effect of Google search for depression [2010], association between suicide and air pollution in Taipei City [2011], and association between cold front and incidence of migraine in Taipei city [2011]. Chemistry and chemical engineering: Phillips et al. [2003] investigated a conformational change in Brownian dynamics and molecular dynamics simulations using a comparative analysis of HHT and wavelet methods. Wiley et al. [2004] used HHT to investigate the effect of reversible digitally filtered molecular dynamics which can enhance or suppress specific frequencies of motion. Montesinos et al. [2002] applied HHT to signals obtained from BWR neuron stability. Financial applications: Huang et al. [2003b] applied HHT to nonstationary financial time series and used a weekly mortgage rate data. Image processing: Hariharan et al. [2006] applied EMD to image fusion and enhancement. Chang et al. [2009] applied an improved EMD to iris recognition, which reported a 100% faster in computational speed without losing accuracy than the original EMD. Atmospheric turbulence: Hong et al. [2010] applied HHT to turbulence data observed in the stable boundary layer to separate turbulent and non-turbulent motions. Scaling processes with intermittency correction: Huang et al. [2008] has generalized the HHT into arbitrary order to take the intermittency correction of scaling processes into account, and applied this HHT-based method to hydrodynamic turbulence data collected in laboratory experiment,; daily river discharge,; Lagrangian single particle statistics from direct numerical simulation,; Tan et al., [2014], vorticity field of two dimensional turbulence,; Qiu et al.[2016], two dimensional bacterial turbulence,; Li & Huang [2014], China stock market,; Calif et al. [2013], solar radiation. A source code to realize the arbitrary order Hilbert spectral analysis can be found at . Meteorological and atmospheric applications: Salisbury and Wimbush [2002], using Southern Oscillation Index data, applied the HHT technique to determine whether the Sphere of influence data are sufficiently noise free that useful predictions can be made and whether future El Nino southern oscillation events can be predicted from SOI data. Pan et al. [2002] used HHT to analyze satellite scatterometer wind data over the northwestern Pacific and compared the results to vector empirical orthogonal function results. Ocean engineering: Schlurmann [2002] introduced the application of HHT to characterize nonlinear water waves from two different perspectives, using laboratory experiments. Veltcheva [2002] applied HHT to wave data from nearshore sea. Larsen et al. [2004] used HHT to characterize the underwater electromagnetic environment and identify transient manmade electromagnetic disturbances. Seismic studies: Huang et al. [2001] used HHT to develop a spectral representation of earthquake data. Chen et al. [2002a] used HHT to determine the dispersion curves of seismic surface waves and compared their results to Fourier-based time-frequency analysis. Shen et al. [2003] applied HHT to ground motion and compared the HHT result with the Fourier spectrum. Solar physics: Nakariakov et al. [2010] used EMD to demonstrate the triangular shape of quasi-periodic pulsations detected in the hard X-ray and microwave emission generated in solar flares. Barnhart and Eichinger [2010] used HHT to extract the periodic components within sunspot data, including the 11-year Schwabe, 22-year Hale, and ~100-year Gleissberg cycles. They compared their results with traditional Fourier analysis. Structural applications: Quek et al. [2003] illustrate the feasibility of the HHT as a signal processing tool for locating an anomaly in the form of a crack, delamination, or stiffness loss in beams and plates based on physically acquired propagating wave signals. Using HHT, Li et al. [2003] analyzed the results of a pseudodynamic test of two rectangular reinforced concrete bridge columns. Structural health monitoring: Pines and Salvino [2002] applied HHT in structural health monitoring. Yang et al. [2004] used HHT for damage detection, applying EMD to extract damage spikes due to sudden changes in structural stiffness. Yu et al. [2003] used HHT for fault diagnosis of roller bearings. System identification: Chen and Xu [2002] explored the possibility of using HHT to identify the modal damping ratios of a structure with closely spaced modal frequencies and compared their results to FFT. Xu et al. [2003] compared the modal frequencies and damping ratios in various time increments and different winds for one of the tallest composite buildings in the world. Speech recognition: Huang and Pan [2006] have used the HHT for speech pitch determination. Astroparticle physics : Bellini et al. [2014] (Borexino collaboration), Measurement of the seasonal modulation of the solar neutrino fluxes with Borexino experiment, Phys. Rev. D 89, 112007 2014 == Limitations == Chen and Feng [2003] proposed a technique to improve the HHT procedure. The authors noted that the EMD is limited in distinguishing different components in narrow-band signals. The narrow band may contain either (a) components that have adjacent frequencies or (b) components that are not adjacent in frequency but for which one of the components has a much higher energy intensity than the other components. The improved technique is based on beating-phenomenon waves. Datig and Schlurmann [2004] conducted a comprehensive study on the performance and limitations of HHT with particular applications to irregular water waves. The authors did extensive investigation into the spline interpolation. The authors discussed using additional points, both forward and backward, to determine better envelopes. They also performed a parametric study on the proposed improvement and showed significant improvement in the overall EMD computations. The authors noted that HHT is capable of differentiating between time-variant components from any given data. Their study also showed that HHT was able to distinguish between riding and carrier waves. Huang and Wu [2008] reviewed applications of the Hilbert–Huang transformation emphasizing that the HHT theoretical basis is purely empirical, and noting that "one of the main drawbacks of EMD is mode mixing". They also outline outstanding open problems with HHT, which include: End effects of the EMD, Spline problems, Best IMF selection and uniqueness. Although the ensemble EMD (EEMD) may help mitigate the latter. === End effect === End effect occurs at the beginning and end of the signal because there is no point before the first data point and after the last data point to be considered together. However, in most cases, these endpoints are not the extreme value of the signal. Therefore, when doing the EMD process of the HHT, the extreme envelope will diverge at the endpoints and cause significant errors. This error distorts the IMF waveform at its endpoints. Furthermore, the error in the decomposition result accumulates through each repetition of the sifting process. When computing the instantaneous frequency and amplitude of IMFs, Fast Fourier Transform (FFT) result may cause Gibbs phenomenon and frequency leakage, leading to information loss. Here are several methods are proposed to solve the end effect in HHT: ==== 1. Characteristic wave extending method ==== This method leverages the inherent variation trend of the signal to extend itself, resulting in extensions that closely resemble the characteristics of the original data. Waveform matching extension [1]: This extension is based on the assumption that similar waveforms repeat themselves within the signal. Therefore, a triangular waveform best matching the signal's boundary is identified within the signal's waveform. Local values within the signal's boundary can then be predicted based on the corresponding local values of the triangular waveform. Mirror extending method: Many signals exhibit internal repetition patterns. Leveraging this characteristic, the mirror extension method appends mirrored copies of the original signal to its ends. This simple and efficient approach significantly improves the accuracy of Intrinsic Mode Functions (IMFs) for periodic signals. However, it is not suitable for non-periodic signals and can introduce side effects. Several alternative strategies have been proposed to address these limitations [2][3] ==== 2. Data extending method ==== design and compute some needed parameters from the original signal for building a particular mathematical model. After that, the model predicts the trend of the two endpoints. Support vector regression machine (SVRM) prediction [4]: This method utilizes machine learning techniques to tackle the end effect in HHT. Its advantages are adaptive, flexible, highly accurate, and effective for both periodic and non-periodic signals. Although computational complexity can be a concern, disregarding this factor reveals SVRM as a robust and effective solution for mitigating the end effect in HHT. Autoregressive (AR) model [5] : By formulating the input-output relationship as linear equations with time-varying coefficients, AR modeling enables statistical prediction of the missing values at the signal's endpoints. This method requires minimal computational resources and proves particularly effective for analyzing stationary signals. However, its accuracy diminishes for non-stationary signals, and the selection of an appropriate model order can significantly impact its effectiveness. Neural network prediction: Leveraging the power of neural network learning, these methods offer a versatile and robust approach to mitigating the end effect in HHT. Various network architectures, including RBF-NN [6] and GRNN [7], have emerged, demonstrating their ability to capture complex relationships within the signal and learn from large datasets. === Mode mixing problem === Mode mixing problem happens during the EMD process. A straightforward implementation of the sifting procedure produces mode mixing due to IMF mode rectification. Specific signals may not be separated into the same IMFs every time. This problem makes it hard to implement feature extraction, model training, and pattern recognition since the feature is no longer fixed in one labeling index. Mode mixing problem can be avoided by including an intermittence test during the HHT process. ==== Masking Method ==== Source: The masking method improves EMD by allowing for the separation of similar frequency components through the following steps: Construction of masking signal: Construct masking signal s ( n ) {\displaystyle s(n)} from the frequency information of the original data, x ( n ) {\displaystyle x(n)} . This masking signal is designed to prevent lower-frequency components from IMFs obtained through EMD. Perform EMD with masking signal: EMD is again performed on the modified signal x+(n) = x(n) + s(n) to obtain the IMF z+(n), and similarly, on x-(n) = x(n) - s(n) to obtain the IMF z-(n). The IMF is then defined as z(n) = (z+(n) + z-(n))/2 . Separation of Components: By appropriately choosing the masking signal frequency, components with similar frequencies can be separated. The masking signal prevents mode mixing, allowing EMD to distinguish between closely spaced frequency components. Error Minimization: The choice of parameters for the masking signal, such as amplitude, will affect the performance of the algorithm. The optimal choice of amplitude depends on the frequencies Overall, the masking method enhances EMD by providing a means to prevent mode mixing, improving the accuracy and applicability of EMD in signal analysis ==== Ensemble empirical mode decomposition (EEMD) ==== Source: EEMD adds finite amplitude white noise to the original signal. After that, decompose the signal into IMFs using EMD. The processing steps of EEMD are developed as follows: Add finite amplitude white noise to the original signal. Decompose the noisy signal into IMFs using EMD. Repeat steps 1 and 2 multiple times to create an ensemble of IMFs. Calculate the mean of each IMF across the ensemble to obtain the final IMF components. The effects of the decomposition using the EEMD are that the added white noise series cancel each other(or fill all the scale space uniformly). The noise also enables the EMD method to be a truly dyadic filter bank for any data, which means that a signal of a similar scale in a noisy data set could be contained in one IMF component, significantly reducing the chance of mode mixing. This approach preserves the physical uniqueness of decomposition and represents a major improvement over the EMD method. == Comparison with other transforms == == See also == Hilbert transform Hilbert spectral analysis Hilbert spectrum Instantaneous frequency Multidimensional empirical mode decomposition Nonlinear Wavelet transform Fourier transform Signal envelope == References == == Further reading == Ditommaso, R.; Mucciarelli, M.; Parolai, S.; Picozzi, M. (2012). "Monitoring the Structural Dynamic Response of a Masonry Tower: Comparing Classical and Time-Frequency Analyses" (PDF). Bulletin of Earthquake Engineering. 10 (4): 1221–1235. doi:10.1007/s10518-012-9347-x. S2CID 51816660. Boudraa, A.O.; Cexus, J.C. (2007). "EMD-Based Signal Filtering" (PDF). IEEE Transactions on Instrumentation and Measurement. 56 (6): 2196–2202. Bibcode:2007ITIM...56.2196B. doi:10.1109/TIM.2007.907967. S2CID 30086370. Huang, N. E.; Shen, Z.; Long, S. R.; Wu, M. C.; Shih, H. H.; Zheng, Q.; Yen, N. C.; Tung, C. C.; Liu, H. H. (1998). "The Empirical Mode Decomposition and the Hilbert Spectrum for Nonlinear and Nonstationary Time Series Analysis" (PDF). Proceedings of the Royal Society of London A. 454 (1971): 903–995. Bibcode:1998RSPSA.454..903H. doi:10.1098/rspa.1998.0193. S2CID 1262186. Archived from the original (PDF) on 2006-09-06. Huang, N. E.; Wu Z. (2008). "A review on Hilbert-Huang transform: Method and its applications to geophysical studies". Rev. Geophys. 46 (2): RG2006. Bibcode:2008RvGeo..46.2006H. doi:10.1029/2007RG000228. Huang, N. E.; Attoh-Okine, N. O. (2005). The Hilbert-Huang Transform in Engineering. CRC Taylor & Francis. ISBN 978-0849334221. Huang, N. E.; Shen, S. S. P. (2005). Hilbert-Huang Transform and its Applications. London: World Scientific. ISBN 978-9812563767. Schmitt, Francois G; Huang, Yongxiang (2016). Stochastic Analysis of Scaling Time Series: From Turbulence Theory to Applications. Combridge University Press. ISBN 9781107067615. Huang, N. E.; Long, S. R.; Shen, Z. (1996). "The Mechanism for Frequency Downshift in Nonlinear Wave Evolution". Advances in Applied Mechanics. 32: 59–111. doi:10.1016/S0065-2156(08)70076-0. ISBN 9780120020324. Huang, N. E.; Shen, Z.; Long, R. S. (1999). "A New View of Nonlinear Water Waves — The Hilbert Spectrum" (PDF). Annual Review of Fluid Mechanics. 31: 417–457. Bibcode:1999AnRFM..31..417H. doi:10.1146/annurev.fluid.31.1.417. Huang, N. E.; Wu, M. L.; Long, S. R.; Shen, S. S.; Qu, W. D.; Gloersen, P.; Fan, K. L. (2003). "A Confidence Limit for the Empirical Mode Decomposition and Hilbert Spectral Analysis" (PDF). Proceedings of the Royal Society of London A. 459 (2037): 2317–2345. Bibcode:2003RSPSA.459.2317H. doi:10.1098/rspa.2003.1123. S2CID 6293882. Wu, Z.; Huang, N. E. (2004). "A Study of the Characteristics of White Noise Using the Empirical Mode Decomposition Method". Proceedings of the Royal Society of London A. 460 (2046): 1597–1611. Bibcode:2004RSPSA.460.1597W. doi:10.1098/rspa.2003.1221. S2CID 53060332. Professor of Jian-Jiun Ding, Department of Electrical Engineering, National Taiwan University. "Time-Frequency Analysis and Wavelet Transform 2021" (PDF). {{cite journal}}: Cite journal requires \|journal= (help)CS1 maint: multiple names: authors list (link)	Wikipedia/Hilbert–Huang_transform
Premature atrial contraction (PAC), also known as atrial premature complexes (APC) or atrial premature beats (APB), are a common arrhythmia characterized by premature heartbeats originating in the atria. While the sinoatrial node typically regulates the heartbeat during normal sinus rhythm, PACs occur when another region of the atria depolarizes before the sinoatrial node and thus triggers a premature heartbeat, in contrast to escape beats, in which the normal sinoatrial node fails, leaving a non-nodal pacemaker to initiate a late beat. The exact cause of PACs is unclear; while several predisposing conditions exist, single isolated PACs commonly occur in healthy young and elderly people. Elderly people that get PACs usually don't need any further attention besides follow-ups due to unclear evidence. PACs are often completely asymptomatic and may be noted only with Holter monitoring, but occasionally they can be perceived as a skipped beat or a jolt in the chest. In most cases, no treatment other than reassurance is needed for PACs, although medications such as beta blockers can reduce the frequency of symptomatic PACs. == Epidemiology == Premature atrial contractions (PACs) are common in the general population, and increase with age. Over 99% of individuals in the general population will have at least one PAC in a 24-hour period. Many PACs can indicate increased risk of atrial fibrillation and/or ischemic stroke. The threshold for number of PACs which substantially raises the risk atrial fibrillation is debatable, but some estimates range between in excess of 500 and 720 PACs per day. == Risk factors == Hypertension, or abnormally high blood pressure, often signifies an elevated level of both psychological and physiological stress. Often, hypertension goes hand in hand with various atrial fibrillations, including PACs. Additional factors that may contribute to spontaneous premature atrial contractions could be: Increased age Abnormal body height Family history of heart disease History of cardiovascular disease (CV) Abnormal atrial natriuretic peptide (ANP) levels Elevated cholesterol == Diagnosis == Premature atrial contractions are typically diagnosed with an electrocardiogram, Holter monitor, long-term continuous monitor, cardiac event monitor, or with a smartwatch with an ECG functionality. === Electrocardiogram === On an electrocardiogram (ECG), PACs are characterized by an abnormally shaped P wave in different ECG leads. Since the premature beat initiates outside the sinoatrial node, the associated P wave appears different from those seen in normal sinus rhythm. Typically, the atrial impulse propagates normally through the atrioventricular node and into the cardiac ventricles, resulting in a normal, narrow QRS complex. However, if the atrial beat is premature enough, it may reach the atrioventricular node during its refractory period, in which case it will not be conducted to the ventricle and there will be no QRS complex following the P wave. In some people, PACs occur in a predictable pattern. Two PACs in a row are called doublets and three PACs in a row are triplets. Depending whether there are one, two, or three normal (sinus) beats between each PACs, the rhythm is called atrial bigeminy, trigeminy, or quadrigeminy. If three or more consecutive PACs occur in a row and at a frequency of 100 or more beats per minute, it may be called atrial tachycardia. == Treatment == Premature atrial contractions are often benign, requiring no treatment. Occasionally, the patient having the PAC will find these symptoms bothersome, in which case the doctor may treat the PACs. Sometimes the PACs can indicate heart disease or an increased risk for other cardiac arrhythmias. In this case, the underlying cause is treated. Often a beta blocker will be prescribed for symptomatic PACs. == Prognosis == In otherwise healthy patients, occasional single premature atrial contractions are a common finding and most of times do not indicate any particular health risk. Rarely, in patients with other underlying structural heart problems, PACs can trigger a more serious arrhythmia such as atrial flutter or atrial fibrillation. In otherwise healthy people, PACs usually disappear with adolescence. == Supraventricular extrasystole == A supraventricular extrasystole (SVES) is an extrasystole or premature electrical impulse in the heart, generated above the level of the ventricle. This can be either a premature atrial contraction or a premature impulse from the atrioventricular node. SVES should be viewed in contrast to a premature ventricular contraction that has a ventricular origin and the associated QRS change. Instead of the electrical impulse beginning in the sinoatrial (SA) node and propagating to the atrioventricular (AV) node, the signal is conducted both to the ventricle and back to the SA node where the signal began. == See also == Premature junctional contraction Premature ventricular contraction == References == == External links ==	Wikipedia/Premature_atrial_contraction
A sinoatrial block (also spelled sinuatrial block) is a disorder in the normal rhythm of the heart, known as a heart block, that is initiated in the sinoatrial node. The initial action impulse in a heart is usually formed in the sinoatrial node (SA node) and carried through the atria, down the internodal atrial pathways to the atrioventricular node (AV) node. In normal conduction, the impulse would travel across the bundle of His (AV bundle), down the bundle branches, and into the Purkinje fibers. This would depolarize the ventricles and cause them to contract. In an SA block, the electrical impulse is delayed or blocked on the way to the atria, thus delaying the atrial beat. (An AV block, occurs in the AV node and delays ventricular depolarisation). SA blocks are categorized into three classes based on the length of the delay. == Symptoms == Sinoatrial blocks are typically well tolerated. They are not as serious as an AV block and most often do not require treatment. In some people, they can cause fainting, altered mental status, chest pain, hypoperfusion, and signs of shock. They can also lead to cessation of the SA node and more serious dysrhythmias. == Types == In a first degree sinoatrial block, there is a lag between the time that the SA node fires and actual depolarization of the atria. This rhythm is not easily detectable using state of the art (the highest level of scientific development at the current state in time) diagnostic equipment, thus is currently not recognizable on an ECG strip because an ECG strip does not denote when the SA node fires. It can be detected only during an electrophysiology study when a small wire is placed against the SA node from within the heart and the electrical impulses can be recorded as they leave the p-cells in the centre of the node [ see pacemaker potential ], followed by observing a delay in the onset of the p wave on the ECG. Second degree SA blocks are broken down into two subcategories just like AV blocks are: The first is a second degree type I, or Wenckebach block. This rhythm is irregular, and the R-R interval gets progressively smaller, while the P-R interval remains constant, until a QRS segment is dropped. Note that this is quite different from the Wenckebach AV block, in which the PR interval gets progressively longer, before the dropped QRS segment. The pause of a second degree type I is less than twice the shortest R-R interval and is not a multiple of the P-R interval. The cause is a gradual lengthening of conduction time from the SA node to the atria. The p-cells in the centre of the node produce the rhythm at a regular rate, but their conduction across the node to where it meets atrial tissue is where the slowing occurs. A second degree type II, or sinus exit block, is a regular rhythm that may be normal or slow. It is followed by a pause that is a multiple of the P-P interval usually (2-4). Conduction across the SA node is normal until the time of the pause when it is blocked. A third degree sinoatrial block looks very similar to a sinus arrest. However, a sinus arrest is caused by a failure to form impulses. A third degree block is caused by failure to conduct them. The rhythm is irregular and either normal or slow. It is followed by a long pause that is not a multiple of the P-R interval. The pause ends with a P wave, instead of a junctional escape beat the way a sinus arrest would. == Treatment == Emergency treatment consists of administration of atropine sulfate or transcutaneous pacing. == References == Bledsoe, Porter, Cherry (2009). Paramedic Care; Principles and Practice. New Jersey: Brady. ISBN 978-0-13-513702-4.{{cite book}}: CS1 maint: multiple names: authors list (link) Schilling McCann, Judith (2009). Cardiovascular Care Made Incredibly Easy. Pennsylvania: Lippincott Williams and Wilkins. ISBN 978-0-7817-8824-3. == External links ==	Wikipedia/Sinoatrial_block
Sinoatrial arrest is a medical condition wherein the sinoatrial node of the heart transiently ceases to generate the electrical impulses that normally stimulate the myocardial tissues to contract and thus the heart to beat. It is defined as lasting from 2.0 seconds to several minutes. Since the heart contains multiple pacemakers, this interruption of the cardiac cycle generally lasts only a few seconds before another part of the heart, such as the atrio-ventricular junction or the ventricles, begins pacing and restores the heart action. This condition can be detected on an electrocardiogram (ECG) as a brief period of irregular length with no electrical activity before either the sinoatrial node resumes normal pacing, or another pacemaker begins pacing. If a pacemaker other than the sinoatrial node is pacing the heart, this condition is known as an escape rhythm. If no other pacemaker begins pacing during an episode of sinus arrest it becomes a cardiac arrest. This condition is sometimes confused with sinoatrial block, a condition in which the pacing impulse is generated, but fails to conduct through the myocardium. Differential diagnosis of the two conditions is possible by examining the exact length of the interruption of cardiac activity. If the next available pacemaker takes over, it is in the following order: Atrial escape (rate 60–80): originates within atria, not sinus node (normal P morphology is lost). Junctional escape (rate 40–60): originates near the AV node; a normal P wave is not seen, may occasionally see a retrograde P wave. Ventricular escape (rate 20–40): originates in ventricular conduction system; no P wave, wide, abnormal QRS. Treatment includes stop medications that suppress the sinus node (beta blocker, calcium channel blocker, digitalis); may need pacing. == References == David Da Costa; et al. (2002-03-02). "ABC of clinical electrocardiography". BMJ (Clinical Research Ed.). 324 (7336): 535–538. doi:10.1136/bmj.324.7336.535. PMC 1122450. PMID 11872557. Retrieved 2008-04-28.	Wikipedia/Sinoatrial_arrest
A medical error is a preventable adverse effect of care ("iatrogenesis"), whether or not it is evident or harmful to the patient. This might include an inaccurate or incomplete diagnosis or treatment of a disease, injury, syndrome, behavior, infection, or other ailments. The incidence of medical errors varies depending on the setting. The World Health Organization has named adverse outcomes due to patient care that is unsafe as the 14th causes of disability and death in the world, with an estimated 1/300 people may be harmed by healthcare practices around the world. == Definitions == A medical error occurs when a health-care provider chooses an inappropriate method of care or improperly executes an appropriate method of care. Medical errors are often described as human errors in healthcare. There are many types of medical error, from minor to major, and causality understanding and assessing if the likelihood that the specific event or factor was responsible for the negative outcome, is often poorly determined. There are many taxonomies for classifying medical errors. === Definitions of diagnostic error === Defining diagnostic error is important for measuring its frequency, identifying its causes, and implementing strategies to reduce harm and these steps that are essential for improving patient safety. The complexity of diagnosis as both a process and an outcome has led to multiple, overlapping definitions and there is no single definition of diagnostic error. One challenge is reflected in part the dual nature of the word diagnosis, which is both a noun (the name of the assigned disease; diagnosis is a label) and a verb (the act of arriving at a diagnosis; diagnosis is a process). At the present time, there are at least 4 definitions of diagnostic error in active use: Diagnostic error has been defined as a diagnosis that is wrong, egregiously delayed, or missed altogether. This is a "label" definition, and can only be applied in retrospect, using some gold standard (for example, autopsy findings or a definitive laboratory test) to confirm the correct diagnosis. Many diagnostic errors fit several of these criteria; the categories overlap. Diagnostic error has also be defined using process-related definitions: Schiff et al. defined diagnostic error as any breakdown in the diagnostic process, including both errors of omission and errors of commission. Similarly, Singh et al. defined diagnostic error as a "missed opportunity" in the diagnostic process, based on retrospective review. In its landmark report, Improving Diagnosis in Health Care, The National Academy of Medicine proposed a new, hybrid definition that includes both label- and process-related aspects: "A diagnostic error is failure to establish an accurate and timely explanation of the patient's health problem(s) or to communicate that explanation to the patient." This is the only definition that specifically includes the patient in the definition wording. === Definition of prescription error === A prescription or medication error, as defined by the National Coordinating Council for Medication Error Reporting and Prevention, is an event that is preventable that leads to or has led to unsuitable use of medication or has led to harm to the person during the period of time that the medicine is controlled by a clinician, the person, or the consumer. Some adverse drug events can also be related to medication errors. == Impact == One extrapolation suggests that 180,000 people die each year partly as a result of iatrogenic injury. The World Health Organization registered 14 million new cases and 8.2 million cancer-related deaths in 2012. It estimated that the number of cases could increase by 70% through 2032. As the number of cancer patients receiving treatment increases, hospitals around the world are seeking ways to improve patient safety, to emphasize traceability and raise efficiency in their cancer treatment processes. Children are often more vulnerable to a negative outcome when a medication error occurs as they have age-related differences in how their bodies absorb, metabolize, and excrete pharmaceutical agents. === UK === In the UK, an estimated 850,000 medical errors occur each year, costing over £2 billion (estimated in the year 2000). The accuracy of this estimate is not clear. Criticism has included the statistical handling of measurement errors in the report, and significant subjectivity in determining which deaths were "avoidable" or due to medical error, and an erroneous assumption that 100% of patients would have survived if optimal care had been provided. A 2006 study found that medication errors are among the most common medical mistakes, harming at least 1.5 million people every year. According to the study, 400,000 preventable drug-related injuries occur each year in hospitals, 800,000 in long-term care settings, and roughly 530,000 among Medicare recipients in outpatient clinics. The report stated that these are likely to be conservative estimates. In 2000 alone, the extra medical costs incurred by preventable drug-related injuries approximated $887 million—and the study looked only at injuries sustained by Medicare recipients, a subset of clinic visitors. None of these figures take into account lost wages and productivity or other costs. === US === According to a 2002 Agency for Healthcare Research and Quality report, about 7,000 people were estimated to die each year from medication errors – about 16 percent more deaths than the number attributable to work-related injuries (6,000 deaths). One in five Americans (22%) report that they or a family member have experienced a medical error of some kind. A 2000 Institute of Medicine report estimated that medical errors result in between 44,000 and 98,000 preventable deaths and 1,000,000 excess injuries each year in U.S. hospitals. A 2001 study in the Journal of the American Medical Association of seven Department of Veterans Affairs medical centers estimated that for roughly every 10,000 patients admitted to the select hospitals, one patient died who would have lived for three months or more in good cognitive health had "optimal" care been provided. A 2001 study estimated that 1% of hospital admissions result in an adverse event due to negligence. Identification or errors may be a challenge in these studies, and mistakes may be more common than reported as these studies identify only mistakes that led to measurable adverse events occurring soon after the errors. Independent review of doctors' treatment plans suggests that decision-making could be improved in 14% of admissions; many of the benefits would have delayed manifestations. Even this number may be an underestimate. One study suggests that adults in the United States receive only 55% of recommended care. At the same time, a second study found that 30% of care in the United States may be unnecessary. For example, if a doctor fails to order a mammogram that is past due, this mistake will not show up in the first type of study. In addition, because no adverse event occurred during the short follow-up of the study, the mistake also would not show up in the second type of study because only the principal treatment plans were critiqued. However, the mistake would be recorded in the third type of study. If a doctor recommends an unnecessary treatment or test, it may not show in any of these types of studies. Cause of death on United States death certificates, statistically compiled by the Centers for Disease Control and Prevention (CDC), are coded in the International Classification of Disease (ICD), which does not include codes for human and system factors. == Causes == The research literature showed that medical errors are caused by errors of commission and errors of omission. Errors of omission are made when providers did not take action when they should have, while errors of commission occur when decisions and action are delayed. A special form of an error of commission occurs when health care professionals commit to unnecessary treatment in the case of Medical child abuse (Munchausen syndrome by proxy). Commission and omission errors have also been attributed with communication failures. A study with data from 67 826 patients found that poor communication was the only identifiable cause of 1 in 10 patient safety incidents, and that poor communication contributes to 25% of patient safety incidents. Medical errors can be associated with inexperienced physicians and nurses, new procedures, extremes of age, and complex or urgent care. Poor communication (whether in one's own language or, as may be the case for medical tourists, another language), improper documentation, illegible handwriting, spelling errors, inadequate nurse-to-patient ratios, and similarly named medications are also known to contribute to the problem. Misdiagnosis may be associated with individual characteristics of the patient or due to the patient multimorbidity. Patient actions or inactions may also contribute significantly to medical errors. === Healthcare complexity === Complicated technologies, powerful drugs, intensive care, rare and multiple diseases, and prolonged hospital stay can contribute to medical errors. In turn, medical errors from carelessness or improper use of medical devices often lead to severe injuries or death. Since 2015, 60 injuries and 23 deaths have been caused by misplaced feeding tubes while using the Cortrak2 EAS system. The FDA recalled Avanos Medical's Cortrak system in 2022 due to its severity and the high toll associated with the medical error. Complexity makes diagnosis especially challenging. There are less than 200 symptoms listed in Wikipedia, but there are probably more than 10,000 known diseases. The World Health Organization's system for the International Classification of Disease, 9th Edition from 1979 listed over 14,000 diagnosis codes. Textbooks of medicine often describe the most typical presentations of a disease, but in many conditions patients may have variable presentations instead of the classical signs and symptoms. To add complexity, the signs and symptoms of a given condition change over time; in the early stages the signs and symptoms may be absent or minimal, and then these evolve as the condition progresses. Diagnosis is often challenging in infants and children who can't clearly communicate their symptoms, and in the elderly, where signs and symptoms may be muted or absent. There are more than 7000 rare diseases alone, and in aggregate these are not uncommon: Roughly 1 in 17 patients will be diagnosed with a rare disease over their lifetime. Physicians may have only learned a handful of these during their education and training. === System and process design === In 2000, The Institute of Medicine released "To Err is Human," which asserted that the problem in medical errors is not bad people in health care—it is that good people are working in bad systems that need to be made safer. Poor communication and unclear lines of authority of physicians, nurses, and other care providers are also contributing factors. Disconnected reporting systems within a hospital can result in fragmented systems in which numerous hand-offs of patients results in lack of coordination and errors. Other factors include the impression that action is being taken by other groups within the institution, reliance on automated systems to prevent error., and inadequate systems to share information about errors, which hampers analysis of contributory causes and improvement strategies. Cost-cutting measures by hospitals in response to reimbursement cutbacks can compromise patient safety. In emergencies, patient care may be rendered in areas poorly suited for safe monitoring. The American Institute of Architects has identified concerns for the safe design and construction of health care facilities. Infrastructure failure is also a concern. According to the WHO, 50% of medical equipment in developing countries is only partly usable due to lack of skilled operators or parts. As a result, diagnostic procedures or treatments cannot be performed, leading to substandard treatment. The Joint Commission's Annual Report on Quality and Safety 2007 found that inadequate communication between healthcare providers, or between providers and the patient and family members, was the root cause of over half the serious adverse events in accredited hospitals. Other leading causes included inadequate assessment of the patient's condition, and poor leadership or training. === Competency, education, and training === Variations in healthcare provider training & experience and failure to acknowledge the prevalence and seriousness of medical errors also increase the risk. The so-called July effect occurs when new residents arrive at teaching hospitals, causing an increase in medication errors according to a study of data from 1979 to 2006. === Human factors and ergonomics === Cognitive errors commonly encountered in medicine were initially identified by psychologists Amos Tversky and Daniel Kahneman in the early 1970s. Jerome Groopman, author of How Doctors Think, says these are "cognitive pitfalls", biases which cloud our logic. For example, a practitioner may overvalue the first data encountered, skewing their thinking. Another example may be where the practitioner recalls a recent or dramatic case that quickly comes to mind, coloring the practitioner's judgement. Another pitfall is where stereotypes may prejudice thinking. Pat Croskerry describes clinical reasoning as an interplay between intuitive, subconscious thought (System 1) and deliberate, conscious rational consideration (System 2). In this framework, many cognitive errors reflect over-reliance on System 1 processing, although cognitive errors may also sometimes involve System 2. Sleep deprivation has also been cited as a contributing factor in medical errors. One study found that being awake for over 24 hours caused medical interns to double or triple the number of preventable medical errors, including those that resulted in injury or death. The risk of car crash after these shifts increased by 168%, and the risk of near miss by 460%. Interns admitted falling asleep during lectures, during rounds, and even during surgeries. Night shifts are associated with worse surgeon performance during laparoscopic surgeries. Practitioner risk factors include fatigue, depression, and burnout. Factors related to the clinical setting include diverse patients, unfamiliar settings, time pressures, and increased patient-to-nurse staffing ratio increases. Drug names that look alike or sound alike are also a problem. Errors in interpreting medical images are often perceptual instead of "fact-based"; these errors are often caused by failures of attention or vision. For example, visual illusions can cause radiologists to misperceive images. A number of Information Technology (IT) systems have been developed to detect and prevent medication errors, the most common type of medical errors. These systems screen data such as ICD-9 codes, pharmacy and laboratory data. Rules are used to look for changes in medication orders, and abnormal laboratory results that may be indicative of medication errors and/or adverse drug events. == Examples == Errors can include misdiagnosis or delayed diagnosis, administration of the wrong drug to the wrong patient or in the wrong way, giving multiple drugs that interact negatively, surgery on an incorrect site, failure to remove all surgical instruments, failure to take the correct blood type into account, or incorrect record-keeping. A 10th type of error is ones which are not watched for by researchers, such as RNs failing to program an IV pump to give a full dose of IV antibiotics or other medication. === Errors in diagnosis === The projected cost of medical errors to the U.S. economy is approximately $20 billion, 87% of which are direct increases in medical costs of providing services to patient affected by medical errors. Medical errors can increase average hospital costs by as much as $4,769 per patient. One common type of medical error stems from x-rays and medical imaging: failing to see or notice signs of disease on an image. The retrospective "miss" rate among abnormal imaging studies is reported to be as high as 30% (the real-life error rate is much lower, around 4-5%, because not all images are abnormal), and up to 20% of missed findings result in long-term adverse effects. A large study reported several cases where patients were wrongly told that they were HIV-negative when the physicians erroneously ordered and interpreted HTLV (a closely related virus) testing rather than HIV testing. In the same study, >90% of HTLV tests were ordered erroneously. A 2008 literature review in The American Journal of Medicine estimated that between 10 and 15% of physician diagnoses are erroneous. Misdiagnosis of lower extremity cellulitis is estimated to occur in 30% of patients, leading to unnecessary hospitalizations in 85% and unnecessary antibiotic use in 92%. Collectively, these errors lead to between 50,000 and 130,000 unnecessary hospitalizations and between $195 and $515 million in avoidable health care spending annually in the United States. === Misdiagnosis of psychological disorders === Female sexual desire sometimes used to be diagnosed as female hysteria. Sensitivities to foods and food allergies risk being misdiagnosed as the eating disorder orthorexia. Studies have found that bipolar disorder has often been misdiagnosed as major depression. Its early diagnosis necessitates that clinicians pay attention to the features of the patient's depression and also look for present or prior hypomanic or manic symptomatology. The misdiagnosis of schizophrenia is also a common problem. There may be long delays of patients getting a correct diagnosis of this disorder. Delayed sleep phase disorder is often confused with: psychophysiological insomnia; depression; psychiatric disorders such as schizophrenia, ADHD or ADD; other sleep disorders; or school refusal. Practitioners of sleep medicine point out the dismally low rate of accurate diagnosis of the disorder, and have often asked for better physician education on sleep disorders. Cluster headaches are often misdiagnosed, mismanaged, or undiagnosed for many years; they may be confused with migraine, "cluster-like" headache (or mimics), CH subtypes, other TACs (trigeminal autonomic cephalalgias), or other types of primary or secondary headache syndrome. Cluster-like head pain may be diagnosed as secondary headache rather than cluster headache. Under-recognition of CH by health care professionals is reflected in consistent findings in Europe and the United States that the average time to diagnosis is around seven years. Asperger syndrome and autism tend to get undiagnosed or delayed recognition and delayed diagnosis or misdiagnosed. Delayed or mistaken diagnosis can be traumatic for individuals and families; for example, misdiagnosis can lead to medications that worsen behavior. Field trials of the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) included "test-retest reliability" which involved different clinicians doing independent evaluations of the same patient—a new approach to the study of diagnostic reliability. === Outpatient vs. inpatient === Misdiagnosis is the leading cause of medical error in outpatient facilities. Since the National Institute of Medicine's 1999 report, "To Err is Human," found up to 98,000 hospital patients die from preventable medical errors in the U.S. each year, government and private sector efforts have focused on inpatient safety. === Medical prescriptions === While in 2000 the Committee on Quality of Health Care in America affirmed medical mistakes are an "unavoidable outcome of learning to practice medicine", at 2019 the commonly accepted link between prescribing skills and clinical clerkships was not yet demonstrated by the available data and in the U.S. legibility of handwritten prescriptions has been indirectly responsible for at least 7,000 deaths annually. Prescription errors concern ambiguous abbreviations, the right spelling of the full name of drugs: improper use of the nomenclature, of decimal points, unit or rate expressions; legibility and proper instructions; miscalculations of the posology (quantity, route and frequency of administration, duration of the treatment, dosage form and dosage strength); lack of information about patients (e.g. allergy, declining renal function) or reported in the medical document. There were an estimated 66 million clinically significant medication errors in the British NHS in 2018. The resulting adverse drug reactions are estimated to cause around 700 deaths a year in England and to contribute to around 22,000 deaths a year. The British researchers did not find any evidence that error rates were lower in other countries, and the global cost was estimated at $42 billion per year. Medication errors in hospital include omissions, delayed dosing and incorrect medication administrations. Medication errors are not always readily identified, but can be reported using case note reviews or incident reporting systems. There are pharmacist-led interventions that can reduce the incident of medication error. Electronic prescribing has been shown to reduce prescribing errors by up to 30%. == Mitigation (after an error) == Mistakes can have a strongly negative emotional impact on the doctors who commit them. === Recognizing that mistakes are not isolated events === Some physicians recognize that adverse outcomes from errors usually do not happen because of an isolated error and actually reflect system problems. This concept is often referred to as the Swiss Cheese Model. This is the concept that there are layers of protection for clinicians and patients to prevent mistakes from occurring. Therefore, even if a doctor or nurse makes a small error (e.g. incorrect dose of drug written on a drug chart by doctor), this is picked up before it actually affects patient care (e.g. pharmacist checks the drug chart and rectifies the error). Such mechanisms include: Practical alterations (e.g.-medications that cannot be given through IV, are fitted with tubing which means they cannot be linked to an IV even if a clinician makes a mistake and tries to), systematic safety processes (e.g. all patients must have a Waterlow score assessment and falls assessment completed on admission), and training programmes/continuing professional development courses are measures that may be put in place. There may be several breakdowns in processes to allow one adverse outcome. In addition, errors are more common when other demands compete for a physician's attention. However, placing too much blame on the system may not be constructive. === Placing the practice of medicine in perspective === Essayists imply that the potential to make mistakes is part of what makes being a physician rewarding and without this potential the rewards of medical practice would be diminished. Laurence states that "Everybody dies, you and all of your patients. All relationships end. Would you want it any other way? [...] Don't take it personally". Seder states "[...] if I left medicine, I would mourn its loss as I've mourned the passage of my poetry. On a daily basis, it is both a privilege and a joy to have the trust of patients and their families and the camaraderie of peers. There is no challenge to make your blood race like that of a difficult case, no mind game as rigorous as the challenging differential diagnosis, and though the stakes are high, so are the rewards." === Disclosing mistakes === Forgiveness, which is part of many cultural traditions, may be important in coping with medical mistakes. Among other healing processes, it can be accomplished through the use of communicative disclosure guidelines. ==== To oneself ==== Inability to forgive oneself may create a cycle of distress and increased likelihood of a future error. However, Wu et al. suggest "...those who coped by accepting responsibility were more likely to make constructive changes in practice, but [also] to experience more emotional distress." It may be helpful to consider the much larger number of patients who are not exposed to mistakes and are helped by medical care. ==== To patients ==== Gallagher et al. state that patients want "information about what happened, why the error happened, how the error's consequences will be mitigated, and how recurrences will be prevented." Interviews with patients and families reported in a 2003 book by Rosemary Gibson and Janardan Prasad Singh, put forward that those who have been harmed by medical errors face a "wall of silence" and "want an acknowledgement" of the harm. With honesty, "healing can begin not just for the patients and their families but also the doctors, nurses and others involved." In a line of experimental investigations, Annegret Hannawa et al. developed evidence-based disclosure guidelines under the scientific "Medical Error Disclosure Competence (MEDC)" framework. A review of studies examining patients' views on investigations of medical harm found commonalities in their expectations of the process. For example, many wanted reviews to be transparent, trustworthy, and person-centred to meet their needs. People wanted to be meaningfully involved in the process and to be treated with respect and empathy. Justice-seekers wanted an honest account of what happened, the circumstances leading up to it, and measures to ensure it does not happen again. Processes that, for example, involved people independent of the organisation responsible for harm gave investigations credibility. A 2005 study by Wendy Levinson of the University of Toronto showed surgeons discussing medical errors used the word "error" or "mistake" in only 57 percent of disclosure conversations and offered a verbal apology only 47 percent of the time. Patient disclosure is important in the medical error process. The current standard of practice at many hospitals is to disclose errors to patients when they occur. In the past, it was a common fear that disclosure to the patient would incite a malpractice lawsuit. Many physicians would not explain that an error had taken place, causing a lack of trust toward the healthcare community. In 2007, 34 states passed legislation that precludes any information from a physician's apology for a medical error from being used in malpractice court (even a full admission of fault). This encourages physicians to acknowledge and explain mistakes to patients, keeping an open line of communication. The American Medical Association's Council on Ethical and Judicial Affairs states in its ethics code: "Situations occasionally occur in which a patient suffers significant medical complications that may have resulted from the physician's mistake or judgment. In these situations, the physician is ethically required to inform the patient of all facts necessary to ensure understanding of what has occurred. Concern regarding legal liability which might result following truthful disclosure should not affect the physician's honesty with a patient." From the American College of Physicians Ethics Manual: "In addition, physicians should disclose to patients information about procedural or judgment errors made in the course of care if such information is material to the patient's well-being. Errors do not necessarily constitute improper, negligent, or unethical behavior, but failure to disclose them may." However, "there appears to be a gap between physicians' attitudes and practices regarding error disclosure. Willingness to disclose errors was associated with higher training level and a variety of patient-centered attitudes, and it was not lessened by previous exposure to malpractice litigation". Hospital administrators may share these concerns. Consequently, in the United States, many states have enacted laws excluding expressions of sympathy after accidents as proof of liability. Disclosure may actually reduce malpractice payments. Reluctance to disclose medical errors to patients may also stem from psychological reasons. In his book, Medical Errors and Medical Narcissism, John Banja defines "medical narcissism" as the need of health professionals to preserve their self-esteem leading to the compromise of error disclosure to patients. ==== To non-physicians ==== In a study of physicians who reported having made a mistake, it was offered that disclosing to non-physician sources of support may reduce stress more than disclosing to physician colleagues. This may be due to the finding that of the physicians in the same study, when presented with a hypothetical scenario of a mistake made by another colleague, only 32% of them would have unconditionally offered support. It is possible that greater benefit occurs when spouses are physicians. ==== To other physicians ==== Discussing mistakes with other physicians is beneficial. However, medical providers may be less forgiving of one another. The reason is not clear, but one essayist has admonished, "Don't Take Too Much Joy in the Mistakes of Other Doctors." ==== To the physician's institution ==== Disclosure of errors, especially "near misses", may be able to reduce subsequent errors in institutions that are capable of reviewing near misses. However, doctors report that institutions may not be supportive of the doctor. ==== Use of rationalization to cover up medical errors ==== Based on anecdotal and survey evidence, Banja states that rationalization (making excuses) is very common among the medical profession to cover up medical errors. ==== By potential for harm to the patient ==== In a survey of more than 10,000 physicians in the United States, when asked the question, "Are there times when it's acceptable to cover up or avoid revealing a mistake if that mistake would not cause harm to the patient?", 19% answered yes, 60% answered no and 21% answered it depends. On the question, "Are there times when it is acceptable to cover up or avoid revealing a mistake if that mistake would potentially or likely harm the patient?", 2% answered yes, 95% answered no and 3% answered it depends. === Legal procedure === Standards and regulations for medical malpractice vary by country and jurisdiction within countries. Medical professionals may obtain professional liability insurances to offset the risk and costs of lawsuits based on medical malpractice. == Prevention == Medical care is frequently compared adversely to aviation; while many of the factors that lead to errors in both fields are similar, aviation's error management protocols are regarded as much more effective. Safety measures include informed consent, the availability of a second practitioner's opinion, voluntary reporting of errors, root cause analysis, reminders to improve patient medication adherence, hospital accreditation, and systems to ensure review by experienced or specialist practitioners. A template has been developed for the design (both structure and operation) of hospital medication safety programmes, particularly for acute tertiary settings, which emphasizes safety culture, infrastructure, data (error detection and analysis), communication and training. Particularly to prevent the medication errors in the perspective of the intrathecal administration of local anaesthetics, there is a proposal to change the presentation and packaging of the appliances and agents used for this purpose. One spinal needle with a syringe prefilled with the local anaesthetic agents may be marketed in a single blister pack, which will be peeled open and presented before the anaesthesiologist conducting the procedure. Physician well-being has also been recommended as an indicator of healthcare quality given its association with patient safety outcomes. A meta-analysis involving 21517 participants found that physicians with depressive symptoms had a 95% higher risk of reporting medical errors and that the association between physician depressive symptoms and medical errors is bidirectional === Reporting requirements === In the United States, adverse medical event reporting systems were mandated in just over half (27) of the states as of 2014, a figure unchanged since 2007. In U.S. hospitals error reporting is a condition of payment by Medicare. An investigation by the Office of Inspector General, Department of Health and Human Services released January 6, 2012 found that most errors are not reported and even in the case of errors that are reported and investigated changes are seldom made which would prevent them in the future. The investigation revealed that there was often lack of knowledge regarding which events were reportable and recommended that lists of reportable events be developed. === Cause-specific preventive measures === Traditionally, errors are attributed to mistakes made by individuals, who then may be penalized. A common approach to respond to and prevent specific errors is requiring additional checks at particular points in the system, whose findings and detail of execution must be recorded. As an example, an error of free flow IV administration of heparin is approached by teaching staff how to use the IV systems and to use special care in setting the IV pump. While overall errors become less likely, the checks add to workload and may in themselves be a cause of additional errors. In some hospitals, a regular morbidity and mortality conference meeting is scheduled to discuss complications or deaths and learn from or improve the overall processes. A newer model for improvement in medical care takes its origin from the work of W. Edwards Deming in a model of Total Quality Management. In this model, there is an attempt to identify the underlying system defect that allowed the error to occur. As an example, in such a system the error of free flow IV administration of heparin is dealt with by not using IV heparin and substituting subcutaneous administration of heparin, obviating the entire problem. However, such an approach presupposes available research showing that subcutaneous heparin is as effective as IV. Thus, most systems use a combination of approaches to the problem. === Anaesthesiology === The field of medicine that has taken the lead in systems approaches to safety is anaesthesiology. Steps such as standardization of IV medications to 1 ml doses, national and international color-coding standards, and development of improved airway support devices has the field a model of systems improvement in care. === Medications === Reducing errors in prescribing, dispensing, compounding/formulating, labelling, and handling medications is a priority and has been the subject of systematic reviews and studies. Examples of areas to reduce medication errors and improve safety include: Training professionals or using databases to compare new and previous prescribed medications to prevent mistakes, also known as "medication reconciliation", prescribing through an electronic medical record system and/or using decision support systems that has automatic checks in place, with computerized alerts or other novel technologies, the use of machine-readable barcodes, healthcare professional and patient training or supplementary educational programs, adding in an extra step for double checking prescriptions (both at the level of the healthcare professional and at the administrator level), using standardized protocols in the workplace that include a check-list, physical markings or writing on syringes to indicate correct doses, programmes that include the person being able to administer the medications themselves, ensuring that the workplace or environment is well-lit, monitoring and adjusting healthcare professional working hours, and the use of an interdisciplinary team. There is weak evidence indicating that a number of these suggested interventions may be helpful in reducing errors or improving patient safety, however, in general, evidence supporting the best or most effective intervention for reducing errors not strong. Evidence supporting improvements aimed at reducing medical errors in medications for pediatric hospitalized patients is also very weak. === Historically === As far back as the 1930s, pharmacists worked with physicians to select, from many options, the safest and most effective drugs available for use in hospitals. The process is known as the Formulary System and the list of drugs is known as the Formulary. In the 1960s, hospitals implemented unit dose packaging and unit dose drug distribution systems to reduce the risk of wrong drug and wrong dose errors in hospitalized patients; centralized sterile admixture services were shown to decrease the risks of contaminated and infected intravenous medications; and pharmacists provided drug information and clinical decision support directly to physicians to improve the safe and effective use of medications. Pharmacists are recognized experts in medication safety and have made many contributions that reduce error and improve patient care over the last 50 years. More recently, governments have attempted to address issues like patient-pharmacist communication and consumer knowledge through measures like the Australian Government's Quality Use of Medicines policy. == Misconceptions == Some common misconceptions about medical error include: Medical error is the "third leading cause of death" in the United States. This canard stems from an erroneous 2016 study which, according to David Gorski, "has taken on a life of its own" and fuelled "a myth promulgated by both quacks and academics". "Bad apples" or incompetent health care providers are a common cause. (Although human error is commonly an initiating event, the faulty care delivery process invariably permits or compounds the harm and so is the focus of improvement.) High-risk procedures or medical specialties are responsible for most avoidable adverse events. (Although some mistakes, such as in surgery, are harder to conceal, errors occur in all levels of care. Even though complex procedures entail more risk, adverse outcomes are not usually due to error, but to the severity of the condition being treated.) However, United States Pharmacopeia has reported that medication errors during the course of a surgical procedure are three times more likely to cause harm to a patient than those occurring in other types of hospital care. If a patient experiences an adverse event during the process of care, an error has occurred. (Most medical care entails some level of risk, and there can be complications or side effects, even unforeseen ones, from the underlying condition or from the treatment itself.) == See also == == References == == Further reading == Gawande, Atul (2002). Complications: A Surgeon's Notes on an Imperfect Science. New York: Metropolitan Books. ISBN 978-0-8050-6319-6. Wachter, Robert; Shojania, Kaveh (2004). Internal Bleeding: The Truth Behind America's Terrifying Epidemic of Medical Mistakes. New York: Rugged Land. ISBN 978-1-59071-016-6. Banja, John (2005). Medical Errors and Medical Narcissism. Boston: Jones and Bartlett. ISBN 978-0-7637-8361-7. Porter, Michael E.; Olmsted Teisberg, Elizabeth (2006). Redefining Health Care: Creating Value-Based Competition on Results. Boston: Harvard Business School Press. ISBN 978-1-59139-778-6. Gibson, Rosemary; Prasad Singh, Janardan (2003). Wall of Silence: The Untold Story of the Medical Mistakes That Kill and Injure Millions of Americans. Washington D.C.: Regnery. ISBN 978-0-89526-112-0. Alldred D.P.; Standage C.; Zermansky A.G.; Jesson B.; Savage I.; Franklin B.D.; Barber N.; Raynor D.K. (2008). "Development and validation of criteria to identify medication-monitoring errors in care home residents". International Journal of Pharmacy Practice. 16 (5): 317–323. doi:10.1211/ijpp.16.5.0007. S2CID 71701489. Committee on Identifying and Preventing Medication Errors; Board on Health Care Services (2007). Preventing medication errors. National Academies Press. ISBN 978-0-309-10147-9. Tewari, A.; Palm, B.; Hines, T.; Royer, T.; Alexander, E. (2014). "VEINROM: A possible solution for erroneous intravenous drug administration". Journal of Anaesthesiology Clinical Pharmacology. 30 (2): 263–266. doi:10.4103/0970-9185.130055. PMC 4009652. PMID 24803770.	Wikipedia/Misdiagnosis
Atrial tachycardia is a type of heart rhythm problem in which the heart's electrical impulse comes from an ectopic pacemaker (that is, an abnormally located cardiac pacemaker) in the upper chambers (atria) of the heart, rather than from the sinoatrial node, the normal origin of the heart's electrical activity. As with any other form of tachycardia (rapid heart beat), the underlying mechanism can be either the rapid discharge of an abnormal focus, the presence of a ring of cardiac tissue that gives rise to a circle movement (reentry), or a triggered rapid rhythm due to other pathological circumstances (as would be the case with some drug toxicities, such as digoxin toxicity). == Classification == Forms of atrial tachycardia (ATach) include multifocal atrial tachycardia (MAT), focal atrial tachycardia and atrial flutter. Paroxysmal atrial tachycardia (PAT) is an episode of arrhythmia that begins and ends abruptly. == Etiology == Atrial tachycardia tends to occur in individuals with structural heart disease, with or without heart failure, and ischemic coronary artery disease. However, focal atrial tachycardia often occurs in healthy individuals without structural heart disease. Other possible etiologies are listed below: Hypoxia Pulmonary disease Ischemic heart disease Stimulants: cocaine, caffeine, chocolate, ephedra Alcohol Metabolic disturbances Digoxin toxicity Heightened sympathetic tone A study noted 10 to 15% of patients presenting for supraventricular tachycardia (SVT) ablation had atrial tachycardia. == Diagnosis == Electrocardiographic features include: Atrial rate: 100 to 250 BPM Ventricular conduction can be variable Irregular or irregularly irregular in the setting of variable AV block Regular if 1 to 1, 2 to 1, or 4 to 1 AV block P wave morphology Unifocal, but similar in morphology to each other Might be inverted Differs from normal sinus P wave May exhibit either long RP or short PR intervals Rhythm may be paroxysmal or sustained May demonstrate an increase in the rate at initiation (e.g., "warm up," or "rev up") May demonstrate a decrease in the rate at termination (e.g., "cool down") == Treatment == Initial management of focal atrial tachycardia should focus on addressing underlying causes: treating acute illness, cessation of stimulants, stress reduction, appropriately managing digoxin toxicity, or chronic disease management. The ventricular rate is controllable with the use of beta blockers or calcium channel blockers. If atrial tachyarrhythmia persists and the patient is symptomatic, the patient may benefit from class IA, IC, or class III antiarrhythmics. Catheter ablation of focal atrial tachycardia may be appropriate in patients failing medical therapy. == Epidemiology == A European study of young males applying for pilot licenses demonstrated that 0.34% had asymptomatic atrial tachycardia and 0.46% had symptomatic atrial tachycardia. == References == == External links ==	Wikipedia/Paroxysmal_atrial_tachycardia
Sinus node dysfunction (SND), also known as sick sinus syndrome (SSS), is a group of abnormal heart rhythms (arrhythmias) usually caused by a malfunction of the sinus node, the heart's primary pacemaker. Tachycardia-bradycardia syndrome is a variant of sick sinus syndrome in which the arrhythmia alternates between fast and slow heart rates. == Signs and symptoms == Often sinus node dysfunction produces no symptoms, especially early in the disease course. Signs and symptoms usually appear in more advanced disease and more than 50% of patients will present with syncope or transient near-fainting spells as well as bradycardias that are accompanied by rapid heart rhythms, referred to as tachycardia-bradycardia syndrome Other presenting signs or symptoms can include confusion, fatigue, palpitations, chest pain, shortness of breath, headache, and nausea. Patients can also present with symptoms of congestive heart failure, stroke or transient ischemic attacks due to the abnormal rhythm. === Complications === The most common complication of sinus node dysfunction is the development of tachycardia-bradycardia syndrome with abnormal atrial rhythms such as atrial tachycardia, atrial fibrillation, and flutter. These rhythms increases the risk of clot formation in the atrium, embolization, and stroke. Developing sinus arrest, sinus node exit block, sinus bradycardia, atrioventricular block, and other types of abnormal rhythms are also common complications. Sinus node dysfunction has a close association with the presence of atrial fibrillation due to their shared etiology of remodeling. == Causes == Sinus node dysfunction can be caused by intrinsic and extrinsic factors that affect the normal functioning of the sinus node. Intrinsic causes can include degeneration, dysfunction, or remodeling of the sinus node while extrinsic causes can create or worsen underlying atrial arrhythmias. Intrinsic causes tend to be responsible for permanent sinus node dysfunction while extrinsic causes are more commonly temporary. === Intrinsic causes === Age-related degenerative fibrosis of the sinus node is often identified as the most common intrinsic cause. Other intrinsic causes include inherited ion channel dysfunctions, remodeling diseases such as heart failure and atrial fibrillation, infiltrative diseases such as sarcoidosis, amyloidosis, hemochromatosis, and connective tissue diseases, inflammatory etiology such as rheumatic fever, Chagas disease, and Lyme disease, as well as atherosclerotic and ischemic changes to the sinus node artery. Inherited sinus node dysfunction has been associated with mutations of the gene responsible for the formation of the alpha subunit of the sodium channel (SCN5A). === Extrinsic causes === Common cardiac pharmacology such as beta-blockers, calcium channel blockers, digoxin, sympatholytic medication, and other antiarrhythmics can alter sinus node function to create an arrhythmia such as sick sinus syndrome. Electrolyte abnormalities such as hyperkalemia, hypokalemia, and hypocalcemia can also alter normal sinus node functioning. Hypothyroidism, hypoxia, hypothermia, and various toxins have also been associated with sinus node dysfunctions. == Diagnosis == === Electrocardiogram === The primary 12-lead electrocardiogram (ECG) finding in sinus node dysfunction is inappropriate sinus bradycardia. Sinus node dysfunction can also present with sudden sinus arrest with or without junctional escape, sinoatrial block, prolonged asystolic period followed by tachycardias, or tachycardia-bradycardia syndrome presenting as various atrial arrhythmias such as atrial fibrillation, flutter, tachycardia, or paroxysmal supraventricular tachycardia. === Clinical diagnosis === Diagnosing sinus node dysfunction requires clinical symptoms as well as ECG abnormalities. If ECG findings cannot be identified, prolonged cardiac monitoring should be pursued either with a Holter monitor in an outpatient setting or telemetry while inpatient, due to the transient nature of abnormal ECG findings. If Holter or telemetry monitoring fails to identify ECG changes and suspicion of sinus node dysfunction remains high due to severe symptoms or episodes of syncope, implantable loop recorders should be considered for extended monitoring up to 24 months. Exercise stress tests can be utilized to identify intrinsic causes of sinus node dysfunction. Tilt table tests can be used to discriminate bradycardia caused by dysfunction of the autonomic nervous system. == Treatment == The primary reason for considering treatment is the presence of symptoms. Pacemaker implantation is the primary treatment modality of symptomatic sinus node dysfunction. The goal of this treatment modality is to relieve symptoms associated with sinus node dysfunction and improve quality of life. Dual chamber pacemakers are preferred due to the possibility of developing atrioventricular block as well as long term cost-effectiveness relative to single-chamber atrial pacemakers. In tachycardia-bradycardia syndrome, medication-based management can treat atrial tachyarrhythmias. However, these medications may exacerbate underlying bradyarrhythmia. Therefore, a dual-chamber pacemaker capable of managing atrial tachyarrhythmias as well as bradyarrhythmias is implanted before drug therapy is begun. == Epidemiology == Overall incidence of sinus node dysfunction increases with age with 1 in 1000 in adults over 45 years old and 1 in 600 cardiac patients over 65 years old. Sinus node dysfunction is the primary indication for approximately 30%-50% of all pacemaker implantation in the United States. Sinus node dysfunction is a relatively uncommon syndrome in the young and middle-aged population. == References == == External links ==	Wikipedia/Sinus_node_dysfunction
A heart rate monitor (HRM) is a personal monitoring device that allows one to measure/display heart rate in real time or record the heart rate for later study. It is largely used to gather heart rate data while performing various types of physical exercise. Measuring electrical heart information is referred to as electrocardiography (ECG or EKG). Medical heart rate monitoring used in hospitals is usually wired and usually multiple sensors are used. Portable medical units are referred to as a Holter monitor. Consumer heart rate monitors are designed for everyday use and do not use wires to connect. == History == Early models consisted of a monitoring box with a set of electrode leads which attached to the chest. The first wireless EKG heart rate monitor was invented in 1977 by Polar Electro as a training aid for the Finnish National Cross Country Ski team. As "intensity training" became a popular concept in athletic circles in the mid-80s, retail sales of wireless personal heart monitors started in 1983. == Technologies == Modern heart rate monitors commonly use one of two different methods to record heart signals (electrical and optical). Both types of signals can provide the same basic heart rate data, using fully automated algorithms to measure heart rate, such as the Pan-Tompkins algorithm. ECG (Electrocardiography) sensors measure the bio-potential generated by electrical signals that control the expansion and contraction of heart chambers, typically implemented in medical devices. PPG (Photoplethysmography) sensors use light-based technology to measure the blood volume controlled by the heart's pumping action. === Electrical === The electrical monitors consist of two elements: a monitor/transmitter, which is worn on a chest strap, and a receiver. When a heartbeat is detected, a radio signal is transmitted, which the receiver uses to display/determine the current heart rate. This signal can be a simple radio pulse or a unique coded signal from the chest strap (such as Bluetooth, ANT, or other low-power radio links). Newer technology prevents one user's receiver from using signals from other nearby transmitters (known as cross-talk interference) or eavesdropping. Note, that the older Polar 5.1 kHz radio transmission technology is usable underwater. Both Bluetooth and Ant+ use the 2.4 GHz radio band, which cannot send signals underwater. === Optical === More recent devices use optics to measure heart rate by shining light from an LED through the skin and measuring how it scatters off blood vessels. In addition to measuring the heart rate, some devices using this technology are able to measure blood oxygen saturation (SpO2). Some recent optical sensors can also transmit data as mentioned above. Newer devices such as cell phones or watches can be used to display and/or collect the information. Some devices can simultaneously monitor heart rate, oxygen saturation, and other parameters. These may include sensors such as accelerometers, gyroscopes, and GPS to detect speed, location and distance. In recent years, it has been common for smartwatches to include heart rate monitors, which has greatly increased in popularity. Some smartwatches, smart bands and cell phones often use PPG sensors. === Fitness metrics === Garmin (Venu Sq 2 and Lily), Polar Electro (Polar H9, Polar H10, and Polar Verity Sense), Suunto, Samsung Galaxy Watch (Galaxy Watch 5 and Galaxy Watch 6), Google (Pixel Watch 2), Spade and Company, Vital Fitness Tracker, Apple Watch (Series 7, Series 9, Apple Watch SE, Apple Watch Ultra 2), Mobvoi (TicWatch Pro 5) and Fitbit (Versa 3* and Versa 4*) are vendors selling consumer heart rate products. Most companies use their own proprietary heart rate algorithms. == Accuracy == The newer, wrist based heart rate monitors have achieved almost identical levels of accuracy as their chest strap counterparts with independent tests showing up to 95% accuracy, but sometimes more than 30% error can persist for several minutes. Optical devices can be less accurate when used during vigorous activity, or when used underwater. Currently, heart rate variability is less available on optical devices. Apple introduced HRV data collection to the Apple Watch devices in 2018. Fitbit started offering HRV monitoring on their devices starting from the Fitbit Sense, released in 2020. === Heart rate prediction === Heart rate prediction using machine learning has gained significant attention in health monitoring and sports performance research. Namazi et.al., 2025 evaluated various models including Long Short-Term Memory (LSTM), Physics-Informed Neural Networks (PINNs), and 1D Convolutional Neural Networks (1D CNNs), using physiological data such as heart rate (HR), breathing rate (BR), and RR intervals collected from wearable sensors during sports activities. The study introduced a hybrid approach combining Singular Spectrum Analysis (SSA) with these models to enhance predictive performance. Among the tested models, the SSA-LSTM method yielded the lowest prediction error, particularly when multivariate inputs (HR + BR + RR) were used. These findings support the use of AI-driven, multivariate prediction models for real-time cardiovascular monitoring in athletic and healthcare settings. == See also == Activity tracker Apple Watch E-textiles eHealth GPS watch Pedometer == References == == External links == Media related to Heart rate monitors at Wikimedia Commons Visualization of ECG recordings using Python program ECG-pyview A simple Python program visualizing raw data produced by chest strap based ECG sportesters. Enables to inspect ECG recordings having lengths up to days. (Open source, non-commercial use, use matplotlib.) A demo video.	Wikipedia/Heart_rate_monitor
Atrial flutter (AFL) is a common abnormal heart rhythm that starts in the atrial chambers of the heart. When it first occurs, it is usually associated with a fast heart rate and is classified as a type of supraventricular tachycardia (SVT). Atrial flutter is characterized by a sudden-onset (usually) regular abnormal heart rhythm on an electrocardiogram (ECG) in which the heart rate is fast. Symptoms may include a feeling of the heart beating too fast, too hard, or skipping beats, chest discomfort, difficulty breathing, a feeling as if one's stomach has dropped, a feeling of being light-headed, or loss of consciousness. Although this abnormal heart rhythm typically occurs in individuals with cardiovascular disease (e.g., high blood pressure, coronary artery disease, and cardiomyopathy) and diabetes mellitus, it may occur spontaneously in people with otherwise normal hearts. It is typically not a stable rhythm and often degenerates into atrial fibrillation (AF). But rarely does it persist for months or years. Similar to the abnormal heart rhythm atrial fibrillation, atrial flutter also leads to poor contraction of the atrial chambers of the heart. This leads to the pooling of the blood in the heart and can lead to the formation of blood clots in the heart, which poses a significant risk of breaking off and traveling through the bloodstream, resulting in strokes. A supraventricular tachycardia with a ventricular heart rate of 150 beats per minute is suggestive (though not necessarily diagnostic) of atrial flutter. Administration of adenosine in the vein (intravenously) can help medical personnel differentiate between atrial flutter and other forms of supraventricular tachycardia. Immediate treatment of atrial flutter centers on slowing the heart rate with medications such as beta blockers (e.g., metoprolol) or calcium channel blockers (e.g., diltiazem) if the affected person is not having chest pain, has not lost consciousness, and if their blood pressure is normal (known as stable atrial flutter). If the affected person is having chest pain, has lost consciousness, or has low blood pressure (unstable atrial flutter), then an urgent electrical shock to the heart to restore a normal heart rhythm is necessary. Long-term use of blood thinners (e.g., warfarin or apixaban) is an important component of treatment to reduce the risk of blood clot formation in the heart and resultant strokes. Medications used to restore a normal heart rhythm (antiarrhythmics) such as ibutilide effectively control atrial flutter about 80% of the time when they are started but atrial flutter recurs at a high rate (70–90% of the time) despite continued use. Atrial flutter can be treated more definitively with a technique known as catheter ablation. This involves the insertion of a catheter through a vein in the groin which is followed up to the heart and is used to identify and interrupt the electrical circuit causing the atrial flutter (by creating a small burn and scar). Atrial flutter was first identified as an independent medical condition in 1920 by the British physician Sir Thomas Lewis (1881–1945) and colleagues. AFL is the second most common pathologic supraventricular tachycardia but occurs at a rate less than one-tenth of the most common supraventricular tachycardia (atrial fibrillation). The overall incidence of AFL has been estimated at 88 cases per 100,000 person-years. The incidence of AFL is significantly lower (~5 cases/100,000 person-years) in those younger than age 50 and is far more common (587 cases/100,000 person-years) in those over 80 years of age. == Signs and symptoms == While atrial flutter can sometimes go unnoticed, its onset is often marked by characteristic sensations of the heart feeling like it is beating too fast or hard. Such sensations usually last until the episode resolves, or until the heart rate is controlled. Atrial flutter is usually well-tolerated initially (a high heart rate is, for most people just a normal response to exercise); however, people with other underlying heart diseases (such as coronary artery disease) or poor exercise tolerance may rapidly develop symptoms, such as shortness of breath, chest pain, lightheadedness or dizziness, nausea and, in some patients, nervousness and feelings of impending doom. Prolonged atrial flutter with fast heart rates may lead to decompensation with loss of normal heart function (heart failure). This may manifest as exercise intolerance (exertional breathlessness), difficulty breathing at night, or swelling of the legs and/or abdomen. === Complications === Although often regarded as a relatively benign heart rhythm problem, atrial flutter shares the same complications as the related condition atrial fibrillation. There is a paucity of published data directly comparing the two, but overall mortality in these conditions appears to be very similar. ==== Rate-related ==== Rapid heart rates may produce significant symptoms in patients with pre-existing heart disease and can lead to inadequate blood flow to the heart muscle and even a heart attack. In rare situations, atrial flutter associated with a fast heart rate persists for an extended period of time without being corrected to a normal heart rhythm and leads to a tachycardia-induced cardiomyopathy. Even in individuals with a normal heart, if the heart beats too quickly for a prolonged period of time, this can lead to ventricular decompensation and heart failure. ==== Clot formation ==== Because there is little, if any, effective contraction of the atria, there is stasis (pooling) of blood in the atria. Stasis of blood in susceptible individuals can lead to the formation of a thrombus (blood clot) within the heart. A thrombus is most likely to form in the atrial appendages. A blood clot in the left atrial appendage is particularly important as the left side of the heart supplies blood to the entire body through the arteries. Thus, any thrombus material that dislodges from this side of the heart can embolize (break off and travel) to the brain's arteries, with the potentially devastating consequence of a stroke. Thrombus material can embolize to any other portion of the body, though usually with a less severe outcome. ==== Sudden cardiac death ==== Sudden death is not directly associated with atrial flutter. However, in individuals with a pre-existing accessory conduction pathway, such as the bundle of Kent in Wolff-Parkinson-White syndrome, the accessory pathway may conduct activity from the atria to the ventricles at a rate that the AV node would usually block. Bypassing the AV node, the atrial rate of 300 beats/minute leads to a ventricular rate of 300 beats/minute (1:1 conduction). Even if the ventricles are able to sustain a cardiac output at such a high rate, 1:1 flutter with time may degenerate into ventricular fibrillation, causing hemodynamic collapse and death. == Pathophysiology == Atrial flutter is caused by a re-entrant rhythm. This usually occurs along the cavo-tricuspid isthmus of the right atrium though atrial flutter can originate in the left atrium as well. Typically initiated by a premature electrical impulse arising in the atria, atrial flutter is propagated due to differences in refractory periods of atrial tissue. This creates electrical activity that moves in a localized self-perpetuating loop, which usually lasts about 200 milliseconds for the complete circuit. For each cycle around the loop, an electric impulse results and propagates through the atria. The impact and symptoms of atrial flutter depend on the heart rate of the affected person. Heart rate is a measure of ventricular rather than atrial activity. Impulses from the atria are conducted to the ventricles through the atrio-ventricular node (AV node). In a person with atrial flutter, a 12-lead electrocardiogram (ECG) will demonstrate the atrial chambers of the heart contracting at a rate of 280–300 beats per minute whereas the ventricular chambers of the heart typically beat at a rate of 140–150 beats per minute. Due primarily to its longer refractory period, the AV node exerts a protective effect on heart rate by blocking atrial impulses in excess of about 180 beats/minute, for the example of a resting heart rate. (This block is dependent on the age of the patient and can be calculated roughly by subtracting patient age from 220). If the flutter rate is 300 beats per minute, only half of these impulses will be conducted, giving a ventricular rate of 150 beats per minute, or a 2:1 heart block. The addition of rate-controlling drugs or conduction system disease can increase this block substantially == Diagnosis == Typical atrial flutter is recognized on an electrocardiogram by the presence of characteristic "flutter waves" at a regular rate of 250 to 350 beats per minute. Flutter waves may not be evident on an ECG in atypical forms of atrial flutter. Individual flutter waves may be symmetrical, resembling p-waves, or maybe asymmetrical with a "sawtooth" shape, rising gradually and falling abruptly or vice versa. If atrial flutter is suspected clinically but is not clearly evident on ECG, acquiring a Lewis lead ECG may be helpful in revealing flutter waves. === Classification === There are two types of atrial flutter, the common type I and rarer type II. Most individuals with atrial flutter will manifest only one of these. Rarely someone may manifest both types; however, they can manifest only one type at a time. ==== Type I ==== Type I atrial flutter, also known as common atrial flutter or typical atrial flutter, has an atrial rate of 240 to 340 beats/minute. However, this rate may be slowed by antiarrhythmic agents. The reentrant loop circles the right atrium, passing through the cavo-tricuspid isthmus – a body of fibrous tissue in the lower atrium between the inferior vena cava, and the tricuspid valve. Type I flutter is further divided into two subtypes, known as counterclockwise atrial flutter and clockwise atrial flutter depending on the direction of current passing through the loop. Counterclockwise atrial flutter (known as cephalad-directed atrial flutter) is more commonly seen. The flutter waves in this rhythm are inverted in ECG leads II, III, and aVF. The re-entry loop cycles in the opposite direction in clockwise atrial flutter, thus the flutter waves are upright in II, III, and aVF. ==== Type II ==== Type II (atypical) atrial flutter follows a significantly different re-entry pathway to type I flutter, and is typically faster, usually 340–350 beats/minute. Atypical atrial flutter rarely occurs in people who have not undergone previous heart surgery or previous catheter ablation procedures. Left atrial flutter is considered atypical and is common after incomplete left atrial ablation procedures. Atypical atrial flutter originating from the right atrium and heart's septum have also been described. == Management == In general, atrial flutter should be managed in the same way as atrial fibrillation. Because both rhythms can lead to the formation of a blood clot in the atrium, individuals with atrial flutter usually require some form of anticoagulation or antiplatelet agent. Both rhythms can be associated with dangerously fast heart rates and thus require medication to control the heart rate (such as beta blockers or calcium channel blockers) and/or rhythm control with class III antiarrhythmics (such as ibutilide or dofetilide). However, atrial flutter is more resistant to correction with such medications than atrial fibrillation. For example, although the class III antiarrhythmic agent ibutilide is an effective treatment for atrial flutter, rates of recurrence after treatment are quite high (70–90%). Additionally, there are some specific considerations particular to treatment of atrial flutter. === Cardioversion === Atrial flutter is considerably more sensitive to electrical direct current cardioversion than atrial fibrillation, with a shock of only 20 to 50 Joules commonly being enough to cause a return to a normal heart rhythm (sinus rhythm). Exact placement of the pads does not appear important. === Ablation === Due to the reentrant nature of atrial flutter, it is often possible to ablate the circuit that causes atrial flutter with radiofrequency catheter ablation or pulsed field ablation. Catheter ablation was considered to be a first-line treatment method for many people with typical atrial flutter due to its high rate of success (>90%) and low incidence of complications, although pulsed field ablation now offers a non-thermal option. This is done in the cardiac electrophysiology lab by causing a ridge of scar tissue in the cavotricuspid isthmus that crosses the path of the circuit that causes atrial flutter. Eliminating conduction through the isthmus prevents reentry, and if successful, prevents the recurrence of the atrial flutter. Atrial fibrillation often occurs (30% within 5 years) after catheter ablation for atrial flutter. == References == == External links ==	Wikipedia/Atrial_flutter
Clinical cardiac electrophysiology (also referred to as cardiac electrophysiology or simply EP), is a branch of the medical specialty of cardiology concerned with the study and treatment of rhythm disorders of the heart. Cardiologists with expertise in this area are usually referred to as electrophysiologists. Electrophysiologists are trained in the mechanism, function, and performance of the electrical activities of the heart. Electrophysiologists work closely with other cardiologists and cardiac surgeons to assist or guide therapy for heart rhythm disturbances (arrhythmias). They are trained to perform interventional and surgical procedures to treat cardiac arrhythmia. The training required to become an electrophysiologist is lengthy and requires eight years after medical school (in the U.S.), entailing three years of internal medicine residency, three years of clinical cardiology fellowship, and two years of clinical cardiac electrophysiology. This is necessary due to the significant complexity of patients that electrophysiologists usually treat, the constant advances in methods and equipment used in their daily practice, making the field of electrophysiology one of the most demanding subspecialties of modern medicine. An electrophysiology study is any of a number of invasive (intracardiac) and non-invasive recording of spontaneous electrical activity, as well as of cardiac responses to programmed electrical stimulation. These studies are performed to assess arrhythmias, elucidate symptoms, evaluate abnormal electrocardiograms, assess risk of developing arrhythmias in the future, and design treatment. In addition to diagnostic testing of the electrical properties of the heart, electrophysiologists are trained in therapeutic and surgical methods to treat many of the rhythm disturbances of the heart. Therapeutic modalities employed in this field include antiarrhythmic drug therapy and surgical implantation of pacemakers and implantable cardioverter-defibrillators. == Scope of practice, tests and procedures == Common rhythms dealt with include atrial fibrillation, ventricular tachycardia, and the supraventricular tachycardias. Abnormal rhythms have multiple ways they can be treated and choosing is often individualized based on symptoms and patient preference. === Diagnostic testing === Electrophysiologists will commonly employ the following diagnostic tests and may be performed or interpreted exclusively by the electrophysiologist. Other tests such as cardiac stress testing may be included in an evaluation but are not exclusive to electrophysiology. Electrocardiogram Ambulatory electrocardiographic monitoring (Holter and event monitor recording and interpretation) Tilt table testing T-wave alternans testing Signal-averaged electrocardiogram (SAECG) interpretation, also referred to as "late potentials" reading Electrophysiology study (EPS) consists in the insertion of pacing and recording electrodes either in the esophagus (intra-esophageal EPS) or, through blood vessels, directly into the heart chambers (intra-cardiac EPS) in order to measure electrical properties of the heart and, in the case of intra-cardiac EPS, to electrically stimulate it in the attempt to induce arrhythmias for diagnostic purposes ("programmed electrical stimulation"). Frequently, an EPS is combined with an ablation in the same procedure if deemed the appropriate therapy. === Medical treatment === Initial administration and monitoring of the effect of drugs for treatment of heart rhythm disorders. Electrophysiologists are often involved when severe or life-threatening arrhythmias are being treated, or when multiple drugs must be used to treat an arrhythmia. Antiarrhythmic agents such as flecainide, dofetilide, and amiodarone are commonly used to try to control rhythms. === Catheter ablation === Ablation therapy is a catheter based ablation of lesions in the heart (with radiofrequency energy, cryotherapy (destructive freezing), microwave, or ultrasound energy) to cure or control arrhythmias (see radiofrequency ablation). Ablation is usually performed during the same procedure as the electrophysiology study during which arrhythmias are attempted to be induced as well as elucidating the mechanism of the arrhythmia for which ablation therapy is sought. "Non-complex" ablations include ablation for arrhythmias such as: AV nodal reentrant tachycardia, accessory pathway mediated tachycardia, typical (CTI-dependent) atrial flutter. These procedures are usually performed using intracardiac catheters (as are used during an electrophysiology study), fluoroscopy (a real-time X-ray camera), and electrical recordings from the inside of the heart. "Complex" ablations include ablation for arrhythmias such as multifocal atrial tachycardia, atrial fibrillation, and ventricular tachycardia. In addition to the apparatus used for a "non-complex" ablation, these procedures often make use of sophisticated electro-anatomic mapping systems to localize the source of the abnormal rhythm and to direct delivery of ablation lesions. Additionally, most of our current electro-anatomic mapping systems have the ability to integrate CT or MR images of the heart to allow electrical activity to be superimposed on anatomic structures. === Surgical procedures: pacemaker and defibrillator implantation and follow up === Implantation of devices include Single- and dual-chamber pacemakers Single- and dual-chamber defibrillators "Biventricular" devices for patients with congestive heart failure Subcutaneous defibrillators Leadless pacemakers Loop recorders is an implanted ECG recorders for long-term monitoring of ECG to allow for diagnosis of an arrhythmia Left atrial appendage occlusion devices Additionally, there are, at times, indications to remove these devices and extraction (ie, removal) of these devices can also be performed by electrophysiologists. Once implanted, long-term clinical follow up and reprogramming of implanted devices also falls to the electrophysiologist. == See also == Cardiology Cardiac arrhythmia Cardiac electrophysiology Electroanatomic mapping == References ==	Wikipedia/Clinical_cardiac_electrophysiology
Atrial tachycardia is a type of heart rhythm problem in which the heart's electrical impulse comes from an ectopic pacemaker (that is, an abnormally located cardiac pacemaker) in the upper chambers (atria) of the heart, rather than from the sinoatrial node, the normal origin of the heart's electrical activity. As with any other form of tachycardia (rapid heart beat), the underlying mechanism can be either the rapid discharge of an abnormal focus, the presence of a ring of cardiac tissue that gives rise to a circle movement (reentry), or a triggered rapid rhythm due to other pathological circumstances (as would be the case with some drug toxicities, such as digoxin toxicity). == Classification == Forms of atrial tachycardia (ATach) include multifocal atrial tachycardia (MAT), focal atrial tachycardia and atrial flutter. Paroxysmal atrial tachycardia (PAT) is an episode of arrhythmia that begins and ends abruptly. == Etiology == Atrial tachycardia tends to occur in individuals with structural heart disease, with or without heart failure, and ischemic coronary artery disease. However, focal atrial tachycardia often occurs in healthy individuals without structural heart disease. Other possible etiologies are listed below: Hypoxia Pulmonary disease Ischemic heart disease Stimulants: cocaine, caffeine, chocolate, ephedra Alcohol Metabolic disturbances Digoxin toxicity Heightened sympathetic tone A study noted 10 to 15% of patients presenting for supraventricular tachycardia (SVT) ablation had atrial tachycardia. == Diagnosis == Electrocardiographic features include: Atrial rate: 100 to 250 BPM Ventricular conduction can be variable Irregular or irregularly irregular in the setting of variable AV block Regular if 1 to 1, 2 to 1, or 4 to 1 AV block P wave morphology Unifocal, but similar in morphology to each other Might be inverted Differs from normal sinus P wave May exhibit either long RP or short PR intervals Rhythm may be paroxysmal or sustained May demonstrate an increase in the rate at initiation (e.g., "warm up," or "rev up") May demonstrate a decrease in the rate at termination (e.g., "cool down") == Treatment == Initial management of focal atrial tachycardia should focus on addressing underlying causes: treating acute illness, cessation of stimulants, stress reduction, appropriately managing digoxin toxicity, or chronic disease management. The ventricular rate is controllable with the use of beta blockers or calcium channel blockers. If atrial tachyarrhythmia persists and the patient is symptomatic, the patient may benefit from class IA, IC, or class III antiarrhythmics. Catheter ablation of focal atrial tachycardia may be appropriate in patients failing medical therapy. == Epidemiology == A European study of young males applying for pilot licenses demonstrated that 0.34% had asymptomatic atrial tachycardia and 0.46% had symptomatic atrial tachycardia. == References == == External links ==	Wikipedia/Ectopic_atrial_tachycardia
The sinoatrial node (also known as the sinuatrial node, SA node, sinus node or Keith–Flack node) is an oval shaped region of special cardiac muscle in the upper back wall of the right atrium made up of cells known as pacemaker cells. The sinus node is approximately 15 mm long, 3 mm wide, and 1 mm thick, located directly below and to the side of the superior vena cava. These cells produce an electrical impulse known as a cardiac action potential that travels through the electrical conduction system of the heart, causing it to contract. In a healthy heart, the SA node continuously produces action potentials, setting the rhythm of the heart (sinus rhythm), and so is known as the heart's natural pacemaker. The rate of action potentials produced (and therefore the heart rate) is influenced by the nerves that supply it. == Structure == The sinoatrial node is an oval-shaped structure that is approximately 15 mm long, 3 mm wide, and 1 mm thick, located directly below and to the side of the superior vena cava. The size can vary but is usually between 10-30 mm long, 5–7 mm wide, and 1–2 mm deep. === Location === The SA node is located in the wall (epicardium) of the right atrium, laterally to the entrance of the superior vena cava in a region called the sinus venarum (hence sino- + atrial). It is positioned roughly between a groove called the crista terminalis located on the internal surface of the heart and the corresponding sulcus terminalis, on the external surface. These grooves run between the entrance of the superior vena cava and the inferior vena cava. === Microanatomy === The cells of the SA node are spread out within a mesh of connective tissue, containing nerves, blood vessels, collagen and fat. Immediately surrounding the SA node cells are paranodal cells. These cells have structures intermediate between that of the SA node cells and the rest of the atrium. The connective tissue, along with the paranodal cells, insulate the SA node from the rest of the atrium, preventing the electrical activity of the atrial cells from affecting the SA node cells. The SA node cells are smaller and paler than the surrounding atrial cells, with the average cell being around 8 micrometers in diameter and 20-30 micrometers in length (1 micrometer= 0.000001 meter). Unlike the atrial cells, SA node cells contain fewer mitochondria and myofibers, as well as a smaller sarcoplasmic reticulum. This means that the SA node cells are less equipped to contract compared to the atrial and ventricular cells. Action potentials pass from one cardiac cell to the next through pores known as gap junctions. These gap junctions are made of proteins called connexins. There are fewer gap junctions within the SA node and they are smaller in size. This is again important in insulating the SA node from the surrounding atrial cells. === Blood supply === The sinoatrial node receives its blood supply from the sinoatrial nodal artery. This blood supply, however, can differ hugely between individuals. For example, in most humans, this is a single artery, although in some cases there have been either 2 or 3 sinoatrial node arteries supplying the SA node. Also, the SA node artery mainly originates as a branch of the right coronary artery; however in some individuals it has arisen from the circumflex artery, which is a branch of the left coronary artery. Finally, the SA node artery commonly passes behind the superior vena cava, before reaching the SA node; however in some instances it passes in front. Despite these many differences, there doesn't appear to be any advantage to how many sinoatrial nodal arteries an individual has, or where they originate. === Venous drainage === There are no large veins that drain blood away from the SA node. Instead, smaller venules drain the blood directly into the right atrium. == Function == === Pacemaking === The main role of a sinoatrial node cell is to initiate action potentials of the heart that can pass through cardiac muscle cells and cause contraction. An action potential is a rapid change in membrane potential, produced by the movement of charged atoms (ions). In the absence of stimulation, non-pacemaker cells (including the ventricular and atrial cells) have a relatively constant membrane potential; this is known as a resting potential. This resting phase (see cardiac action potential, phase 4) ends when an action potential reaches the cell. This produces a positive change in membrane potential, known as depolarization, which is propagated throughout the heart and initiates muscle contraction. Pacemaker cells, however, do not have a resting potential. Instead, immediately after repolarization, the membrane potential of these cells begins to depolarise again automatically, a phenomenon known as the pacemaker potential. Once the pacemaker potential reaches a set value, the threshold potential, it produces an action potential. Other cells within the heart (including the Purkinje fibers and atrioventricular node) can also initiate action potentials; however, they do so at a slower rate and therefore, if the SA node is functioning properly, its action potentials usually override those that would be produced by other tissues. Outlined below are the 3 phases of a sinoatrial node action potential. In the cardiac action potential, there are 5 phases (labelled 0-4), however pacemaker action potentials do not have an obvious phase 1 or 2. Phase 4 This phase is also known as the pacemaker potential. Immediately following repolarization, when the membrane potential is very negative (it is hyperpolarised), the voltage slowly begins to increase. This is initially due to the closing of potassium channels, which reduces the flow of potassium ions (Ik) out of the cell (see phase 2, below). Hyperpolarization also causes activation of hyperpolarisation-activated cyclic nucleotide–gated (HCN) channels. The activation of ion channels at very negative membrane potentials is unusual, therefore the flow of sodium (Na+) and some K+ through the activated HCN channel is referred to as a funny current (If). This funny current causes the membrane potential of the cell to gradually increase, as the positive charge (Na+ and K+) is flowing into the cell. Another mechanism involved in pacemaker potential is known as the calcium clock. This refers to the spontaneous release of calcium from the sarcoplasmic reticulum (a calcium store) into the cytoplasm, also known as calcium sparks. This increase in calcium within the cell then activates a sodium-calcium exchanger (NCX), which removes one Ca2+ from the cell, and exchanges it for 3 Na+ into the cell (therefore removing a charge of +2 from the cell, but allowing a charge of +3 to enter the cell) further increasing the membrane potential. Calcium later reenters the cell via SERCA and calcium channels located on the cell membrane. The increase in membrane potential produced by these mechanisms, activates T-type calcium channels and then L-type calcium channels (which open very slowly). These channels allow a flow of Ca2+ into the cell, making the membrane potential even more positive. Phase 0 This is the depolarization phase. When the membrane potential reaches the threshold potential (around -20 to -50 mV), the cell begins to rapidly depolarise (become more positive). This is mainly due to the flow of Ca2+ through L-type calcium channels, which are now fully open. During this stage, T-type calcium channels and HCN channels deactivate. Phase 3 This phase is the repolarization phase. This occurs due to the inactivation of L-type calcium channels (preventing the movement of Ca2+ into the cell) and the activation of potassium channels, which allows the flow of K+ out of the cell, making the membrane potential more negative. == Nerve supply == Heart rate depends on the rate at which the sinoatrial node produces action potentials. At rest, heart rate is between 60 and 100 beats per minute. This is a result of the activity of two sets of nerves, one acting to slow down action potential production (these are parasympathetic nerves) and the other acting to speed up action potential production (sympathetic nerves). Modulation of heart rate by ANS is carried by two types of channel: Kir and HCN (members of the CNG gated channels). The sympathetic nerves begin in the thoracic region of the spinal cord (in particular T1-T4). These nerves release a neurotransmitter called noradrenaline (NA). This binds to a receptor on the SA node membrane, called a beta-1adrenoceptor. Binding of NA to this receptor activates a G-protein (in particular a Gs-Protein, S for stimulatory) which initiates a series of reactions (known as the cAMP pathway) that results in the production of a molecule called cyclic adenosinemonophosphate (cAMP). This cAMP binds to the HCN channel (see above). Binding of cAMP to the HCN increases the flow of Na+ and K+ into the cell, speeding up the pacemaker potential, so producing action potentials at a quicker rate and increasing heart rate. An increase in heart rate is known as positive chronotropy. The parasympathetic nerves supplying the SA node (in particular the Vagus nerves) originate in the brain. These nerves release a neurotransmitter called acetylcholine (ACh). ACh binds to a receptor called an M2 muscarinic receptor, located on the SA node membrane. Activation of this M2 receptor then activates a protein called a G-protein (in particular Gi protein, i for inhibitory). Activation of this G-protein blocks the cAMP pathway, reducing its effects, therefore inhibiting sympathetic activity and slowing action potential production. The G-protein also activates a potassium channel GIRK-1 and GIRK-4, which allows K+ to flow out of the cell, making the membrane potential more negative and slowing the pacemaker potential, therefore decreasing the rate of action potential production and therefore decreasing heart rate. A decrease in heart rate is known as negative chronotropy. The first cell to produce the action potential in the SA node isn't always the same; this is known as pacemaker shift. In certain species of animals—for example, in dogs—a superior shift (i.e., the cell that produces the fastest action potential in the SA node is higher than previously) usually produces an increased heart rate whereas an inferior shift (i.e. the cell producing the fastest action potential within the SA node is further down than previously) produces a decreased heart rate. == Clinical significance == Sinus node dysfunction also known as sick sinus syndrome is a group of irregular heartbeat conditions caused by faulty electrical signals of the heart. When the heart's sinoatrial node is defective, the heart's rhythms become abnormal—typically too slow or exhibiting pauses in its function or a combination, and very rarely faster than normal. Blockage of the arterial blood supply to the SA node (most commonly due to a myocardial infarction or progressive coronary artery disease) can therefore cause ischemia and cell death in the SA node. This can disrupt the electrical pacemaker function of the SA node, and can result in sinus node dysfunction. If the SA node does not function or the impulse generated in the SA node is blocked before it travels down the electrical conduction system, a group of cells further down the heart will become its pacemaker. == History == The sinoatrial node was first discovered by a young medical student, Martin Flack, in the heart of a mole, whilst his mentor, Sir Arthur Keith, was on a bicycle ride with his wife. They made the discovery in a makeshift laboratory set up in a farmhouse in Kent, England, called Mann's Place. Their discovery was published in 1907. == Additional images == == See also == Cardiac pacemaker Cardiology Heart block Sinus bradycardia Sinus tachycardia Cardiothoracic Surgery == References == == External links == Anatomy figure: 20:06-01 at Human Anatomy Online, SUNY Downstate Medical Center - "The conduction system of the heart." Diagram at gru.net thoraxlesson4 at The Anatomy Lesson by Wesley Norman (Georgetown University) (thoraxheartinternalner) https://web.archive.org/web/20070929080346/http://www.healthyheart.nhs.uk/heart_works/heart03.shtml	Wikipedia/Sinoatrial_node
Legionnaires' disease is a form of atypical pneumonia caused by any species of Legionella bacteria, quite often Legionella pneumophila. Signs and symptoms include cough, shortness of breath, high fever, muscle pains, and headaches. Nausea, vomiting, and diarrhea may also occur. This often begins 2–10 days after exposure. A legionellosis is any disease caused by Legionella, including Legionnaires' disease (a pneumonia) and Pontiac fever (a related upper respiratory tract infection), but Legionnaires' disease is the most common, so mentions of legionellosis often refer to Legionnaires' disease. The bacterium is found naturally in fresh water. It can contaminate hot water tanks, hot tubs, and cooling towers of large air conditioners. It is usually spread by breathing in mist that contains the bacteria. It can also occur when contaminated water is aspirated. It typically does not spread directly between people, and most people who are exposed do not become infected. Risk factors for infection include older age, a history of smoking, chronic lung disease, and poor immune function. Those with severe pneumonia and those with pneumonia and a recent travel history should be tested for the disease. Diagnosis is by a urinary antigen test and sputum culture. No vaccine is available. Prevention depends on good maintenance of water systems. Treatment of Legionnaires' disease is commonly conducted with antibiotics. Recommended agents include fluoroquinolones, azithromycin, or doxycycline. Hospitalization is often required. The fatality rate is around 10% for healthy persons and 25% for those with underlying conditions. The number of cases that occur globally is not known. Legionnaires' disease is the cause of an estimated 2–9% of pneumonia cases that are acquired outside of a hospital. An estimated 8,000 to 18,000 cases a year in the United States require hospitalization. Outbreaks of disease account for a minority of cases. While it can occur any time of the year, it is more common in the summer and autumn. The disease is named after the outbreak where it was first identified, at a 1976 American Legion convention in Philadelphia. == Signs and symptoms == The length of time between exposure to the bacteria and the appearance of symptoms (incubation period) is generally 2–10 days, but can more rarely extend to as long as 20 days. For the general population, among those exposed, between 0.1 and 5.0% develop the disease, while among those in hospital, between 0.4 and 14% develop the disease. Those with Legionnaires' disease usually have fever, chills, and a cough, which may be dry or may produce sputum. Almost all experience fever, while around half have cough with sputum, and one-third cough up blood or bloody sputum. Some also have muscle aches, headache, tiredness, loss of appetite, loss of coordination (ataxia), chest pain, or diarrhea and vomiting. Up to half of those with Legionnaires' disease have gastrointestinal symptoms, and almost half have neurological symptoms, including confusion and impaired cognition. "Relative bradycardia" may also be present, which is low to normal heart rate despite the presence of a fever. Laboratory tests may show that kidney functions, liver functions, and electrolyte levels are abnormal, which may include low sodium in the blood. Chest X-rays often show pneumonia with consolidation in the bottom portion of both lungs. Distinguishing Legionnaires' disease from other types of pneumonia by symptoms or radiologic findings alone is difficult; other tests are required for definitive diagnosis. People with Pontiac fever, a much milder illness caused by the same bacterium, experience fever and muscle aches without pneumonia. They generally recover in 2–5 days without treatment. For Pontiac fever, the time between exposure and symptoms is generally a few hours to two days. == Cause == Over 90% of cases of Legionnaires' disease are caused by Legionella pneumophila. Other types include L. longbeachae, L. feeleii, L. micdadei, and L. anisa. === Transmission === Legionnaires' disease is usually spread by the breathing in of aerosolized water or soil contaminated with the Legionella bacteria. Experts have stated that Legionnaires' disease is not transmitted from person to person. In 2014, one case of possible spread from someone sick to the caregiver occurred. Rarely, it has been transmitted by direct contact between contaminated water and surgical wounds. The bacteria grow best at warm temperatures and thrive at water temperatures between 25 and 45 °C (77 and 113 °F), with an optimum temperature of 35 °C (95 °F). Temperatures above 60 °C (140 °F) kill the bacteria. Sources where temperatures allow the bacteria to thrive include hot water tanks, cooling towers, and evaporative condensers of large air conditioning systems, such as those commonly found in hotels and large office buildings. Pre-1988, energy conservation programs from the late 1970s and early 1980s still mandated a maximum hot water generation, storage and distribution temperature of 110 °F (43 °C), unknowingly, legionella bacteria's ideal breeding temperature. To minimize risks of bacterial growth, the American Society of Heating, Refrigerating and Air-Conditioning Engineers' 1988 ASHRAE Standard 188 and subsequent ASHRAE Guideline 12-2000 increased recommended hot water generation and storage temperatures to 135–140 °F (57–60 °C) with minimum distribution temperatures of 124 °F (51 °C). Though the first known outbreak was in Philadelphia, cases of legionellosis have occurred throughout the world. === Reservoirs === L. pneumophila thrives in aquatic systems, where it is established within amoebae in a symbiotic relationship. Legionella bacteria survive in water as intracellular parasites of water-dwelling protozoa, such as amoebae. Amoebae are often part of biofilms, and once Legionella and infected amoebae are protected within a biofilm, they are particularly difficult to destroy. In the built environment, central air conditioning systems in office buildings, hotels, and hospitals are sources of contaminated water. Other places the bacteria can dwell include cooling towers used in industrial cooling systems, evaporative coolers, nebulizers, humidifiers, whirlpool spas, hot water systems, showers, windshield washers, fountains, room-air humidifiers, ice-making machines, and misting systems typically found in grocery-store produce sections. The bacteria may also be transmitted from contaminated aerosols generated in hot tubs if the disinfection and maintenance programs are not followed rigorously. Freshwater ponds, creeks, and ornamental fountains are potential sources of Legionella. The disease is particularly associated with hotels, fountains, cruise ships, and hospitals with complex potable water systems and cooling systems. Respiratory-care devices such as humidifiers and nebulizers used with contaminated tap water may contain Legionella species, so using sterile water is very important. Other sources include exposure to potting mix and compost. == Mechanism == Legionella spp. enter the lungs either by aspiration of contaminated water or inhalation of aerosolized contaminated water or soil. In the lung, the bacteria are consumed by macrophages, a type of white blood cell, inside of which the Legionella bacteria multiply, causing the death of the macrophage. Once the macrophage dies, the bacteria are released from the dead cell to infect other macrophages. Virulent strains of Legionella kill macrophages by blocking the fusion of phagosomes with lysosomes inside the host cell; normally, bacteria are contained inside the phagosome, which merges with a lysosome, allowing enzymes and other chemicals to break down the invading bacteria. == Diagnosis == People of any age may develop Legionnaires' disease, but the illness most often affects middle-aged and older people, particularly those who smoke cigarettes or have chronic lung disease. Immunocompromised people are also at higher risk. Pontiac fever most commonly occurs in those who are otherwise healthy. The most useful diagnostic tests detect the bacteria in coughed-up mucus, find Legionella antigens in urine samples, or allow comparison of Legionella antibody levels in two blood samples taken 3–6 weeks apart. A urine antigen test is simple, quick, and very reliable, but only detects L. pneumophila serogroup 1, which accounts for 70% of disease caused by L. pneumophila, which means use of the urine antigen test alone may miss as many as 30% of cases. This test was developed by Richard Kohler in 1982. When dealing with L. pneumophila serogroup 1, the urine antigen test is useful for early detection of Legionnaire's disease and initiation of treatment, and has been helpful in early detection of outbreaks. However, it does not identify the specific subtypes, so it cannot be used to match the person with the environmental source of infection. The Legionella bacteria can be cultured from sputum or other respiratory samples. Legionella spp. stain poorly with Gram stain, stain positive with silver, and are cultured on charcoal yeast extract with iron and cysteine (CYE agar). A significant under-reporting problem occurs with legionellosis. Even in countries with effective health services and readily available diagnostic testing, about 90% of cases of Legionnaires' disease are missed. This is partly due to the disease being a relatively rare form of pneumonia, which many clinicians may not have encountered before, thus may misdiagnose. A further issue is that people with legionellosis can present with a wide range of symptoms, some of which (such as diarrhea) may distract clinicians from making a correct diagnosis. == Prevention == Although the risk of Legionnaires' disease being spread by large-scale water systems cannot be eliminated, it can be greatly reduced by writing and enforcing a highly detailed, systematic water safety plan appropriate for the specific facility involved (office building, hospital, hotel, spa, cruise ship, etc.) Some of the elements that such a plan may include are: Keep water temperature either below or above the 20–55 °C (68–131 °F) range in which the Legionella bacterium thrives. Prevent stagnation, for example, by removing from a network of pipes any sections that have no outlet (dead ends). Where stagnation is unavoidable, as when a wing of a hotel is closed for the off-season, remedial measures are recommended, e.g., maintaining elevated temperatures throughout the hot-water distribution system and periodic disinfection or permanent chlorination of cold-water systems. Prevention of biofilms is crucial because once established they become more difficult to remove from piping systems. The likelihood of formation is increased by pipe scale and corrosion; warm water temperatures; stagnation and the quantity of nutrients that enter the system. Periodically disinfect the system, by high heat or a chemical biocide, and use chlorination where appropriate. Monochloramine is likely more effective than free chlorine (sodium hypochlorite), being more resistant with residuals likely to persist to the point of delivery. Monochloramine is also more likely to penetrate legionella biofilms. Treatment of water with copper-silver ionization or ultraviolet light may also be effective. System design (or renovation) can reduce the production of aerosols and reduce human exposure to them, by directing them well away from building air intakes. An effective water safety plan also covers such matters as training, record-keeping, communication among staff, contingency plans, and management responsibilities. The format and content of the plan may be prescribed by public health laws or regulations. To inform the water safety plan, the undertaking of a site specific legionella risk assessment is often recommended in the first instance. The legionella risk assessment identifies the hazards, the level of risk they pose and provides recommendations of control measures to put in place within the overarching water safety plan. == Treatment == Effective antibiotics include most macrolides, tetracyclines, ketolides, and quinolones. Legionella spp. multiply within the cell, so any effective treatment must have excellent intracellular penetration. Current treatments of choice are the respiratory tract quinolones (levofloxacin, moxifloxacin, gemifloxacin) or newer macrolides (azithromycin, clarithromycin, roxithromycin). The antibiotics used most frequently have been levofloxacin, doxycycline, and azithromycin. Macrolides (azithromycin) are used in all age groups, while tetracyclines (doxycycline) are prescribed for children above the age of 12 and quinolones (levofloxacin) above the age of 18. Rifampicin can be used in combination with a quinolone or macrolide. Whether rifampicin is an effective antibiotic to take for treatment is uncertain. The Infectious Diseases Society of America does not recommend the use of rifampicin with added regimens. Tetracyclines and erythromycin led to improved outcomes compared to other antibiotics in the original American Legion outbreak. These antibiotics are effective because they have excellent intracellular penetration in Legionella-infected cells. The recommended treatment is 5–10 days of levofloxacin or 3–5 days of azithromycin, but in people who are immunocompromised, have severe disease, or other pre-existing health conditions, longer antibiotic use may be necessary. During outbreaks, prophylactic antibiotics have been used to prevent Legionnaires' disease in high-risk individuals who have possibly been exposed. The mortality at the original American Legion convention in 1976 was high (29 deaths in 182 infected individuals) because the antibiotics used (including penicillins, cephalosporins, and aminoglycosides) had poor intracellular penetration. Mortality has plunged to less than 5% if therapy is started quickly. Delay in giving the appropriate antibiotic leads to higher mortality. == Prognosis == The fatality rate of Legionnaires' disease has ranged from 5–30% during various outbreaks and approaches 50% for nosocomial infections, especially when treatment with antibiotics is delayed. Hospital-acquired Legionella pneumonia has a fatality rate of 28%, and the principal source of infection in such cases is the drinking-water distribution system. == Epidemiology == Legionnaires' disease acquired its name in July 1976, when an outbreak of pneumonia occurred among people attending a convention of the American Legion at the Bellevue-Stratford Hotel in Philadelphia. Of the 182 reported cases, mostly men, 29 died. On 18 January 1977, the causative agent was identified as a previously unknown strain of bacteria, subsequently named Legionella, and the species that caused the outbreak was named Legionella pneumophila. Following this discovery, unexplained outbreaks of severe respiratory disease from the 1950s were retrospectively attributed to Legionella. Legionnaires' disease also became a prominent historical example of an emerging infectious disease. Outbreaks of Legionnaires' disease receive significant media attention, but this disease usually occurs in single, isolated cases not associated with any recognized outbreak. When outbreaks do occur, they are usually in the summer and early autumn, though cases may occur at any time of year. Most infections occur in those who are middle-aged or older. National surveillance systems and research studies were established early, and in recent years, improved ascertainment and changes in clinical methods of diagnosis have contributed to an upsurge in reported cases in many countries. Environmental studies continue to identify novel sources of infection, leading to regular revisions of guidelines and regulations. About 8,000 to 18,000 cases of Legionnaires' disease occur each year in the United States, according to the Bureau of Communicable Disease Control. Between 1995 and 2005, over 32,000 cases of Legionnaires' disease and more than 600 outbreaks were reported to the European Working Group for Legionella Infections. The data on Legionella are limited in developing countries, and Legionella-related illnesses likely are underdiagnosed worldwide. Improvements in diagnosis and surveillance in developing countries would be expected to reveal far higher levels of morbidity and mortality than are currently recognised. Similarly, improved diagnosis of human illness related to Legionella species and serogroups other than Legionella pneumophila would improve knowledge about their incidence and spread. A 2011 study successfully used modeling to predict the likely number of cases during Legionnaires' outbreaks based on symptom onset dates from past outbreaks. In this way, the eventual likely size of an outbreak can be predicted, enabling efficient and effective use of public-health resources in managing an outbreak. During the COVID-19 pandemic, some researchers and organisations raised concerns about the impact of the COVID-19 lockdowns on Legionnaire's disease outbreaks. Additionally, at least two people in England died from a co-infection of Legionella and SARS-CoV-2. === Outbreaks === An outbreak is defined as two or more cases where the onset of illness is closely linked in time (weeks rather than months) and space, where a suspicion or evidence exists of a common source of infection, with or without microbiological support (i.e. common spatial location of cases from travel history). In April 1985, 175 people in Stafford, England, were admitted to the District or Kingsmead Stafford Hospitals with chest infection or pneumonia. A total of 28 people died. Medical diagnosis showed that Legionnaires' disease was responsible and the immediate epidemiological investigation traced the source of the infection to the air-conditioning cooling tower on the roof of Stafford District Hospital. In March 1999, a large outbreak in the Netherlands occurred during the Westfriese Flora flower exhibition in Bovenkarspel; 318 people became ill and at least 32 people died. This was the second-deadliest outbreak since the 1976 outbreak and possibly the deadliest, as several people were buried before Legionnaires' disease had been diagnosed. The world's largest outbreak of Legionnaires' disease happened in July 2001, with people appearing at the hospital on 7 July, in Murcia, Spain. More than 800 suspected cases were recorded by the time the last case was treated on 22 July; 636–696 of these cases were estimated and 449 confirmed (so, at least 16,000 people were exposed to the bacterium) and six died, a case-fatality rate around 1%. In September 2005, 127 residents of a nursing home in Canada became ill with L. pneumophila. Within a week, 21 of the residents had died. Culture results at first were negative, which is not unusual, as L. pneumophila is a "fastidious" bacterium, meaning it requires specific nutrients, living conditions, or both to grow. The source of the outbreak was traced to the air-conditioning cooling towers on the nursing home's roof. In an outbreak in lower Quebec City, Canada, 180 people were affected with 13 resulting deaths due to contaminated water in a cooling tower. In November 2014, 302 people were hospitalized following an outbreak of legionellosis in Portugal, and seven related deaths were reported. All cases emerged in three civil parishes from the municipality of Vila Franca de Xira in the northern outskirts of Lisbon, and were treated in hospitals of the greater Lisbon area. The source is suspected to be located in the cooling towers of the fertilizer plant Fertibéria. Twelve people were diagnosed with the disease in an outbreak in the Bronx, New York, in December 2014; the source was traced to contaminated cooling towers at a housing development. In July and August 2015, another, unrelated outbreak in the Bronx killed 12 people and made about 120 people sick; the cases arose from a cooling tower on top of a hotel. At the end of September, another person died of the disease and 13 were sickened in yet another unrelated outbreak in the Bronx. The cooling towers from which the people were infected in the latter outbreak had been cleaned during the summer outbreak, raising concerns about how well the bacteria could be controlled. On 28 August 2015, an outbreak of Legionnaire's disease was detected at San Quentin State Prison in Northern California; 81 people were sickened and the cause was sludge that had built up in cooling towers. Between June 2015, and January 2016, 87 cases of Legionnaires' disease were reported by the Michigan Department of Health and Human Services for the city of Flint, Michigan, and surrounding areas. The outbreak may have been linked to the Flint water crisis, in which the city's water source was changed to a cheaper and inadequately treated source. Ten of those cases were fatal. In November 2017, an outbreak was detected at Hospital de São Francisco Xavier, Lisbon, Portugal, with up to 53 people being diagnosed with the disease and five of them dying from it. In Quincy, Illinois, at the Illinois Veterans Home, a 2015 outbreak of the disease killed 12 people and sickened more than 50 others. It was believed to be caused by infected water supply. Three more cases were identified by November 2017. In the autumn of 2017, 22 cases were reported in a Legionnaires' disease outbreak at Disneyland in Anaheim, California. It was believed to have been caused by a cooling tower that releases mist for the comfort of visitors. The contaminated droplets likely spread to the people in and beyond the park. In July 2019, 11 former guests of the Sheraton Atlanta hotel were diagnosed with the disease, with 55 additional probable cases. In September 2019, 141 visitors to the Western North Carolina Mountain State Fair were diagnosed with Legionnaires' disease, with four reported deaths, after a hot tub exhibit is suspected to have developed and spread the bacteria. At least one additional exposure apparently occurred during the Asheville Quilt Show that took place a few weeks after the fair in the same building where the hot tub exhibit was held. The building had been sanitized after the outbreak. In December 2019, the government of Western Australia's Department of Health was notified of four cases of Legionnaires' disease. Those exposed had recently visited near Bali's Ramayana Resort and Spa in central Kuta. In February 2024, Minnesota Department of Health issued a news release stating that fourteen (14) cases were identified in Grand Rapids, Minnesota since April 2023 which they attributed to the municipal water supply. In January 2024, NSW Health issued an alert for Legionnaires' disease for Sydney CBD. As of 3 January 2024, 7 known cases requiring hospitalization had been reported. == References == == External links == "Legionnaires' Disease". MedlinePlus. U.S. National Library of Medicine.	Wikipedia/Legionnaires'_disease

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